CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 205677Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) BIOPHARMACEUTICS REVIEW - ADDENDUM Of?ce of New Drug Quality Assessment Application No.: NDA 205-677 Reviewer: Kareen Riviere. Submission Dates: 5/31/13: 8/20/13: 10/10/13: 10/25/13 Division: DNP Team Leader: Angelica Dorantes. Applicant: Vanda Pharmaceuticals Acting Supervisor: Richard Lostritto. Trade Name: Hetlioz (tasimelton) Capsules Date 6/4/ 13 . . Date of Generic Name: Tasrmelteon 12/4/13 Rewew: Treatment of Non-24-Hour Disorder in Type of Submission: 505(b)(l) New Drug Indication: . . . the totally Application IR Capsule/ 20 mg Route of Administration: Oral SYNOPSIS: This document is an Addendum to the original Biopharmaceutics review by Dr. Kareen Riviere dated October 30. 2013 in DARRTS. In Dr. Riviere?s original review it was concluded that tasimelton drug substance is (wet) soluble and the proposed drug product is however. the ?nal ONDQA and OCP joint Reviewers recommendation for the BC Class If designation of tasimelteon drug substance was pending. because the Clinical Pharmacology reviewer. Dr. Jagan Parepally. had not yet determined whether the drug substance could be classi?ed as permeable. On November 8. 2013. Dr. Parepally?s Clinical Pharmacology review was entered in DARRTS. In his review. Dr. Parepally determined that the current available permeability data are inconclusive for tasimelteon to be considered as a permeable drug due to of the following de?ciencies: 0 In the mass-balance study. about 84% of the radiolabel dose was recovered from urine. and feces. which is less than the threshold recommended by the BCS guidance. 0 Tasimelteon is metabolized extensively. The overall AUC of tasimelteon in plasma is approximately 10-15 times lower when compared to total radioactivity. The sponsor did not provide evidence that tasimelteon is absorbed (4) In conclusion. although the provided data demonstrated that tasimelteon drug substance is soluble and the proposed drug product is based on assessment stating that tasimelteon is in simulated gastric and simulated intestinal ?uids but it is not a permeable drug. the Applicant?s request for a BCS-Class: classi?cation for tasimelteon is not fully supported and therefore is not acceptable. Note that only those BC requests that are fully supported are submitted to the BCS Committee for the fmal of?cial BC S-C lass If assessment and reconmiendation. RECOMMENDATION: The provided permeability data does not support the Applicant?s request and therefore a BCS Class; designation has not been granted for tasimelteon drug substance/Hetlioz drug product. Note that this BC reconmlendation does not have any impact on the approvability of NDA 205-677. Thus. Hetlioz (tasimelteon) capsules. 20 mg is still recommended for approval from a Biopharmaceutics standpoint. Kareen Rivierea Angelica Dorantesa Biopharmaceutics Reviewer Biophamiaceutics Team Leader Of?ce of New Drug Quality Assessment Of?ce of New Drug Quality Assessment cc: Dr. Richard Lostritto Reference ID: 3416812 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KAREEN RIVIERE 12/04/2013 ANGELICA DORANTES 12/04/2013 Reference ID: 3416812 CLINICAL PHARMACOLOGY REVIEW NDA: 205677 Brand Name: Hetlioz Generic Name: Tasimelteon, VEC-162, BMS-214778 Dosage Form & Strength: Capsule (20 mg) Indication: Treatment of totally blind patients with Non-24-Hour Disorder (Non-24) Applicant: Vanda Pharmaceuticals Submission: 505(b)(1), Priority Submission Date: 5/31/2013 OND Division: OND-1/Division of Neurology Drug Products OCP Divisions: Clinical Pharmacology DCP-1 Primary Reviewer: Jagan Mohan Parepally, Ph.D., Team Leader: Angela Men, M.D., Ph.D. Pharmacogenomics (PG) reviewer: Robert Schuck, Pharm.D., Ph.D. PG Secondary Reviewer: Michael Pacanowski, Pharm.D., M.P.H. The OCP office level briefing was held on Friday, October 11, 2013. TABLE OF CONTENTS 1.   Executive Summary ....................................................................................................2  1.1   Recommendation .....................................................................................................2  1.2   Phase IV Commitments ...........................................................................................2  1.3   Summary of Important Clinical Pharmacology and Biopharmaceutics Findings ...2  2.   Question Based Review ..............................................................................................7  2.1  General Attributes ....................................................................................................7  2.2   General Clinical Pharmacology ...............................................................................7  2.3   Intrinsic Factors .....................................................................................................17  2.4   Extrinsic Factors ....................................................................................................23  2.5   General Biopharmaceutics .....................................................................................27  2.6   Analytical section ..................................................................................................29  3.   Detailed Labeling Recommendations .......................................................................31  4.  Appendices ...............................................................................................................38  4.1   Consult Reviews ....................................................................................................38  4.2 Individual Study Reviews ........................................................................................43  4.3 OCP Filing/Review Form ......................................................................................143  1 Reference ID: 3403865 1. Executive Summary The sponsor is seeking the approval of Hetlioz (tasimelteon, VEC-162) for the treatment of totally blind patients with a circadian rhythm (Non-24) disorder. Tasimelteon is a circadian regulator, which presumed to act through activation of melatonin MT1 and MT2 receptors. The proposed dosing regimen is 20 mg per day taken orally approximately same time prior to bedtime every night. To support the approval of the application, the sponsor conducted a single Phase 2 and two placebo-controlled efficacy studies in subjects with Non-24 Disorder and the clinical pharmacology program consisted of single and multiple-dose studies, mass-balance and metabolic characterization study, thorough QT study and studies evaluating effect of intrinsic and extrinsic factors on tasimelteon. The pharmacokinetics of tasimelteon is linear following single ascending doses ranging from 3 to 300 mg and multiple doses ranging from 1 to 50 mg. The time to peak concentration of tasimelteon ranges from 0.5 to 3 hours under fasting condition and the mean elimination half-life ranges 1.3 - 2.6 hours. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Drug interaction studies with CY1A2 inhibitor, fluvoxamine and CYP3A4 inducer, rifampin resulted in 6.5 fold increase and 90% decrease in tasimelteon exposure respectively. CYP1A1, CYP2C9/19, and CYP2D6 also minimally contribute to tasimelteon metabolism. In women, the mean overall exposure of tasimelteon was approximately 32% higher when compared to males. In the elderly subjects, AUC increased by about 2 fold when compared to the young. Cigarette smoking resulted in increased clearance of tasimelteon and decreased exposure about 40%. Subjects with severe renal impairment had a 30% lower clearance when compared to healthy subjects. The AUC of tasimelteon increased 43% and 110% in patients with mild and moderate hepatic impairment, respectively. The selection of 20 mg used in the phase III clinical studies for the Non-24 indication was based on two dose-finding clinical studies (Study 2101 and 3101) of chronic phase-shifting/ entrainment activity. Tasimelteon should be avoided in subjects taking strong CYP1A2 inhibitors and CYP3A4 inducers. Increase in tasimelteon dose may be needed in smokers. 1.1 Recommendation The Office of Clinical Pharmacology/ Division of Clinical Pharmacology 1 (OCP/DCP-1) has reviewed the submission and finds NDA 205677 acceptable from an OCP perspective provided that an agreement is reached between the Sponsor and the Agency regarding the revised labeling language. 1.2 Phase IV Commitments None 1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings Pharmacokinetics 2 Reference ID: 3403865 The PK of tasimelteon is essentially dose-proportional over the range of 3-300 mg following single dose administration and over the range of 1-50 mg following multiple dose administration qhs (bedtime every day) for 28 consecutive days. Dose-linearity following tasimelteon administration up to 300 mg was demonstrated. The tasimelteon PK parameters displayed high inter-individual variability. Absorption: Tasimelteon is absorbed with Tmax ranging from 0.5 to 3 hours after single- or multiple-dose administration under fasting conditions. As determined by mass-balance study, total urinary recovery of tasimelteon and metabolites is 80.4%. Food delayed the absorption by approximately 1.75 hours and reduced Cmax by 44% without a change in overall exposure (AUC). Tasimelteon shows apparent permeability, Papp values of (apical to basolateral) and (b) (b) (4) (4) (basolateral to apical) determined in the Caco-2 cell model system. The overall AUC of tasimelteon in plasma is approximately 10-15 times lower when compared to total radioactivity. From the available information in the NDA, it cannot be confirmed that (b) (4) tasimelteon is absorbed in its form in humans. (b) (4) (b) (4) Distribution: The apparent volume of distribution at steady state ranges from 56 - 126 L in young healthy subjects. At therapeutic concentrations, tasimelteon is about ~ 90% bound to proteins. Metabolism: Tasimelteon is extensively metabolized by CYP enzymes in the liver. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism and CYP1A1, CYP2D6, CYP2C19, and CYP2C9 play a minor role. Phenolic glucuronidation is the major phase II metabolic route. The major metabolites formed include M12, M13, M9, M11 and M14. These metabolites are eliminated at similar rate when compared to tasimelteon. The parent to metabolite exposure ratio is 1.6, 0.96, 0.92, 0.38 and 0.05 for M12, M13, M9, M11 and M14 respectively. Metabolite M12, M14 and M9 are inactive. M13 (parent to metabolite ratio, 0.96) is approximately 13-times lower in potency at MT1 and MT2 receptors. M11 (parent to metabolite ratio, 0.38) is approximately 800-times lower in potency at MT1 and 50 times lower at MT2 receptors. Elimination: The major route of elimination of tasimelteon is excretion in urine. Mass balance studies show a mean recovery of 84.1% of the administered dose, out of which 80.4% of total radioactivity is excreted in urine and approximately 3.7% in feces. Less than 1% of the dose is excreted in urine as the parent compound. The elimination half-life (t1/2) ranges from 1.3 to 2.6 hrs. Dose-Response Relationships: There is no dose-response relationship established. A 20 mg dose was studied in both pivotal phase 3 studies VP-VEC-162-3201 and VP-VEC-162-3203. The selection of 20 mg as the dose used in the phase III clinical studies for the Non-24 indication is based on two dose-finding clinical studies (Study 2101 and 3101) of chronic phase-shifting/ entrainment activity. Study 2101 was a placebo controlled, lab-based, dose-finding, PK, PD study of 10, 20, 50, and 100 mg of tasimelteon. This study demonstrated tasimelteon’s ability to phase advance circadian rhythms on the first night of treatment in a dose dependent manner as measured by melatonin. 3 Reference ID: 3403865 The results show that 20 mg tasimelateon was the lowest dose that was numerically separated from placebo on inducing melatonin secretion. In this study, healthy subjects were kept in the time isolation unit for seven days and were asked to initiate sleep 5 hours prior to their scheduled sleep time. Study 3101 used a 5-hour circadian challenge to induce transient insomnia in 412 healthy subjects. This study showed significant improvement in both objective latency to persistent sleep (LPS) and wake after sleep onset (WASO) at 20 mg and 50 mg of tasimelteon but not the 100 mg. Note: There was no apparent dose-safety relationship identified in clinical trials. There were 2 (2/52) serious adverse events (SAEs) in tasimelteon group in phase 3 study. Overall there were 10 SAEs in the entire data base; most of the adverse events were mild to moderate in nature. Intrinsic Factors: Age, gender or BMI: In women, the mean overall AUC of tasimelteon was approximately 32% higher and Cmax was about 60% higher when compared to males. In elderly subjects, the mean Cmax and AUC increased by about 2 fold when compared to the young. Clearance of tasimelteon was inversely related to BMI (see details in section 2.3.1). Due to the well tolerated safety profile of tasimelteon, there is no dose adjustment for the female and the elderly. Renal Impairment: The effect of renal impairment was evaluated in subjects with severe renal impairment including subjects on dialysis compared to healthy subjects with normal renal function. Subjects with severe renal impairment had a 30% lower clearance when compared to healthy subjects. However, mean clearance in subjects with end stage renal disease (ESRD) was comparable to that of healthy subjects. These results may be due to small sample size. All the PK parameters were characterized by wide 90% CIs. No dose adjustment is needed for renal impaired patients. Hepatic Impairment: The effect of hepatic impairment on tasimelteon PK was evaluated in subjects with mild or moderate hepatic impairment compared to healthy subjects with normal hepatic function in an open-label, single-dose, parallel-group study including 32 subjects. The AUC of tasimelteon increased 43% and 110% in patients with mild and moderate hepatic impairment respectively. Cmax increased by about 20% in both mild and moderate hepatic impairment when compared to healthy subjects. No dose adjustment is necessary for subjects with mild and moderate hepatic impairment. The effect of severe hepatic impairment on tasimelteon PK was not evaluated. Tasimelteon is not recommended in patients with severe hepatic impairment. Extrinsic Factors: Drug-Drug Interaction (DDI) In vitro studies: Tasimelteon and its most abundant human metabolites M9, M12, and M13 are unlikely to cause inhibition on the following CYP enzymes, CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5, and transporters OATP1B1, OATP1B3, OAT1, BCRP, OCT2 and OAT3 at the therapeutic concentration. 4 Reference ID: 3403865 Tasimelteon and its metabolites M9, M12, and M13 are neither P-gp substrates nor inhibitors. (b) (4) They are not actively transported by OATP1B1 and OATP1B3. Tasimelteon shows (b) (4) (b) (4) apparent permeability with Papp values of (apical to basolateral) and (basolateral to (b) (4) apical) determined in the Caco-2 cell model system. The induction potential on CYP450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5) was assessed by evaluating mRNA expression of several microsomal preparations following treatment of primary cultures of human hepatocytes with tasimelteon. The results indicate that tasimelteon had the potential to induce the activity of CYP3A4/5 and CYP2C8. Effect of co-administered drugs and alcohol on tasimelteon:     Inhibition of CYP1A2: Fluvoxamine 50 mg QD for 6 days resulted in an 85% decrease in tasimelteon CL/F leading to a 6.5-fold increase in AUC and 2.5 fold increase in Cmax. Coadministration of strong CYP1A2 inhibitors should be avoided. Inhibition of CYP3A4: Ketoconazole increased the Cmax and AUC of tasimelteon 33% and 53% respectively. No dose adjustment necessary when tasimelteon is administered with CYP3A4 inhibitors. Induction of CYP3A4: Rifampin, a strong CYP3A4 and moderate CYP2C8, CYP2C9/2C19 inducer, decreased the exposure of tasimelteon by approximately 90%. Decrease in exposure to tasimelteon in the presence of rifampin may reduce the efficacy and is not recommended to be co-administered. Alcohol increased tasimelteon exposure ranging from 10% to 25%. PD parameters evaluated on subjective measures, or on sustained attention, cognition, balance or psychomotor performance in this study did not show any additive trend. Most of the impairments on PD measures were related to ethanol and not to the addition of tasimelteon. Effect of smoking on tasimelteon exposure Cigarette smoking (CYP1A2 induction) increased the clearance of tasimelteon and decreased AUC by approximately 40%. Decrease in exposure to tasimelteon in smokers may reduce the efficacy. Increase in tasimelteon dose may be needed in smokers. Effect of tasimelteon on co-administered drugs: The in vitro studies suggested that tasimelteon had the potential to induce the activity of CYP3A4/5 and CYP2C8. Daily administration of tasimelteon 20 mg for 14 days did not significantly change the AUC of midazolam and 1-OH midazolam. Similarly, there was no change in 1-OH midazolam Cmax although there was a relatively small increase (13%) in midazolam Cmax. Tasimelteon 20 mg administered daily for 16 days did not significantly change the plasma concentrations and mean pharmacokinetic parameters of rosiglitazone. Food Effect 5 Reference ID: 3403865 When tasimelteon was administered with high fat, high calorie meal, the extent of absorption, [AUC(inf)] was comparable under both fed and fasted conditions with geometric mean ratios of 108% and 106%, respectively. 90% confidence intervals were within the 80% to 125%. However, Cmax was reduced by 44% and the median Tmax was delayed from 0.75 hours to 2.5 hours. Tasimelteon is taken preferably without food. Jagan Mohan Parepally, Ph.D. Reviewer, Neurology Drug Products DCP-1, Office of Clinical Pharmacology Concurrence: Angela Men, M.D., Ph.D. Team Leader, Neurology Drug Products Office of Clinical Pharmacology cc: HFD-120 HFD-860 NDA 205677 CSO/C Micheloski /DDD DCP-1/R. Uppoor /DD DCP-1/M. Mehta 6 Reference ID: 3403865 2. Question Based Review 2.1 General Attributes 2.1.1 What are therapeutic indication(s) and the proposed mechanisms of action of Tasimelteon? Tasimelteon is proposed for treatment of totally blind patients with Non-24-Hour Disorder (Non24). Non-24 is a circadian rhythm disorder characterized by the inability to entrain (synchronize) the master body clock with the 24-hour day-night cycle. Patients with Non-24 have prolonged periods of misalignment of circadian rhythms, including the timing of melatonin and cortisol secretion and the sleep-wake cycle, which are associated with significant impairments in social and occupational functioning, or marked subjective distress. The presumed mechanism of action i.e., circadian regulation by tasimelteon is mediated through activation of melatonin MT1 and MT2 receptors. 2.1.2 What are the highlights of physico-chemical properties of the drug substance? Tasimelteon, the active ingredient of Hetlioz is chemically known as (1R, 2R)-N-[2-(2, 3Dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide containing two chiral centers. The compound is produced as the (1R-trans)-enantiomer, with molecular formula C15H19NO2, and molecular weight 245.32. The structural formula is provided in the Figure below. The only available strength of Hetlioz is 20 mg. O O N H 2.1.3 What are the proposed dosage(s) and route(s) of administration? The sponsor proposes 20 mg per day taken orally before bedtime preferably at the same time every night. 2.2 General Clinical Pharmacology 2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support dosing or claims? The sponsor conducted 14 clinical pharmacology and biopharmaceutics studies, including singledose and multiple dose studies in healthy subjects, renal and hepatic impaired patients. The efficacy and safety of 20 mg tasimelteon was supported by two Phase 2 studies and two pivotal efficacy studies in totally blind Non-24 disorder patients. 7 Reference ID: 3403865 Study Objective(s) of the Study Study Design and Type of Control Number of Subjects Duration of Treatment CN116001 Safety and Tolerability, PK and PD Randomized, double-blind, sequential, escalating dose design, placebo- controlled study Total = 48 (36 tasimelteon and 12 PBO) Single dose PBO lead-in followed by Single dose CN116002 Short-term; Safety and Tolerability, PK and PD Randomized, double-blind, sequential, escalating dose, controlled study Total = 32 (24 tasimelteon and 8 PBO) Single dose PBO lead-in followed by 28 days CN116003 Comparison of PK across populations (age and gender); Safety and Tolerability; PD Randomized, double-blind, placebo- controlled, parallel- group, 2 period crossover Total = 40 Single doses, separated by 7 day wash-out VP-VEC162-1101 Assess AME; Safety and Tolerability Open-Label Total = 6 Single dose VP-VEC162-1102 Assess Food Effect on PK; Safety and Tolerability Randomized, open-label, 2 period, 2 sequence, crossover Total = 26 2 single doses (1 Fasted; 1 Fed), separated by 7 day washout VP-VEC162-1103 Effects on QT interval; Safety and Tolerability Randomized, double-blind, placebo- and positivecontrolled, 4 period, crossover Total = 44 3 daysfollowed by 4 day washout VP-VEC162-1104 PK interaction with midazolam; Safety and Tolerability Open-label, singlesequence Total = 24 7 days tasimelteon, 2 single doses midazolam VP-VEC162-1105 Effect of hepatic impairment on PK , Safety and Tolerability Open-label, parallel- group Total = 29 Single dose VP-VEC162-1106 Effect of renal impairment on PK; Safety and Open-label, parallel- group Total = 32 Single dose VP-VEC162-1107 Assess smoking status, age, gender, weight, and BMI on PK, Open-label, parallel- group Total = 60 Single dose 8 Reference ID: 3403865 VP-VEC162-1108 PK/PD interactions with Ethanol; Safety and Tolerability Randomized, doublemasked, 4 period crossover Total = 28 2 single doses of tasimelteon and ethanol in combination with each other and VP-VEC162-1110 Assess impact on CYP450 3A4 and 2C8; Safety and Tolerability Open-label, single sequence Total = 24 16 days tasimelteon, 2 single doses of midazolam and rosiglitazone VP-VEC162-1111 Assess impact of combination treatment of a CYP1A2 inhibitor on PK parameters; Open-label, single sequence Total = 24 2 single doses tasimelteon, 7 days fluvoxamine VP-VEC162-1112 Assess impact of combination treatment of a CYP3A4 Inhibitor and CYP3A4 Inducer on PK parameters; Safety and Tolerability Open-label, single sequence, 2 cohorts Total = 48 2 single doses tasimelteon, Cohort 1 = 5 days ketoconazole Cohort 2 = 10 days rifampin VP-VEC162-2101 Efficacy; Dose comparison; PK; Safety and Tolerability Randomized, double-blind, placebo- controlled, parallel-study Total = 39 (31 tasimelteon and 8 3 days VP-VEC162-3101 Efficacy; Dose comparison; Safety Randomized, double-blind, placebo- controlled, parallel-study Total = 412 (309 tasimelteon and 103 PBO) Single dose Phase 2 Studies Phase 3 Studies Two pivotal phase 3 studies were conducted for marketing approval of tasimelteon including VPVEC-162-3201 (SET) and VP-VEC-162-3203 (RESET). VP-VEC-162-3201 (SET) This was a randomized, double-masked, placebo-controlled, parallel-study conducted to assess entrainment rate and clinical response following treatment with tasimelteon. At the prerandomization, 136 subjects were included, out of which conducted in 84 blind subjects with Non-24 hour disorder were randomized to either placebo or treatment group for 28 weeks. Sixty two subjects completed the study. The following schematic represents the study design. 9 Reference ID: 3403865 Study Design Pro-randomization Randomization I I Screening tau ln-phase Double-mask Evaluation Washout Visit estimation Transition 28' 35 20 mg Taslmelteon 0154 Hos 57. 14.21. 23 k. 48 ?8 Placebo 21. 28. 35 0154 mm - 48 EOS auto ?8 48 i 6 weeks 28 weeks randomization - - Variable length I 48 hour urine collection for assessment Cl 48 hour urine collection for and cortisol assessment Collection of P80 and Preso from screening until 2.5 circadian cycles or 6 months Post-rand. whichever IS less I 2-weell washout segment with collection of BWSQ and 3-day collection P30 The responder rate in this study was approximately 20%-25%. Following table represents clinical response parameters and AN OVA results evaluated in this study. Endpoint CGIC AN COVA (p value) 0.0515 0.0097 0.0284 0.1296 0.192 0.0086 lower quartile of nights of subjective nighttime total sleep time upper quartile of days of subjective daytime sleep duration MOST: midpoint of sleep timing nighttime total sleep time days of subjective daytime sleep duration CGIC: Clinical Global Impression-Change (RESET) This study was a randomized, withdrawal, placebo-controlled, parallel-study. In this study subjects with Non-24 hour disorder who were treated with tasimelteon for 6 months were randomized to placebo or treatment for 8 weeks to evaluate maintenance effects mainly Reference ID: 3403865 10 entrainment rate and clinical response of tasimelteon conducted in 20 subjects. The following schematic represents the study design. Study Design Pro-randomization Randomized withdrawal 20 mg TaSImelteon 20 mg Tasimelteon ?Sncrii?eeninq Taimstima?on 5 021' 028. D35. D42 E08 8 342.349.356.363 D21, 028, 035, D42 eos ~11 weeks Randomization ~8 weeks 48-hour urine collection for tau calculation Collection of P80 and Following table represents clinical response parameters and AN OVA results evaluated in this study. Endpoint AN COVA (p value) 0.0233 0.0266 0.0108 0.1315 0.0547 lower quartile of nights of subjective nighttime total sleep time upper quartile of days of subjective daytime sleep duration midpoint of sleep timing nighttime total sleep time days of subjective daytime sleep duration 2.2.2 Is there a biomarker for estimating entrainment of circadian Can the biomarker be used to predict the clinical responses? Non-24 is a circadian disorder characterized by the inability to entrain the master body clock with the 24-hour day-night cycle. Patients with Non-24 have periods of misalignment of circadian measured by melatonin and cortisol which are associated with signi?cant impairments in the sleep and wake cycle. 11 Reference ID: 3403865 The sponsor proposed to use the biomarker, urinary 6-sulfatoxymelatonin (aMT6s) for the proportion of entrainment and non-entrainment of the circadian melatonin rhythm. Literature suggests that peak urinary aMT6s production normally occurs 3.5 hours before wake time, albeit with a wide range in the normal population, while peak plasma melatonin normally occurs 6 hours before wake time. However, according to the Agency, aMT6s is a biomarker not wellenough understood in Non-24 disorder to take the place of clinically meaningful endpoints. The Agency disagreed with the sponsor in use of biomarker aMT6s as a primary efficacy end-point. 2.2.3 Dose-Response 2.2.3.1. Is there any significant dose-response relationship? And does the relationship support the proposed dosing regimen? There is no dose-response (clinical endpoints for efficacy and safety) relationship established as only one dose, 20 mg, was studied in both pivotal phase 3 studies VP-VEC-162-3201 and VPVEC-162-3203. The selection of 20 mg as the dose used in the phase III clinical studies for the Non-24 indication is based on two dose-finding clinical studies (Study 2101 and 3101) of chronic phase-shifting/ entrainment activity. Study 2101 demonstrated tasimelteon’s ability to phase advance circadian rhythms on the first night of treatment in a dose dependent manner as measured by melatonin (see figure below). Melatonin secretion was dose-dependent. The results showed that 20 mg tasimelteon was the lowest dose that numerically separated from placebo. In this study, healthy subjects were kept in the time isolation unit for seven days and were asked to initiate sleep 5 hours prior to their scheduled sleep time. Change in DLMO25%, LOQ 5 between night 4 and night 3 by dose Study 3101 used a 5-hour circadian challenge to induce transient insomnia in 412 healthy subjects. This study showed significant improvement in both objective latency to persistent sleep (LPS) and wake after sleep onset (WASO) at 20 mg and 50 mg of tasimelteon but not at 100 mg [LPS=21.5 min, p<0.001 and 26.3 min, p<0.001, 22.8 min, p<0.001 for 20, 50, and 100 mg 12 Reference ID: 3403865 respectively; WASO= 24.2 min, p=0.017, 33.7 min, p=0.001, and 17.4 min, p=0.081 for 20, 50, and 100 mg respectively.] 2.2.3.2 Does this drug prolong the QT or QTc interval? No, tasimelteon did not produce a significant QTc prolongation effect (see figure below) in healthy subjects who received tasimelteon 20 mg and 300 mg (supratherapeutic dose). Figure: QTcI Change from Baseline versus VEC-162 Concentration 2.2.4 What are the PK characteristics of the drug and its major metabolite? Tasimelteon is absorbed with median Tmax ranging from 0.5 to 3 hours. Tasimelteon is extensively metabolized by CYP1A2 and CYP3A4 and CYP1A1, CYP2C9/19, and CYP2D6 minimally contribute to tasimelteon metabolism. The observed mean elimination half-life is 1.32 hours. The mean terminal elimination half-life of the main metabolites ranges from 1.26 to 3.67. The pharmacokinetics of tasimelteon is linear following single ascending doses ranging from 3 mg to 300 mg and multiple doses ranging from 1 mg to 50 mg. 2.2.4.1 What are the single and multiple dose PK parameters? PK characteristics of tasimelteon following single and multiple dose administration was evaluated in several studies, CN116-001, CN116-002, CN116-003, VP-VEC-162-1101, VPVEC-162-1102 and VP-VEC-162-110. Tasimelteon is absorbed with a median Tmax of 0.5 hrs (ranging from 0.5 to 3 hours) following single- or multiple-dose administrations. Tasimelteon PK parameters, Cmax and AUC, are essentially dose-proportionality in the 3-300 mg range following single dose and in the 1-50 mg range following multiple dose administrations. An average (± SD) tasimelteon Cmax is 235 ± 128 ng/mL occurred at a median Tmax of 0.50 hours (range 0.25 -2.00 hours), and AUC average (± SD) is 411.4 ± 327.8 h*ng/mL. Tmax, is variable and dependent on the food intake with high13 Reference ID: 3403865 fat, high calorie meal. The median Tmax was about 2.25-hours. The accumulation index at steady state ranged from 1.22 to 2.22. The tasimelteon exposure profiles displayed high interindividual variability. The elimination half-life (t1/2) ranges from 1.3 to 3.05 hrs. Following table illustrates PK parameters of tasimelteon and its main metabolites calculated from studies VP-VEC-162-1105, 1106, 1107, 1110, and 1112 in healthy volunteers (n=115) Tasimelteon M3 M9 M11 M12 M13 M14 Parameter Units N Arithmetic Mean SD Minimu m Median Maximum Cmax ng/mL 115 234.9 127.7 40.18 214.8 838.1 Tmax h 115 0.569 0.233 0.250 0.500 2.000 AUC h*ng/ml 115 411.4 327.8 55.67 344.9 2,102 T½ h 115 1.32 0.431 0.648 1.26 3.05 Cmax ng/mL 32 133.19 52.72 43.64 129.46 243.87 Tmax h 32 0.658 0.201 0.500 0.500 1.050 AUC h*ng/ml 16 220.4 62.32 90.06 233.7 312.3 T½ h 16 3.67 2.22 1.32 2.77 9.74 Cmax ng/mL 115 238.7 96.7 47.43 229.3 675.6 Tmax h 115 0.690 0.251 0.250 0.750 2.00 AUC h*ng/ml 115 379.4 105.8 182.1 359.7 718.6 T½ h 115 1.41 0.405 0.703 1.33 3.02 Cmax ng/mL 115 49.52 16.31 20.05 49.92 92.49 Tmax h 115 1.10 0.389 0.500 1.000 3.000 AUC h*ng/ml 103 155.8 64.04 51.84 155.80 342.0 T½ h 103 2.02 0.632 0.782 1.91 3.94 Cmax ng/mL 115 96.48 28.40 31.21 94.19 173.08 Tmax h 115 1.38 0.958 0.250 1.00 6.00 AUC h*ng/ml 115 655.2 349.7 155.2 594.6 2,095 T½ h 115 3.33 1.32 1.36 3.11 8.54 Cmax ng/mL 115 288.8 93.92 90.82 285.7 616.3 Tmax h 115 0.585 0.242 0.250 0.500 2.00 AUC h*ng/ml 115 393.7 138.7 151.6 372.8 926.7 T½ h 115 1.26 0.480 0.439 1.19 3.01 Cmax ng/mL 115 6.427 3.337 1.467 5.646 19.12 Tmax h 115 0.820 0.512 0.250 0.750 3.00 14 Reference ID: 3403865 AUC 11*ng/ml 107 21.98 20.10 3.770 15.29 105.0 TV: 11 107 1.98 1.02 0.493 1.77 6.34 2.2.4.2 What are the characteristics of drug absorption? Tasimelteon is absorbed with a Tmax ranging from 0.5 to 3 hours after single- or multiple-dose administration under fasting conditions. Following administration of tasimelteon (single 100 mg dose) with high-fat, high calorie meal, the Cmax was 44% lower than that when given in a fasted state. Median Tmax was delayed by approximately 1.75 horu?s. However, the overall AUC was not affected. Tasimelteon shows in vitro apparent permeability with Papp values of (mo (apical to basolateral) and W4) (basolateral to apical) (4) determined in the aco-2 cell model system. Tasimelteon is stable in simulated gastric ?uid and simulated intestinal ?uid for 3 hours. The overall AUC of tasimelteon in plasma is approximately 10-15 times lower when compared to total radioactivity. From the available inf01mation in the NDA, it cannot be con?rmed that tasimelteon is absorbed in its (no) form in hmnans. 2.2.4.3 What are the characteristics of drug distribution? The apparent volmne of distribution at steady state in the y01mg healthy subjects ranges from 56 - 126 L. At therapeutic concentrations, tasimelteon is about 89% - 90% b01md to proteins. 2.2.4.4 What are the characteristics of drug metabolism? Tasimelteon is extensively metabolized by YP enzymes in the liver. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism and CYP1A1, CYP2D6, CYP2C19, and CYP2C 9 play a minor role. Phenolic glucuronidation is the major phase II metabolic route. The major metabolites formed include M12, M13, M9, M11 and M14. These metabolites are eliminated at similar rate when compared to tasimelteon. The parent to metabolite AUC ratio is 1.6, 0.96, 0.92, 0.38 and 0.05 respectively. Metabolite M12 is inactive, shows higher parent to metabolite ratio (1.6). M13 (parent to metabolite ratio, 0.92) is approximately 13-times lower in potency at and MT2 receptors. M11 (parent to metabolite ratio, 0.38) is approximately 800-times lower in potency at and 50 times lower at MT2 receptors as shown in the table below. Following table indicates activities of tasimelteon and its major metabolites at and MT2 receptors. Potency of tasimelteon and metabolites M9, M11, and M13 for hlunan melatonin and MT2 receptors 15 Reference ID: 3403865 2.2.4.5 What are the characteristics of drug elimination? The major elimination route of tasimelteon is excretion in urine. Mass balance studies show a mean recovery of 84.1% of the administered dose, out of which 80.4% of total radioactivity was excreted in urine and approximately 3.72% in feces. Less than 1% of the dose was excreted in urine as the parent compound. The elimination half-life (t1/2) ranged from 1.3 to 2.6 hrs. 2.2.4.6 Based on tasimelteon PK parameters, what is the degree of linearity in the doseconcentration relationship? Tasimelteon PK parameters increase in an essentially dose proportional manner (figures below) over the range of 3-300 mg and 1-50 mg, following single-dose and multiple-dose, respectively. The maximum concentration (Cmax) and AUC show high inter-individual variability. However, in multiple dose study AUC(tau) increase more than proportionally from 50 to 150 mg. The halflife of tasimelteon is approximately 2 hours. Steady state is achieved by Day 15. The accumulation index at steady state ranged from 1.22 to 2.22. Mean (SD) PK Parameters Cmax and AUC(inf) Following Single Dose Levels of 3 to 300 mg. 16 Reference ID: 3403865 2.2.4.7 How does the PK of tasimelteon in healthy subjects compare to that in patients? It is unknown. PK samples were not collected in the Non-24 population due to the difficulty of nighttime sample collection that would interfere with the measurement of key study endpoints. 2.2.4.8 What is the inter-subject variability of PK parameters in healthy subjects and patients? The PK parameters inter-subject variability of tasimelteon and its main metabolites are generally moderate to high. The mean inter-subject variability of Cmax and AUC is approximately in the range of 54 to 80% in single and multiple dose studies. The mean estimate of inter-subject variability of Tmax and T1/2 ranges from 32% to 41%. Following figure represents the AUC of tasimelteon following 20 mg dose from five studies (total n=115). In studies including subjects with renal and heaptic impairment, the inter-subject variability was upto 3 fold when compared to that of healthy controls. The apparent factors contributing to the inter-subject variability were gender, age and BMI. 2.3 Intrinsic Factors 2.3.1 What intrinsic factors influence exposure and/or response and what is the impact of any differences in exposure on efficacy or safety of tasimelteon? The influence of intrinsic factors such as age and gender on PK of tasimelteon was evaluated in study CNN116-003. The influence of age and BMI on PK of tasimelteon was evaluated in Study 1107. In women, the mean exposure of tasimelteon was approximately 20-30% higher when compared to males. In elderly subjects, Cmax and AUC increased by about 2 fold when compared to the young as shown in the table below. Summary of pharmacokinetic parameters for tasimelteon after oral administration of single 50 mg dose to young and elderly healthy male and female subjects Gender Parameter Males Females 17 Reference ID: 3403865 Age Young Cmax (ng/mL) Tmax (h) AUC(inf) (h×ng/mL) t½ (h) 261 ± 104 (10) 426 ± 254 (10) 1.00 (10) [0.50 2.00] 0.88 (10) [0.50 1.00] 697 ± 303 (10) 920 ± 534 (10) 2.79 ± 1.81 (10) 3.44 ± 2.11 (10) Elderly Cmax (ng/mL) Tmax (h) AUC(inf)(h×ng/mL) t½ (h) 604 ± 269 (10) 601 ± 266 (10) 0.50 (10) [0.50 – 1.00] 0.75 (10) [0.50 – 1.00] 1,429 ± 1,200 (10) 2.99 ± 1.34 (10) 1,466 ± 755 (10) 3.30 ± 0.52 (10) Following figure illustrates individual distribution of Cmax and AUCinf along with mean and standard deviation. Note: One of the subjects (#24) elderly males) had unusually high Cmax and AUC. The reason for high tasimelteon levels in this subject is not clearly understood. This subject did not have adverse events.During the course of clinical development, 153 total subjects > 65 years of age were treated with tasimelteon in placebo-controlled studies in doses ranging from 1 mg to 50 mg per day for 4-26 weeks. In two Phase 3 studies 5/52 subjects were in tasimelteon treatment group. The adverse event profile of these subjects is similar to the overall adverse event profile in pivotal Phase 3 studies in blind subjects with Non-24. No dose adjustment for tasimelteon is recommended for individuals older than 65 years of age or for females. 18 Reference ID: 3403865 The clearance of tasimelteon is inversely related to BMI as shown in the figure below. Relationship between Tasimelteon CL/F and BMI after Oral Administration of Single 20 mg doses of Tasimelteon to Young and Elderly Non-Smokers (Study 1107). Approximately two fold decrease in CL/F is observed among the subjects with about two fold change in BMI. No dose adjustment for tasimelteon is recommended for obese subjects. 2.3.1.1 Renal impairment The effect of renal impairment is evaluated using 20 mg tasimelteon in subjects with severe renal impairment including subjects on dialysis compared to healthy subjects with normal renal function in study VP-VEC-162-1106 (n=32). Subjects with severe renal impairment had a 30% lower a clearance when compared to that of healthy subjects. However, mean clearance in subjects with ESRD was comparable to that of healthy subjects. All the PK parameters were characterized by wide 90% CIs as shown in the figure below. Impact of renal impairment on tasimelte on pharmacokinetics Following figure illustrates individual distribution of Cmax and AUCinf along with mean and standard deviation. 19 Reference ID: 3403865 Note: One of the subjects in severe renal impairment group had unusually high AUC. The reason for high tasimelteon levels in this subject is not clearly understood. There were no SAEs, severe AEs, or discontinuations during the study. There were no clinically significant changes in chemistry, hematology, ECG, and physical examinations following dosing with tasimelteon for subjects in any of the renal function groups. (b) (6) Metabolite M13 showed approximately 20% decrease in geometric mean exposure in ESRD patients when compared to the matched controls. Severely impaired subjects have similar exposure compared to the matched controls characterized by wide confidence intervals as shown in the table below. Metabolite M11 showed approximately 80% increase in geometric mean exposure in ESRD patients when compared to matched controls, Severely impaired subjects have similar exposure compared to the matched controls characterized by wide confidence intervals as shown in the table below. 20 Reference ID: 3403865 There was no apparent dose-safety relationship identified in clinical trials. There were 2 (2/52) serious adverse events (SAEs) in tasimelteon group in phase 3 study. Overall there were ten SAEs in the entire data base; most of the adverse events were mild to moderate in nature. In single ascending dose and multiple ascending dose studies tasimelteon was tolerated upto 300 mg and 150 mg respectively without any SAEs. No dose adjustment is indicated for exposure increases related to renal impairment. 2.3.1.2 Hepatic Impairment The effect of hepatic impairment on tasimelteon PK was evaluated in subjects with mild or moderate hepatic impairment in an open-label, single-dose, parallel-group study including 32 subjects in Study VP-VEC-162-1105. The AUC of tasimelteon increased by 43% and 110% in patients with mild and moderate HI respectively and Cmax increased by about 20% in both mild and moderate HI when compared to healthy subjects. Impact of hepatic impairment on tasimelteon pharmacokinetics Following figure illustrates individual distribution of Cmax and AUCinf along with mean and standard deviation. 21 Reference ID: 3403865 Note: One of the subjects in moderate hepatic impairment group had unusually high AUC. The reason for high tasimelteon levels in this subject is not clearly understood. This subject did not have adverse events. (b) (6) Metabolite M13 ratio was 7% to 28% lower when compared to the matched controls in mild HI subjects. The Cmax was approximately 60% lower and AUC was approximately 30% lower in subjects with moderate HI. All the PK parameters were characterized by wide confidence intervals as shown in the table below. Statistical comparison of pharmacokinetic parameters for M13 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls Metabolite M11 ratio for PK parameters was similar when compared to matched controls in mild HI subjects. However, Cmax was approximately 36% lower and AUC was approximately 11% lower in subjects with moderate HI. All the PK parameters were characterized by wide confidence intervals as shown in the table below. 22 Reference ID: 3403865 Statistical comparison of pharmacokinetic parameters for M11 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls No dose adjustment is necessary for subjects with mild and moderate hepatic impairment. The effect of severe hepatic impairment on tasimelteon PK iss not evaluated. Tasimelteon is not recommended in patients with severe hepatic impairment. 2.3.2 Is there a potential impact of genetic variation in drug metabolizing enzymes on tasimelteon exposure and whether additional pharmacogenetic studies are indicated on the basis of these results? The applicant evaluated associations between CYP2D6, CYP1A2, CYP2C9, and CYP2C19 genotype and exposure of tasimelteon in four healthy subject studies (n=112). CYP1A2, CYP2C9 and CYP2C19 genotype were not associated with tasimelteon exposure in any study. In VP-VEC-162-1102, CYP2D6 poor metabolizers had significantly lower AUC and longer t1/2 compared to extensive metabolizers. This unexpected finding (based on in vitro data) was not replicated in two additional studies (CNN116-001 or CNN116-002), which found no association between CYP2D6 genotype and tasimelteon PK. The applicant suggests that CYP2D6 generates a metabolite that subsequently inhibits tasimelteon metabolism; however, no data are provided to support this hypothesis. Given the lack of a significant exposure-response relationship for efficacy or safety endpoints the high PK variability is not likely to be clinically significant at the proposed doses. Additional gene-drug or drug-drug interaction studies do not appear to be indicated on the basis of these findings. 2.4 Extrinsic Factors 2.4.1 Is the drug and/or the major metabolite a substrate, inhibitor or inducer of CYP enzymes on an in vitro basis? 23 Reference ID: 3403865 Metabolism by CYP: The in vitro data indicates that tasimelteon is mainly metabolized by CYP1A2 and CYP3A4 with minor contribution from CYP1A1, CYP2C9/19, and CYP2D6. Inhibition potential: The potential for tasimelteon and its most abundant human metabolites to inhibit, the major CYP enzymes in human liver microsomes CYP1A2, CYP2B6, CYP2C8, (b) (4) CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 was investigated in studies 12A024, (b) (4) (b) (4) 065016 and 135015. Study results indicate that tasimelteon and its most abundant metabolites are unlikely to cause inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19 or 3A4/5 at the therapeutic dose. Induction potential: Potential for induction of CYP450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5) was assessed by evaluating mRNA expression of several microsomal preparations following treatment of primary cultures of human hepatocytes with tasimelteon in (b) (4) Study 063014. The results indicate that tasimelteon had the potential to induce the activity of CYP3A4/5 and CYP2C8. 2.4.2 Is the drug and/or the major metabolite a substrate and/or an inhibitor of Pglycoprotein transport processes or any other transporter system? The inhibition potential of tasimelteon and its major metabolites towards major transporters including human OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 uptake transporters and the human BCRP efflux transporters was evaluated in Study 12700. Tasimelteon and its metabolites M9, M12, and M13 were not actively transported by OATP1B1 and OATP1B3. Tasimelteon and its metabolites have low likelihood of in vivo inhibition of transporters, OATP1B1, OATP1B3, OAT1, BCRP, OCT2 and OAT3 at therapeutic concentrations. The P-gp inhibition potential of tasimelteon and its major metabolites was evaluated using the Caco-2 assay (Study 10VNDAP1R1).The bidirectional transport of the P-gp substrate digoxin in the presence cyclosporine (inhibitor for P-gp), tasimelteon and metabolites M9, M12 and M13 was measured. Tasimelteon and its major metabolites are neither P-gp substrates nor inhibitors at the nominal concentrations of 0.6 μM and 60 μM of tasimelteon and 0.5 μM to 5 μM nominal concentrations of metabolites. 2.4.3 Are there any in vivo drug-drug interaction studies that indicate the exposures alone and/or exposure-response relationships are different when drugs are co-administered? If yes, is there a need for dosage adjustment? 2.4.3.1 Effect of co-administered drugs on tasimelteon The effect of coadministration of CYP1A2 inhibitor, fluvoxamine was evaluated in Study VPVEC-162-1111. This study was an open-label, single-sequence study in healthy subjects conducted to evaluate the single-dose pharmacokinetics of tasimelteon alone and in combination with a fluvoxamine at steady-state. Inhibition of CYP1A2 by treatment with fluvoxamine 50 mg QD for 6 days resulted in an 85% decrease in tasimelteon CL/F leading to a 6.5-fold increase in AUC and 2.5 fold increase in Cmax. There was a 2-fold increase in tasimelteon half-life. Coadministration of moderate to strong CYP1A2 inhibitors should be avoided when using tasimelteon. 24 Reference ID: 3403865 The effect of co-administration of strong CYP3A4 inhibitor, ketoconazole and CYP3A4 inducer, rifampin was evaluated in Study VP-VEC-162-1112. When administered in combination with ketoconazole the Cmax and AUC of tasimelteon increased by 33% and 53% respectively. Tasimelteon is tolerated upto 300 mg in single ascending dose and upto 150 mg in a multiple ascending dose tolerability studies. There was no clear dose-safety relationship and most of the adverse events were mild to moderate. Therefore, no dose adjustment is necessary for increase in exposure when tasimelteon is coadministered with ketoconazole. When administered in combination with rifampin, a strong CYP3A4 and moderate CYP2C8, CYP2C9/2C19 inducer, the overall AUC of tasimelteon was reduced by approximately 90%. Decrease in exposure to tasimelteon in the presence of rifampin may reduce the efficacy. Therefore, co-administration of tasimelteon with rifampin or strong CYP3A4 inducers should be avoided. Pharmacokinetic and pharmacodynamic interaction of tasimelteon and ethanol was evaluated (VP-VEC-162-1108) in healthy subjects. Coadministration of tasimelteon with alcohol resulted in relatively small increase in exposure (AUC0-inf, AUC0-t, and Cmax) to tasimelteon. The magnitude of increase in exposure ranged from 10% to 25%. PD parameters evaluated on subjective measures, or on sustained attention, cognition, balance or psychomotor performance in this study did not show any trend. Most of the impairments on PD measures were related to ethanol and not due to the addition of tasimelteon. Following figure summarizes the effect of coadministration of drugs on the PK of tasimelteon. Impact of other drugs on tasimelteon pharmacokinetics No dose adjustment is needed in subjects taking alcohol. 2.4.3.2 Effect of smoking on tasimelteon exposure Tasimelteon is mainly metabolized by CYP1A2 and CYP3A4. The levels of CYP1A2 are higher in smokers due to induction. The effect of smoking on tasimelteon exposure was evaluated in a single-dose, parallel group study VP-VEC-162-1107. Cigarette smoking resulting in induction of CYP1A2, increased the clearance of tasimelteon and decreased exposure about 40%, which may 25 Reference ID: 3403865 decrease the efficacy. Following figure represents geometric mean ratios for Cmax and AUC, and 90% confidence intervals outside the 80% to 125%. Dose of tasimelteon may need to be increased for smokers. Impact of smoking on tasimelteon 2.4.3.3 Effect of tasimelteon on co-administered drugs The in vitro studies suggested that tasimelteon had the potential to induce the activity of CYP3A4/5 and CYP2C8.The effect of tasimelteon on CYP3A4 and CYP2C8 activity at steady state was evaluated using midazolam and rosiglitazone as markers respectively in a clinical study VP-VEC-162-1110. Tasimelteon 20 mg daily administration for 14 days did not significantly change the overall AUC of midazolam and 1-OH midazolam. Similarly there was no change in 1-OH midazolam Cmax. There was a relatively small increase (13%) in midazolam Cmax. Tasimelteon 20 mg administred daily for 16 days did not significantly change the plasma concentrations and mean pharmacokinetic parameters of rosiglitazone. Following figure summarizes the effect of tasimelteon on the PK of co-administered drugs Impact of tasimelteon on pharmacokinetics of other drugs 26 Reference ID: 3403865 2.5 General Biopharmaceutics 2.5.1 Based on the biopharmaceutics classification system (BCS) principles, in what class is this drug? The Sponsor submitted information requesting formal BCS b classification for tasimelteon. ) Absolute bioavailability was not determined for tasimelteon. The apparent permeability of (b) (4) tasimelteon as measured using Caco2 assay for AP to BL was The (b) (4) The assay was conducted using apparent permeability for BL to AP was (b) (4) permeability markers. The Caco2 assay was validated (b) (4) (b) (4) In vitro permeability of tasimelteon is approximately (b) (4) Tasimelteon is in simulated gastric fluid and simulated intestinal fluid for (b) (4) (b) (4) Based on the solubility data, the drug can be classified as soluble. But the current (b) (4) available permeability data are inconclusive for tasimelteon to be considered as permeable drug because of the following deficiencies. (  In the mass-balance study, about 84% of the radiolabel dose was recovered from urine, and feces, which is less than the threshold (90%) recommended by the BCS guidance.  Tasimelteon is metabolized extensively. The overall AUC of tasimelteon in plasma is approximately 10-15 times lower when compared to total radioactivity. The sponsor did (b) (4) not provide evidence that tasimelteon is absorbed 2.5.2 What is the relative bioavailability of the proposed to-be-marketed formulation and the formulation used in clinical trials? 27 Reference ID: 3403865 Relative bioavailability study is not necessary as the formulation used in clinical trials is same as to-be-marketed formulation. 2.5.3. What is the effect of food on the bioavailability (BA) of the drug from the dosage form? What dosing recommendation should be made, if any, regarding administration of the product in relation to meals or meal types? The effect of food on BA of tasimelteon was evaluated in a single-dose, randomized, cross-over study with a standard high fat diet (>50% of calories derived from fat, VP-VEC-162-1102). When tasimelteon was administered with high fat, high calorie meal, the extent of absorption, AUC(0-t) and AUC(inf) was comparable under both fed and fasted conditions with geometric mean ratios of 108% and 106%, respectively, and 90% confidence intervals were within the 80% to 125%. However, Cmax was reduced by 44% and the Tmax was delayed from 0.75 hours to 2.5 hours (table below). It is recommended that tasimelteon should be taken without food preferably before bedtime and at approximately the same time every day for maximum efficacy. Summary of Pharmacokinetic Parameters for VEC-162 after Single Oral 100 mg Doses Under Fasted and Fed Conditions Following figure shows individual median Tmax distribution along with mean and standard deviation under fasted and fed conditions. 28 Reference ID: 3403865 5- 4- l? 2.. Note: This study was conducted using 100 mg tasimelteon dose in healthy subjects. The two capsule 20 mg and 100 mg are (hm Dose linearity was demonstrated for tasimelteon upto 300 mg in single dose study. Dissolution pro?les for 20 mg and 100 mg capsules are similar. 2.6 Analytical section 2.6.1 What analytical methods were used to determine drug and metabolite concentrations and were these analytical assay methods adequately validated? Validated LC methods were used to quantitate tasimelteon and its metabolites in plasma. Smnmary of bioanalytical assay validation for tasimelteon and its active metabolites M13 and M11 are provided in the tables below. Parameter Tasimelteon Method LLOQ 0.1 rig/mL Linear range 0.1. 0.3. 1. 3. 10. 30. 60. and 10011g/111L QC samples 0.1, 0.3, 45, and 90 ng/mL QC Inter-day accuracy and precision %Bias -7.0 to 3.1 4.7 to 7.5. . . . %Bias -6.0 to 6.0 QC Intra-day accuracy and p1ec151011 CV 1.6 to 3.2 Freeze-thaw stability 5 cycles 29 Reference ID: 3403865 Bench-top stability at RT 19 hours Auto sample stability at RT 138 hours 43 Days at -20oC Long-term stability in K3EDTA human plasma Stock solution stability at -20 oC 175 days at -20 oC Selectivity <20% LLOQ for analyte <5% for internal standard 500 ng/mL diluted to 100-fold Dilution Integrity Metabolite M13 Analyte Name Internal Standard (IS) Analytical Method Type Extraction Method QC Concentrations Standard Curve Concentrations Lower Limit Of Quantitation Upper Limit Of Quantitation Average Recovery of Drug (%) Average Recovery of Internal Standard (%) QC Intraday Precision Range (%CV) QC Intraday Accuracy Range (%RE) QC Interday Precision Range (%CV) QC Interday Accuracy Range (%RE) Stock Solution Solvent Master Stock Solution Stability in Methanol Master Stock Solution Stability in Methanol Reinjection Reproducibility in Processed Samples Interference Tests for Fluvoxamine, Paroxetine, and Repaglinide Benchtop Stability in Plasma Freeze/Thaw Stability in Plasma Long-term Storage Stability in Plasma Dilution Integrity Selectivity M13 M13-d3 LC-MS/MS Liquid-liquid 0.1, 0.3, 45, and 90 ng/mL 0.1, 0.3, 1, 3, 10, 30, 75, and 100 ng/mL 0.1 ng/mL 100 ng/mL 70.5 71.1 3.2 to 11.9 -17.0 to 1.0 4.0 to 11.8 -7.0 to -2.8 Methanol 280 Days at -20 C 8 Hours at Room Temperature 138 Hours at 4 C No interference from co-administered drugs to M13 19 Hours at Room Temperature 5 Cycles at -70 C 96 Days at -20 C 96 Days at -70 C 500 ng/mL diluted 50-fold ≤ 20.0% LLOQ for analyte; ≤ 5.0% for IS Metabolite M11 Analyte Name M11 30 Reference ID: 3403865 Internal Standard (IS) Analytical Method Type Extraction Method QC Concentrations Standard Curve Concentrations Lower Limit Of Quantitation Upper Limit Of Quantitation Average Recovery of Drug (%) Average Recovery of Internal Standard (%) QC Intraday Precision Range (%CV) QC Intraday Accuracy Range (%RE) QC Interday Precision Range (%CV) QC Interday Accuracy Range (%RE) Stock Solution Solvent Master Stock Solution Stability in Methanol Master Stock Solution Stability in Methanol Reinjection Reproducibility in Processed Samples Interference Tests for Fluvoxamine, Paroxetine, and Repaglinide Benchtop Stability in Plasma Freeze/Thaw Stability in Plasma Long-term Storage Stability in Plasma Dilution Integrity Selectivity 3. M11-d3 LC-MS/MS Liquid-liquid 0.1, 0.3, 45, and 90 ng/mL 0.1, 0.3, 1, 3, 10, 30, 75, and 100 ng/mL 0.1 ng/mL 100 ng/mL 86.0 86.3 1.4 to 11.6 -10.0 to -2.0 2.4 to 7.6 -8.0 to -2.3 Methanol 280 Days at -20 C 8 Hours at Room Temperature 138 Hours at 4 C No interference from co-administered drugs to M11 19 Hours at Room Temperature 5 Cycles at -70 C 96 Days at -20 C 96 Days at -70 C 500 ng/mL diluted 50-fold ≤ 20.0% LLOQ for analyte; ≤ 5.0% for IS Detailed Labeling Recommendations Labeling recommendation to be sent to the Sponsor: The following describes the proposed changes: the underlined text is the proposed change to the label language; the Strikethrough text is recommendation for deletion from the perspective of OCP. 31 Reference ID: 3403865 DOSAGE AND ADMJNISTRATION The recommended dose of is 20 (13 taken - before at the same time every night. DRUG INTERACTIONS Reference ID: 3403865 (b) (4) 8. USE IN SPECIFIC POPULATIONS 8.5. Geriatric use (b) (4) 33 Reference ID: 3403865 8.6. Hepatic Impairment -Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, ITRADENAMEI is not recommended in patients with severe hepatic QB. airment. 12. CLINICAL PHARMACOLOGY 12.3. Pharmacokinetics The pharmacokinetics of is linear over doses ranging from 3_ to 300 mg. The harmacokinetics of TRADENAME and its metabolites did not chan with re ated dail dosin Absomtion 34 Reference ID: 3403865 -The peak concentration (Tmn) of tasimelteon occmre to 3 hours after fasted oral administration. When administered with a high-fat meal, the Cm -of tasimelteon was 44% lower than when 'ven in a fasted state dela ed a roximatel 1.75 hours._ Therefore, Distribution The apparent oral volume of distribution at steady state of M?in young healthy subjects is approximately 56 - 126 L. At therapeutic concentrations, tasimelteon -is about bound to proteins. Metabolism I Tasimelteon is extensively metabolized. Metabolism of M-consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 I are the major isozymes involved in the metabolism of M. Phenolic glucuronidation is the major phase II metabolic route. Metabolite shows 13 fold less activig at melatonin receptors com: ared to tasimelteon. -Elimination Following oral administration of radiolabeled 8(l% of total radioactivity was excreted in urine and approximately in feces, resulting in a mean recovery of Less than 1% of the dose was excreted in urine as the parent compound. The observed mean elimination half-life for tasimelteon is l. 0.4'hours. The mean terminal elimination half-life 3: standard deviation of the main metabol es ranges from 1.26 i 0.48 to 3.67 :t 2.22. Repeated once daily dosin with TRADENAME does not result in PK arameter changes or signi?cant accumulation of M. Elderly: In elderly subjects, tasimelteon ex osur increased a roximatel 2 fold 35 Reference ID: 3403865 In women, the mean overall ex osure of tasimelteon Iwas approximately 20- 30% higher when compared to males? Raca The ffect of race on exposure of lwas not evaluated. Renal Impairment The harmacokinetic of tasimelteon a 20 mg dose to eight subjects with severe renal impairment (estimated glomerular ?ltration rate 29 mL/min/ 1.73m2 ei sub'ects with end-sta renal disease ESRD 15 mL/min/ 1.73m2 re uirin hemodial sis and sixteen health matched controls. There was no apparent relationship between and renal function as measured bv either estimated creatinine clearance or Subjects with severe renal im airment had a 30% lower a clearance and -clearance in sub'ects with ESRD was co arable to that of healthy subjects. No dose adjustment is necessg for renal impaired patients. Hepatic Impairment The pharmacolginetics pro?le of 20 mg- in eight patients with mild hepatic impairment (Child-Pugh Score >5 and <6 points). atients with moderate he atic impairment (Child-Pugh Score >7 and <9 points) was com ared to 13 healthy matched controls. iTasimelteon ex osure 2-fold in sub'ects with moderate he atic im airment No dose adjustment is needed for mild and moderate he atic aired atients. TRADENAME has not been studied in patients with severe hepatic im airment Child-Pu Class . is not recommended in patients Drug Interaction Studi_es ect Other Dru TRADENAIVIE Drugs that inhibit CYP1A2 and CYP3A4 are exp_ected to alter the metabolism of TRADENAME . Iuvoxamine (strong CYP1A2 inhibitorz. When ?uvoxamine 50 ngday was administered for6 days prior to single-dose co-administration of 5 mg and 50 mg ?uvoxamine, exposure .increased administered on the 36 Reference ID: 3403865 Ri am in stron CYP3A4 and moderate CYP2CI9 inducer Administration of rifam in 600 once dail for 11 da resulted in decrease in exposure by approximately.% Ef?cac ma be reduced when TRADENAME is used in combination with stron CYP3A4 inducers such as rifam in. i ect 0 Alcohol on RADENAME i ect TRADENAME on Other Drugs Midazolam CYP3A4 substrate Administration of 20 m; for 14 days did not roduce an si '?cant chan es in the or AUC of midazolam or midazolam indicates that there is no induction of CYP3A4 by at this dose. Rosiglitazone (CYP2C8 substrate): Administration of 20 mg. for 16 days did not produce any sigm?cant changes in the T295, ng, or AUC of rosiglitazone after oral administration of 4 mg. This indicates that there is no induction of CYP2C8 by at this dose. 37 Reference ID: 3403865 4. Appendices 4.1 Consult Reviews Reference ID: 3403865 OFFICE OF CLINICAL PHARMACOLOGY GENOMICS AND TARGETED THERAPY GROUP REVIEW NDA/BLA Number Submission Date Applicant Name Generic Name Proposed Indication Primary Reviewer Secondary Reviewer 1 205677 6/18/2013 Vanda Pharmaceuticals Inc. Tasimelteon Treatment of non-24-hour disorder in the totally blind Robert Schuck, Pharm.D., Ph.D. Michael Pacanowski, Pharm.D., M.P.H. Background The current submission is a NDA for tasimelteon, a dual melatonin receptor agonist (MT1 and MT2), for the treatment of non-24 hour disorder in the totally blind. Non-24-hour disorder is a condition that results in a circadian rhythm of greater than 24 hours. By activating the MT1 and MT2 melatonin receptors in the suprachiasmatic nuclei, tasimelteon is purported to synchronize the circadian rhythm to a 24-hour day. Clinical pharmacology studies showed high intersubject variability in tasimelteon pharmacokinetics (PK). In vitro studies demonstrated that tasimelteon is primarily metabolized by CYP1A2 and CYP3A4; CYP1A1, CYP2C9, CYP2C19, and CYP2D6 contribute to a lesser extent. As such, the impact of CYP2D6, CYP1A2, CYP2C9, and CYP2C19 genotype on tasimelteon PK was evaluated in phase 1 studies. CYP2D6 genotype was associated with tasimelteon PK; however, this association was not consistent across studies. The purpose of this review is to evaluate the potential impact of genetic variation in drug metabolizing enzymes on tasimelteon exposure and whether labeling or additional pharmacogenetic studies are indicated on the basis of these results. 2 Submission Contents Related to Genomics The applicant conducted 14 phase 1 clinical pharmacology studies, four of which evaluated the association between CYP genotypes and tasimelteon PK (Table 1). Genotyping results were included within each individual study report. Table 1: Studies evaluating associations between cytochrome P450 genotype and PK. Study N Objective Genes Assessed Dose/ Regimen VP-VEC-162-1101* 6 Mass Balance CYP2D6, CYP1A2, 100 mg single dose CYP2C9 VP-VEC-162-1102 26 Food Effect CYP2D6, CYP1A2, 100 mg single dose (fasted) CYP2C9, CYP2C19 CNN116-001 48 Single Ascending Dose CYP2D6 1-300 mg CNN116-002 32 Multiple Ascending CYP2D6 1-150 mg daily for 28 days Dose 39 Reference ID: 3403865 *The applicant noted insufficient representation of the different genotypes to conduct the planned genetic analysis. Genotyping of CYP2D6 and CYP2C19 was performed using the Roche AmpliChip CYP450 test, and were genotyped using Tag-It. Reviewer comments: The Roche AmpliChip is FDA-cleared for CYP450 genotype testing. Phenotype assignment was not specified. However, the parameterization o?ered by AmipliChip is generally acceptable. Analytical performance information was submitted for the CYP1A2 *1 polymorphism, but not the CYP2C9 *2 or CYP2C9 *3 polymorphisms; however, genotvpe??equencies appear consistent with those reported in the literature. 3 Key Questions and Summary of Findings 3.1 Do genetic polymorphisms in CYP2D6, CYP1A2, CYP2C9, or CYP2C19 affect tasimelteon 3.1.1 Pertinent positive ?ndings Study VP-VEC-162-1102 evaluated food effects on tasimelteon PK in 26 healthy subjects. PK parameters were analyzed by CYP2D6, CYP1A2, CYP2C9, and CYP2C 19 genotype. Findings from this study demonstrated that CYP2D6 genotype was signi?cantly associated with AUC (Figure 1A, p=0.0477) and 11/2 (Figure 1B, which was driven by lower exposure in poor metabolizers In addition, a trend toward lower Cmax was observed in poor metabolizers compared to extensive metabolizers (p=0.05 70). Figure 1. Individual Subject AUC (A) and tm (B) by CYP2D6 Genotype After a Single Oral 100 mg Dose Under Fasted Conditions. A .- 6006 - int?) 011mg <04? - (a OWO I I P001 huennedmte Evens? Poul l'xlensn Reviewer comment.? In vitro data suggests that CYP2D6 poor metabolizers should have higher AUC and compared to extensive metabolizers, which is in contrast to these ?ndings. The sponsor proposes that CYP2D6 might generate a metabolite that inhibits metabolism of tasimelteon by a di?erent drug metabolizing enzyme. Study CNN116-001 evaluated single ascending doses in 48 healthy subjects, and study CNN116- 002 evaluated multiple ascending doses in 32 healthy subjects. No genotype effects on tasimelteon PK were observed in either study. One individual with two null CYP2D6 alleles had 40 Reference ID: 3403865 oral clearance of tasimelteon that was at least 2-fold higher than any other individual, but metabolism was potentially confounded by smoking in that subject induction of CYP1A2). 3.1.2 Pertinent negative ?ndings The VP-VEC-162-1102 study also demonstrated that there was not a signi?cant association between genotype and tasimelteon AUC (Figure 2A) or l1/2 (Figure 2B). The lack of an association between genotype and tasimelteon PK is notable because 1) CYP1A2 is the main enzyme responsible for metabolism of tasimelteon, 2) ?uvoxamine (a strong CYP1A2 inhibitor) co-administration resulted in a 6.5-fold increase in tasimelteon exposure (VP-VEC-162-1111), and 3) smoking (an inducer of CYP1A2) resulted in a 40% decrease in tasimelteon exposure (VP-VEC ?162-1 107). Similar to the lack of an association between CYP1A2 genotype and tasimelteon exposure, CYP2C9 and genotype was not associated with tasimelteon all subjects were CYP2C19 extensive metabolizers so no PK analysis was performed. Figure 2. Individual Subject AUC (A) and tm (B) by Genotype After a Single Oral 100 mg Dose Under Fasted Conditions. A 7500 - 5 0 6?00 - 4 . 4'3000 - 0 9 7: 8 8 [500 - Reviewer Comment.? We were unable to assess the potential interaction between smoking and CYPIA2 genotype status due to the absence of a studv with both genotype data ana1 smoking status data. Summary and Conclusions The applicant evaluated associations between CYP2D6, CYP1A2, CYP2C 9, and CYP2C 19 genotype and exposure to tasimelteon in four healthy subject studies (n=112). CYP1A2, CYP2C 9 and CYP2C 19 genotype were not associated with tasimelteon exposure in any study. In VP-VEC -162-1 102, CYP2D6 poor metabolizers had signi?cantly lower AUC and longer t1/2 compared to extensive metabolizers. This unexpected ?nding (based on in vitro data) was not replicated in two additional studies or CNN116-002), which found no association between CYP2D6 genotype and tasimelteon PK. The applicant suggests that CYP2D6 generates a metabolite that subsequently inhibits tasimelteon metabolism; however, no data are provided to support this hypothesis. Given the lack of a signi?cant exposure-response relationship for 41 Reference ID: 3403865 efficacy or safety endpoints the high PK variability is not likely to be clinically significant at the proposed doses. Additional gene-drug or drug-drug interaction studies do not appear to be indicated on the basis of these findings. Recommendations The submission is acceptable from a Genomics and Targeted Therapy Group perspective. Additional gene-drug or drug-drug interaction studies do not appear to be indicated on the basis of these findings. Post-marketing studies None. Label Recommendations None. APPEARS THIS WAY ON ORIGINAL 42 Reference ID: 3403865 4.2 Individual Study Reviews Table of Contents 1.1  CNN116-001: Safety, Tolerance, Pharmacokinetics and Pharmacodynamics of Single Doses of BMS-214778 in Healthy Subjects ..................................................................44  1.2  CNN116-002: Safety, Tolerance, Pharmacokinetics and Pharmacodynamics of Multiple Doses of BMS-214778 in Healthy Subjects: Protocol CN116-002...............................48  1.3  CNN116-003: Comparison of the Pharmacokinetics of Single-Doses of BMS-214778 in Young and Elderly Subjects ..........................................................................................52  1.4  VP-VEC-162-1101: A Phase I, Open Label, Single-Center Study of the Absorption, Metabolism and Excretion of VEC-162 in Healthy Male Subjects ...............................55  1.5  VP-VEC-162-1103: A double-blind, randomized, crossover trial to define the ECG effects of VEC-162 using a clinical and a supratherapeutic dose compared to placebo and moxifloxacin (a positive control) in healthy men and women: a thorough ECG trial. .60  1.6  VP-VEC-162-1106: An Open-Label, Single-Dose, Parallel-Group Study to Compare the Pharmacokinetics of Tasimelteon in Subjects with Renal Impairment With That in Matched Control Subjects with Relatively Normal Renal Function ............................................64  1.7  VP-VEC-162-1105: An Open-Label, Single-Dose, Parallel-Group Study to Compare the Pharmacokinetics of Tasimelteon in Subjects with Mild or Moderate Hepatic Impairment with that in Matched Healthy Control Subjects. ....................................................................71  1.8  VP-VEC-162-1111: An open-label, single-sequence study in healthy subjects to evaluate the single-dose pharmacokinetics of tasimelteon alone and in combination with a CYP1A2 inhibitor, fluvoxamine. ..................................................................................................79  1.9  VP-VEC-162-1112: An open-label, single-sequence study in two cohorts of healthy subjects to evaluate the single-dose pharmacokinetics of tasimelteon alone and in combination with a CYP3A4 inhibitor, ketoconazole, or a CYP3A4 inducer, rifampin. ..................87  1.10  VP-VEC-162-1108: A randomized, double-mask, four period crossover study in healthy subjects to evaluate the pharmacodynamic and pharmacokinetic interactions of tasimelteon and ethanol .....................................................................................................................97  1.11  VP-VEC-162-1107: An open-label, single dose, parallel group study to assess the effect of smoking status, age and body size on the pharmacokinetics, safety, and tolerability of tasimelteon in healthy volunteers. ...............................................................................108  1.12  VP-VEC-162-1110: An open-label, single-sequence study to assess the effect of multiple doses of tasimelteon on the cytochrome P450 3A4 and 2C8 enzymes using midazolam and rosiglitazone as substrates in healthy subjects. ............................................................112  1.13  VP-VEC-162-1102: An Open-label, Two-period, Two-sequence, Randomized, Single Oral Dose, Crossover Study to Evaluate the Effect of Food on the Absorption of 100 mg VEC162 in Healthy Subjects ...............................................................................................120  1.14  In vitro determination of protein binding of [14C]BMS-214778 in human, monkey, rat, and mouse sera. ............................................................................................................122  1.15  VEC-162/Tasimelteon: Cytochrome P450 Reaction Phenotyping......................124  1.16  In Vitro Evaluation ofVEC-162 as an Inhibitor of Human Cytochrome P450 Enzymes 126  1.17  In Vitro Evaluation of M9, M12 and M13 as Potential Inhibitors of Cytochrome P450 (CYP) Enzymes in Human Liver Microsomes ............................................................128  43 Reference ID: 3403865 1.18  In Vitro Evaluation of Tasimelteon as an Inhibitor of CYP2B6 in Human Liver Microsomes..................................................................................................................131  1.19  In vitro Evaluation of VEC-162 as an Inducer of Cytochrome P450 Expression in Cultured Human Hepatocytes ......................................................................................133  1.20  In Vitro Evaluation of Tasimelteon and Metabolites M9, M12 and M13 as Inducers of Cytochrome P450 Expression in Cultured Human Hepatocytes .................................135  1.21  In vitro Interaction Studies of Tasimelteon and Metabolites M9, M12, and M13 with the Human BCRP ABC (Efflux) Transporter, and with Human OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 Uptake Transporters .......................................................................137  1.22  P-gp Interaction Assessment of the Customer's Test Compound (VEC-162) and Metabolites ..................................................................................................................139  1.1 CNN116-001: Safety, Tolerance, Pharmacokinetics and Pharmacodynamics of Single Doses of BMS-214778 in Healthy Subjects Objectives: To evaluate pharmacokinetics, safety and tolerability profile of single oral doses of BMS214778 (tasimelteon) in healthy subjects. An additional objective was the assessment of the effects of BMS-214778 on core body temperature, subjective sedation and cognition. Study Design Study Population Sampling: Analysis This study was a randomized, double-blind, sequential, escalating dose design, placebo controlled study. Healthy male Age: 18-42 years BMI: 20 to 30 kg/m2. Forty eight subjects were enrolled and 48 completed the study. Doses 1, 3, 10, 30, 100 and 300 mg BMS-214778 administered orally in 6 groups of 8 healthy subjects (48 subjects). Blood samples for the determination of VEC-162 in plasma were taken for each subject at pre-dose and 1, 2, 4, 8, 12, 24 and 48 hours post-dosing. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Quality Control Samples 0.5, 50, and 80 ng/mL 0.9% to 2.9% Standard Curve Samples 0.1, 0.25, 1, 10, 30, 70 and 100 ng/mL 1.0 to 7.5 -9.0% to 5.7%. -12.2 to 5.2 Weighted linear equation (1/X2), mean r= 0.995 44 Reference ID: 3403865 Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods 0.1 to 100 ng/mL 0.1 ng/mL Serial blood samples were collected prior to and for 48 hr post-dosing for the determination of BMS-214778 plasma pharmacokinetics. A cumulative urine sample was collected for 24 hr post-dose for the determination of BMS214778 eliminated in the urine. The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. All adverse events recorded during the study were listed and tabulated by treatment, body system and primary term. Any serious adverse event was identified. All laboratory abnormalities meeting predefined criteria were listed and tabulated by treatment and laboratory test. Observed values of each of the pharmacokinetic parameters were plotted against dose. Summary statistics were tabulated by dose level: geometric means, coefficients of variation, minima and maxima for Cmax (the maximum observed plasma concentration) and AUC(inf) (the area under the plasma concentration-time curve from zero time extrapolated to infinity); medians, minima and maxima for Tmax; means, standard deviations, minima and maxima for t1/2 (the plasma terminal half-life) and UR(%) (BMS-214778 recovered in the urine from 0-24 hrs). No formal hypothesis testing of dose proportionality was performed. Summary statistics (means, standard deviations, medians, minima and maxima) were tabulated by dose level and time point for each of the pharmacodynamic variables and their respective changes from baseline (Study Day -1). Pharmacodynamic Data Set The pharmacodynamic data set consisted of all available data from subjects who received study drug (active or placebo) and for whom data were available. Core body temperature (CBT) and the following psychometric test results were summarized for Analog Mood Scales (Tension, Depression, Anger, Fatigue and Confusion), and Digit Symbol Substitution Test (DSST) (sec/digit). RESULTS: Following figure illustrates PK profile of tasimelteon following single ascending doses upto 300 mg. Mean (SD) Plasma Concentration-Time Profiles of BMS-214778 Following Single Oral Doses to Healthy Subjects in Study CN116-001 (N=6 per Dose Group) 45 Reference ID: 3403865 Following table summarizes PK parameters of tasimelteon following single ascending doses upto 300 mg. Pharmacokinetic parameters for BMS-214778 are summarized in the table below: Parameter Dose Level 1 mg 3mg 10mg 30mg 100mg 300mg Cmax (ng/mL) Geo. Mean (C.V.) 8.3 (46.5%) 15.6 (43.6%) 66.6 (32.3%) 103.5 (83.5%) 312.8 (37.2%) 900.5 (51.3%) AUC(inf) (ng.h/mL) Geo. Mean (C.V.) 14.0 (61.5%) 20.8 (60.4%) 0.63 (0.5,1.0) 110.8 (33.5%) 0.75 (0.5,1.0) 188.9 (76.9%) 935.3 (47.2%) 2943.2 (45.8%) 0.75 (0.25,1.0) 1.25 (0.75,1.5) 1.00 (0.5,1.5) Tmax (hr) Median (Min,Max) 0.50 (0.5,1.0) T1/2 (hr) Mean (S.D.) 1.11 (0.26) 1.48 (1.03) 1.95 (0.96) 1.95 (0.86) 4.8 (1.65) 5.07 (1.52) UR Mean (S.D.) 0.42 (0.33) 0.80 (0.42) 0.43 (0.33) 0.44 (0.30) 0.21 (0.09) 0.25 (0.08) (%) Mean (SD) Peak Plasma Concentrations (Cmax) of BMS-214778 and the Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC(inf)) as a Function of Increment in the Dose Levels for Doses of 3 to 300 mg. 46 Reference ID: 3403865 Pharmacodynamic Results: PD parameters were evaluated for exploratory purposes’. There were also no apparent treatmentrelated trends in psychometric test scores or core body temperature. Changes from baseline were small and similar to those in the placebo group. For all of the psychometric variables, the mean changes from baseline within a treatment group were small and similar to those in the placebo group. Safety Results Number (Percent) of Subjects Reporting Treatment-Emergent Adverse Events CONCLUSIONS:   The pharmacokinetics of tasimelteon appeared to be essentially dose-proportional over the dose range of 3 mg to 300 mg characterized by large variability. Peak concentrations of tasimelteon were achieved with a Tmax of 0.5 to 1 hr. The terminal half-life was approximately 5 hr. There were no apparent treatment-related trends in pharmacodynamic variables tested. 47 Reference ID: 3403865  The primary treatment-emergent adverse event following morning administration was sleepiness. Mild postural hypotension and mild constipation were also reported. There were no Serious Adverse Events or discontinuations due to adverse events in this study. 1.2 CNN116-002: Safety, Tolerance, Pharmacokinetics and Pharmacodynamics of Multiple Doses of BMS-214778 in Healthy Subjects: Protocol CN116-002 Objectives:  To assess the safety and tolerability profile of 1 to 150 mg BMS-214778 administered orally qhs (bedtime every day) for 28 consecutive days.  To evaluate the single dose and steady state pharmacokinetics of BMS-214778.  To assess effects on core body temperature and subjective sedation. In addition, the effects of BMS-214778 on dim light melatonin onset were assessed and data were collected on luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T) in healthy male subjects. Study Design Study Population Sampling: Analysis This randomized, double-blind, sequential, escalating dose, placebo controlled study assessed the safety profile, tolerance, pharmacokinetics and pharmacodynamics of 1, 10, 50 and 150 mg BMS-214778 administered orally qhs for 28 days in 4 groups of 8 healthy subjects (32 subjects), all men. Healthy male Age: 18-50 years BMI: 18 to 35 kg/m2. Thirty two subjects were enrolled and 30 completed the study Blood samples for the determination of VEC-162 in plasma were taken for each subject before dosing and 20, 40 min, 1, 1.5, 2, 3, 10, 12 and 24 hours after dosing on days 1 and 28. On days 2 and 13, 14, 15, 26 and 27 samples were collected prior to dosing. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Quality Control Samples 0.5, 50, and 80 ng/mL 1.5% to 4.5% Standard Curve Samples 0.1, 0.25, 1, 10, 30, 70 and 100 ng/mL 0.6 to 7.5 -10.8% to 9.0%. -6.3 to 11.7 Weighted linear equation (1/X2), mean r= 0.995 0.1 to 100 ng/mL 0.1 ng/mL Serial blood samples were collected following administration of BMS-214778 48 Reference ID: 3403865 Assessments PD Assessments Safety Assessments Statistical Methods on Days 1, 15 and 28. Blood samples for BMS-214778 Cmin (trough concentration) determinations were taken on Days 13, 14, 26 and 27. The pharmacokinetic parameters Cmax, Tmax, AUCtau, AUCinf, apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentrationtime data using noncompartmental analysis. The pharmacodynamic variables evaluated include core body temperature, subjective sedation (Analogue Mood Scales test), dim light melatonin onset (determined from salivary melatonin measurements). Safety assessments included physical examinations, vital signs (systolic/diastolic blood pressure, pulse rate, respiration rate, and oral body temperature), clinical laboratory tests (hematology, chemistry, and urinalysis), 12-lead electrocardiograms, and reported or observed adverse events. Summary statistics were tabulated by dose level and study day: geometric means, coefficients of variation, Cmin, Cmax, AUC(inf), AUC(tau); medians, minima and maxima for Tmax; means, standard deviations, minima and maxima for the others. The general dependencies of Cmax and AUC(tau) on dose were explored by comparing the increasing ratios of the doses to the corresponding ratios of the dose level geometric means. Ninety-five percent (95%) confidence intervals were constructed for the mean AI. No formal hypothesis testing dose proportionality was performed. Pharmacodynamic Data: Summary statistics (means, standard deviations, medians, minima and maxima) were tabulated by dose level, study day and measure time for each of the pharmacodynamic variables and their respective changes from baseline (Study Day -1). For core body temperature data, intervals pre-dose and hourly (60 minute) post-dose were formed, and core body temperatures were averaged over these intervals for each subject. These hourly means were used in the calculation of summary statistics. The first time at which a minimum CBT measure was observed was tabulated and summarized. This value was captured prior to the formation of the hourly CBT intervals. RESULTS: Following figure illustrates PK profile of tasimelteon following multiple ascending doses upto 150 mg. Mean (SD) Plasma Concentration-Time Profiles of BMS-214778 on Days 1, 15 and 28 Following Single Daily Oral Doses of 1 mg (+), 10 mg (O), 50 mg (▲) or 150 mg (□) ofBMS214778 49 Reference ID: 3403865 Following table summarizes PK parameters of tasimelteon following multiple ascending doses 1 mg to 150 mg (qhs). Mean VEC-162 phamiacokinetic parameters are presented in the table below Parameter Cmax (ng/mL) AUC(tau) (ng•h/mL) Tmax (h) T-half (h) Statistic Geo. Mean (C.V.) Geo. Mean (C.V.) Median (Min, Max) Mean (S.D.) Dose 1 Day 1 5 (55) Study Day Day 15 7 (49) 10 33 (58) 48 (81) 51 (54) 50 173 (49) 256 (41) 261 (37) 150 394 (41) 652 (48) 873 (40) 1 8 (19) 12 (48) 17 (25) 10 59 (80) 98 (78) 96 (64) 50 426 (50) 519 (36) 611 (50) 150 1823 (47) 3243 (54) 3797 (39) 1 0.67 (0.33, 1.00) 0.67 (0.33, 1.50) 0.67 (0.33, 1.50) 10 0.67 (0.67, 1.00) 1.00 (0.67, 2.00) 0.83 (0.67, 1.00) 50 1.00 (0.67, 1.50) 0.67 (0.67, 1.50) 0.67 (0.67, 1.00) 150 2.25 (1.00, 3.00) 2.00 (1.50, 3.00) 2.00 (1.50, 2.00) 1 1.75 (1.35) 1.64 (1.33) 1.49 (1.12) 10 1.29 (0.39) 1.44 (0.34) 1.44 (0.40) 50 2.37 (1.52) 2.38 (1.45) 2.57 (1.69) 150 2.78 (0.51) 2.38 (0.17) 2.63 (0.52) Day 28 12 (43) 50 Reference ID: 3403865 Dose (mg) AUC(TAU) Accumulation Index Geometric Mean (95% Confidence Intervals) Day 15 Day 28 1 1.59 (1.14, 2.21) 2.22 (1.66, 2.96) 10 1.66 (0.98, 2.82) 1.63 (1.20, 2.22) 50 1.22 (0.94, 1.58) 1.43 (1.10, 1.86) 150 1.80 (1.43, 2.27) 2.11 (1.46, 3.05) Individual and Mean Cmax and AUC(tau) Values of BMS-214778 Versus Dose Administered on Day 28 PHARMACODYNAMIC RESULTS: A greater decrease in core body temperature over time was observed in the BMS-214778 treated groups compared to placebo. 51 Reference ID: 3403865 The tasimelteon treated subjects tended to have an earlier occurrence of minimum temperature relative to baseline compared to placebo treated subjects. The other PD measures did not show any apparent trend. Greater increases in salivary melatonin concentrations were observed in the BMS-214778 treated groups compared to placebo. For the earliest times at which salivary melatonin concentrations exceeded or were equal to 3.0 pg/mL (Dim Light Melatonin Onset, or DLMO), the BMS-214778 treated subjects tended to have an earlier occurrence relative to baseline compared to placebo treated subjects. Median Time of Dim Light Melatonin Onset during Evening Administration of 1, 10, 50 or 150 mg BMS-214778 or Placebo for 28 Consecutive Days CONCLUSIONS: • • • 1.3 The Cmax values appeared to increase essentially proportional to the dose upto 150 mg. AUC(tau) appeared to increase approximately proportionally to dose up to 50 mg and more than proportionally from 50 to 150 mg. The half- life was approximately 2 h. Steady state was achieved by Day 15. The accumulation index at steady state ranged from 1.22 to 2.22. Salivary melatonin concentrations increased with increase in tasimelteon doses when compared to placebo. Dim Light Melatonin Onset was earlier in tasimelteon treated subjects in most cases relative to baseline when compared to placebo treated subjects. CNN116-003: Comparison of the Pharmacokinetics of SingleDoses of BMS-214778 in Young and Elderly Subjects Objectives: 52 Reference ID: 3403865 To assess the effects of age and gender on the pharmacokinetics of a single oral dose of 50 mg BMS-214778. The second objective was to assess the safety and tolerance profile of BMS214778 in young and elderly healthy subjects of both sexes. The third objective was to assess the effects of a single dose of BMS-214778 on subjective sleepiness and cognition in young and elderly subjects of both sexes. Study Design This was a double-blind, placebo-controlled, parallel group, 2 period crossover study designed to assess the effects of age and gender on the pharmacokinetics, safety and tolerability profile and pharmacodynamics of a single oral dose of 50 mg BMS-214778. Administration of the 2 treatments was separated by 7 days. Study Population Healthy: Adult male and female and elderly male and female Ten (10) subjects were enrolled into each of the following 4 parallel groups: healthy young men, age 18 to 45 years; healthy young women, age 18 to 45 years; healthy elderly men, age 65 years or older; and healthy elderly women, age 65 years or older. BMI: 18 to 35 kg/m2. Forty subjects were enrolled and 40 completed the study Sampling: A 7-ml venous blood sample was obtained in a K3EDTA tube for plasma for pharmacokinetic analysis at the times relative to study drug administration on Day 1 of Study Periods 1 and 2 at predose and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours after dosing. Analysis The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Statistical Methods Quality Control Samples 0.5, 50, 80 and 500 ng/mL 3.3% to 4.9% Standard Curve Samples 0.1, 0.25, 1, 10, 30, 70 and 100 ng/mL 1.9 to 4.0 -2.1% to 1.0%. -5.7 to 5.1 Weighted linear equation (1/X2), mean r= 0.998 0.1 to 100 ng/mL 0.1 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Comparison of the pharmacokinetic parameters Cmax and AUC(inf) for tasimelteon between gender and age group was done using an analysis of variance (ANOVA) model with gender, age group, and gender × age group as 53 Reference ID: 3403865 the classification variables, using the natural logarithms of the data. Confidence intervals (CI) (90%) were constructed for the geometric mean ratios (GMR) male-to-female and young-to-elderly of both parameters using the log transformed data and the two one-sided t-tests procedure. The GMRs and CIs were exponentiated back to the original scale. RESULTS: Following table summarizes PK parameters of tasimelteon following single 50 mg dose in young and elderly subjects. Summary of pharmacokinetic parameters for tasimelteon after oral administration of single 50 mg doses to young and elderly healthy male and female subjects. Gender Parameter* Males Females Age Young Cmax (ng/mL) Tmax (h) AUC(inf) (h×ng/mL) t½ (h) 261 ± 104 (10) 1.00 (10) [0.50 2.00] 697 ± 303 (10) 2.79 ± 1.81 (10) Elderly Cmax (ng/mL) 604 ± 269 (10) Tmax (h) 0.50 (10) [0.50 – 1.00] AUC(inf)(h×ng/mL) 1,429 ± 1,200 (10) t½ (h) 2.99 ± 1.34 (10) 426 ± 254 (10) 0.88 (10) [0.50 - 1.00] 920 ± 534 (10) 3.44 ± 2.11 (10) 601 ± 266 (10) 0.75 (10) [0.50 – 1.00] 1,466 ± 755 (10) 3.30 ± 0.52 (10) * Arithmetic mean ± standard deviation (N) except Tmax for which the median (N) is reported Following table summarizes statistical comparisons of tasimelteon PK parameters.! Statistical comparison of pharmacokinetic parameters for tasimelteon after oral administration of single 50 mg doses to young and elderly healthy male and female subjects. Parameter Geometric Mean Ratio (%) Estimate 90% Confidence Interval 54 Reference ID: 3403865 Males vs Fennles Cmax 81.52 63.78 - 104.20 AUC(int) 83.58 61.65 - 113.32 Elderly vs. Young Cmax 182.55 142.82 - 233.34 169.94 125.34 - 230.40 Note: Arithmetic mean comparisons show greater differences in mean PK parameters when compared to geometric means because of large variability in PK parameters. Following ?glu?e illustrates frequency distribution data for males and females 5000- 3 4000- 3000- 5 n. .E 2000- 0 1000 gel\be' CONCLUSIONS: 0 The max and AUC were about 63% and 32% higher respectively in young females when compared to yomig males. 0 There were no apparent difference was seen between elderly males and elderly females. 0 The max and AUC was higher in elderly subjects when compared to young subjects by approximately 2-fold respectively. 1.4 Phase I, Open Label, Single-Center Study of the Absorption, Metabolism and Excretion of VEC-162 in Healthy Male Subjects Objectives: Reference ID: 3403865 • • To investigate the absorption, metabolic profile and excretion of [14C]-VEC-162 in healthy male subjects following a single oral administration of 100 mg VEC-162 labeled with approximately 100 μCi of 14C. To identify and characterize the metabolite profile of [14C]-VEC-162 in humans. Study Design Study Population Sampling: Analysis This was an open-label, 9-day, inpatient, single-center study. Six healthy male subjects were enrolled. CYP2C9, CYP2D6, and CYP1A2 genotyping samples were collected for all subjects Healthy males Age: 18-50 years BMI: 18 to 35 kg/m2. Six subjects were enrolled and 6 completed the study Blood samples for the determination of VEC-162 in plasma were taken for each subject before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 16, 24, 48, 72, 96, 120, 144 and 168 hours after dosing. Pooled urine samples were collected for 0-6, 6-12, 12- 24, 24-48, 48-72, 7296, 96-120, 120- 144, 144-168, 168-192 hours to determine concentration of tasimelteon and total radioactivity. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) Quality Control Samples 0.3, 45, and 90 ng/mL 5.9 to 11.6 Standard Curve Samples 0.1, 0.3, 1, 3, 10, 30, 60 and 100 ng/mL 3.0 to 12.4 -8.0 to -2.9 -2.7 to 2.4 Weighted linear equation (1/X2), mean r= 0.991 0.1 to 100 ng/mL 0.1 ng/mL The urine samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Accuracy (%RE) Linearity Quality Control Samples 3, 45, and 90 ng/mL Standard Curve Samples 1, 3, 10, 30, 60, 80 and 100 ng/mL -8.0 to -2.9 -6.4 to 4.5 Weighted linear equation (1/X2), mean r= 0.998 56 Reference ID: 3403865 Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods 0.1 to 100 ng/mL 0.1 ng/mL Serial PK blood samples were drawn predose and postdose through discharge. All urine and feces were collected during the study and analyzed for total radioactivity. Metabolite Radioprofiling and Identification: Metabolite elucidation /identification was performed in plasma, urine, and feces. Plasma and urine samples were each pooled for metabolic profiling. Metabolites were identified in all 3 matrices. Metabolic profiles for plasma and/or urine samples were generated for individual subjects and for pooled samples. Safety assessments included physical examinations, vital signs (systolic/diastolic blood pressure, pulse rate, respiration rate, and oral body temperature), clinical laboratory tests (hematology, chemistry, and urinalysis), 12-lead electrocardiograms, and reported or observed adverse events. The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. The urine and feces, collected during the course of the study were analyzed for total radioactivity. RESULTS: A summary of mean PK parameters for VEC-162 in plasma, and total radioactivity in plasma and whole blood, is presented below. Summary of mean (SD) a pharmacokinetic parameters in plasma and whole blood Mean Plasma Concentration versus Time Profile for VEC-162 and Total Radioactivity 57 Reference ID: 3403865 A summary of mean recovery parameters for VEC-162 in urine and total radioactivity in urine and feces is presented below. Table: Summary of mean (SD) pharmacokinetic parameters in urine and feces Metabolite Radioprofiling and Identification: In addition to the unchanged tasimelteon, 8 metabolites were identified. M3 was characterized as an aryl glucuronide of phenolic VEC-162. M9 was identified as a phenol-carboxylic acid derivative of VEC-162. M11 was proposed to be hydroxy-phenol VEC-162. M8 was identified a glucuronide of M11. M12 and M14 were α and β-isomers of 7-hydroxy VEC-162. M13 was identified as 8-hydroxy VEC 16. M1 was identified as 8-O-glucuronide of VEC-162. The major metabolic routes of VEC-162 in humans were oxidation at multiple sites and oxidative dealkylation resulting opening of the furan ring (O-dealkylation), followed by further oxidation to give carboxylic acid. Glucuronidation was the major Phase II metabolic route. Summary of [14C]-VEC-162 and Metabolites in Human Plasma, Urine, and Feces 58 Reference ID: 3403865 Plasma AUC values for total radioactivity were higher than those for whole blood, indicating no uptake of total radioactivity into red blood cells. Proposed metabolic pathway for tasimelteon based on human liver microsomes studies 59 Reference ID: 3403865 CONCLUSIONS:    1.5 Recovery of total radioactivity in urine and feces combined was 84.1%. Plasma exposure to tasimelteon (as measured by Cmax and AUC values) was 10- to 15fold lower than exposure to total radioactivity. Tasimelteon is highly metabolized following absorption after oral administration. Less than 1% of the administered tasimelteon dose was recovered unchanged in urine. VP-VEC-162-1103: A double-blind, randomized, crossover trial to define the ECG effects of VEC-162 using a clinical and a supratherapeutic dose compared to placebo and moxifloxacin (a positive control) in healthy men and women: a thorough ECG trial. Objectives:  To characterize the effect of 20 and 300 mg/day of VEC-162 on QT intervals in healthy volunteers 60 Reference ID: 3403865  To assess the pharmacokinetic-pharmacodynamic (PK/PD) relationship between plasma concentrations of VEC-162 and its effect, if any, on electrocardiogram (ECG) parameters Study Design Study Population Sampling: Analysis This was a 4-period, randomized, double-blind (except for the use of moxifloxacin), multiple-dose, crossover study in healthy men and women. Forty-four subjects were enrolled with the intention that at least 40 subjects complete the study. Healthy male and female subjects (22 females, 22 males) Age: 18-45 years BMI: 18 to 35 kg/m2. Blood samples for the determination of VEC-162 in plasma were taken for each subject on Day 3 of each treatment period. The PK plasma samples were collected after the last ECG replicate for that time point before dosing (trough level) and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18 and 23.5 hours after dosing The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods Quality Control Samples 0.3, 45, and 90 ng/mL 10.8 to 6.9 Standard Curve Samples 0.1, 0.3, 1, 3, 10, 30, 60 and 100 ng/mL 4.9 to 6.3 -4.7 to -1.6 -4.0 to 2.3 Weighted linear equation (1/X2), mean r= 0.996 0.1 to 100 ng/mL 0.1 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. The safety of VEC-162 was assessed by: adverse events (AEs), clinical laboratory tests, vital signs, physical examinations, and single, standard, digital 12-lead ECGs. The safety population consisted of all subjects who received at least one dose of any study treatment. The PK population included all subjects who received at least one VEC-162 treatment and had evaluable PK data. The PD (ECG) population consisted of all subjects who received at least one dose of any study treatment and had evaluable ECG data. Descriptive statistics included the number of subjects, mean, standard deviation, median, minimum, and maximum. Percentages were calculated using the number of subjects within each treatment as the denominator. Summary tables present descriptive statistics and/or frequency by treatment. Descriptive statistics were calculated for age, weight, height, and body mass index. Frequency counts were tabulated for gender, race, and ethnicity. 61 Reference ID: 3403865 RESULTS: Following figure illustrates PK profile of tasimelteon in healthy subjects following 20 mg and 300 mg dose. Mean Plasma Concentrations of VEC-162 versus Time by Treatment Mean Pharmacokinetic Parameters for VEC-162 by Treatment 20 mg (N = 43) 300 mg (N = 43) Pharmacokinetic parameter (units) n AUC0-t (ng·h/mL) 43 396.4 (182.3) 43 10609.8 (5780.2) AUC0-tau (ng·h/mL) 43 396.8 (182.3) 43 10609.8 (5780.2) AUC0-inf (ng·h/mL) 30 438.5 (177.0) 43 10641.4 (5841.7) Cmax (ng/mL) 43 194.6 (82.7) 43 2491.5 (1058.3) Tmax (h) 43 0.58 (0.58, 1.08) 43 1.08 (0.58, 3.08) T1/2(h) 30 2.34 (1.48) 43 2.68 (0.85) CL/F (L/h) 43 64.4 (37.1) 43 39.9 (28.0) Vd/F (L) 30 172.2 (121.6) 43 162.3 (151.9) a n PHARMACOKINETIC RESULTS: 62 Reference ID: 3403865 Following daily oral dosing for three days, mean AUCs and Cmax of VEC-162 increased with increasing the dose from 20 mg/day to 300 mg/day for three days. The increase was greater than dose proportional for AUCs, while Cmax appeared to increase proportionally with increasing dose. The apparent clearance was lower in the 300-mg dose group. Tmax reached approximately 0.6 hours to 1.1 hours after dosing. The mean half-life for both doses ranged from 2.3 hours to 2.7 hours. PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIP The PK/PD model showed the slopes for QTcI and QTcF were negative (-0.0015 for both). The predicted QTc and QTcF changes at Cmax resulted in negative slopes (-3.1171 and -3.0999, respectively). The data shows that tasimelteon did not produce a significant QTc prolongation effect in healthy subjects who received 20 mg and 300 mg tasimelteon (supratherapeutic dose). Figure: QTcI Change From Baseline Versus VEC-162 Concentration Note: A separate review of QTc data with respect to tasimelteon concentrations will be reviewed as a part of QT-IRT review. CONCLUSIONS: • The increase in tasimelteon overall (AUC) exposure from 20 mg to 300 mg was not doseproportional. The mean Cmax concentration increase was less than proportional for 20 mg and 300 mg. 63 Reference ID: 3403865 • The apparent clearance was lower in the 300-mg dose group. The mean half-life ranged from 2.3 hours to 2.7 hours. 1.6 VP-VEC-162-1106: An Open-Label, Single-Dose, Parallel-Group Study to Compare the Pharmacokinetics of Tasimelteon in Subjects with Renal Impairment With That in Matched Control Subjects with Relatively Normal Renal Function Objectives: Primary: To assess plasma concentrations and pharmacokinetics (PK) of tasimelteon in subjects with severe renal impairment including subjects on dialysis compared to healthy subjects with normal renal function. Secondary:  To assess plasma concentrations, PK and the percent protein binding of tasimelteon Metabolites M3, M9, M11, M12, M13, and M14 in subjects with severe renal impairment including subjects on dialysis compared to healthy subjects with normal renal function.  To assess the effects of hemodialysis on the PK of tasimelteon and its metabolites.  To assess the safety and tolerability of a single 20-mg oral dose of tasimelteon. Study Design Study Population Sampling: Analysis This study was an open-label, parallel-group design. Thirty-two subjects were enrolled in 3 groups:  Group 1 consisted of 8 subjects with end stage renal disease (ESRD) requiring dialysis;  Group 2 consisted of 8 subjects with severe (Stage 4) renal impairment;  Group 3 consisted of 16 healthy subjects with normal renal function matched by gender, age, body mass index (BMI), and smoking status to Groups 1 or 2. Healthy subjects and patients with renal impairment (22 male and 10 female) Age: 18-79 years BMI: 18 to 40 kg/m2. Thirty two subjects were enrolled and 32 completed the study. Plasma PK samples were collected at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30, and 36 hours after dosing. At the 0.5 and 3 hours post-dose blood draw, an additional 3 mL of blood was collected for protein binding measurements. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control Samples Standard Curve Samples 64 Reference ID: 3403865 Quality Control or Standard Curve Concentration (ng/mL) 0.9, 135, and 270 ng/mL Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity 2.6% to 4.3% 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 2.3 to 5.6 -9.3% to 4.3% -9.3 to 4.7 Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods Weighted linear equation (1/X2), mean r= 0.998 0.3 to 300 ng/mL 0.3 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Comparison of the pharmacokinetic parameters was done by analysis of variance. Safety was assessed by adverse event (AE) and serious adverse event (SAE) monitoring, changes in clinical laboratory parameters that were relevant to safety. Influence of trial medication on vital signs and electrocardiogram (ECG) parameters. Pharmacokinetic: Comparison of the pharmacokinetic parameters Cmax, AUC(0-t), AUC(inf), and t½ for tasimelteon and metabolites and CL/F and Vz/F for tasimelteon between groups - ESRD and matching controls or severe impairment and matching controls - was done using an analysis of variance (ANOVA) model with renal function group as the classification variable, using the natural logarithms of the data. Confidence intervals (CI) (90%) were constructed for the ratios of ESRD-to-control or severe impairment-to-control subjects of all applicable parameters using the log transformed data and the two one-sided ttests procedure. The point estimates and CIs were exponentiated back to the original scale. Relationships between individual subject tasimelteon CL/F and Creatinine Clearance and between the individual subject tasimelteon CL/F and estimated glomerular filtration rate were examined graphically for subjects with ESRD, subjects with severe impairment, and matched controls. Individual subject tasimelteon t½ was also examined by renal function group. RESULTS: Following figure illustrates PK profile of tasimelteon in healthy subjects and in subjects with renal impairment. Mean Plasma Concentrations of Tasimelteon After Oral Administration of Single 20 Mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment, and Matched Controls 65 Reference ID: 3403865 ESRD Controls for ESRD (?nnc (ngmL) Severe Impainnent Controls for Severe Impairment Summary of Pharmacokinetic Parameters for Tasimelteon after Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment, and Matched Controls. ESRD Severe Impairment Parameter" Patients Controls Patients Controls Cmax (ng/mL) 197:1: 121 (8) 197i 75.8 (8) 255 142(8) 1761933 (8) Tmax 0.50 (8) 0.50 (8) 0.50 (8) 0.50 (8) (h.ng/mL209 (8) (h.ng/mL209 (8) 212 0.2934 0.2196 (7) 0.5617 0.2009 (8) 0.3517 0.1446 (8) 0.5302 0.1471 (8) 1mm) 340$ 1.77 (7) 13910.53 (8) 2.32 :t 1.01 (8) 14210.49 (8) CL/F(mL/min) 1.417s 1.024(7) 1.556i 1633(8) 1.075i814 (8) 1.561 :t 1.545(8) (L) 3991-430 (7) 149:1: 101 (8) 188: 149(8) 161:1: 113(8) Statistical Comparison of Phannacokinetic Parameters for Tasimelteon after Oral Administration of Single 20 Mg Doses of Tasimelteon to Subjects with ESRD, Subjects With Severe Impairment, and Matched Controls. ESRD vs. Matched Controls Severe Inpaimrnt vs. Matched Controls Geometric Mean Ratio Geometric Mean Ratio Paranrter Estimate 90% Con?dence Interval Estirmte 90% Con?dence Interval 95.66 59.94 152.69 143.22 84.47 242.83 92.61 44.43 193.03 141.97 67.28 299.57 AUC(int) 1022.3 47.45 220.29 141.80 67.36 298.49 IV: 221.54 137.07 358.04 157.19 112.84 218.96 97.82 45.40 210.77 70.52 33.50 148.45 V211: 216.70 107.56 436.55 110.85 60.86 201.90 Reference ID: 3403865 66 Relationship Between the Individual Subject Tasimelteon and reatinine Clearance After Oral Administration of Single 20 Mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment, and Matched Controls. 6000 5000 4000 3000 JF (ml min) 2000 160 (?Let (mL/min) ESRD A Severe Impairment 0 Controls for ESRD A Controls for Severe Impairment The mean protein binding for tasimelteon in this study was 89.7% in ESRD patients, 90.0% in patients with severe impairment and 88.6% and 90.1% for the respective matched healthy controls. Metabolite M12 ESRD Severe Impairment Parameter" Patients Controls Patients Controls Cmax (ng/mL) 91.0 :t 29.6 (8) 96.7 i 27.6 (8) 120 i 68.3 (8) 85.4 16.7 (8) Tmax 1.25 (8) 1.25 (8) 1.25 (8) 1.25 (8) (hxng/mL211 (8) AUC(inf) (hxng/mL211 (8) 0.2344 :t 0.1188(8) 0.1781 i 0.0726(8) 0.2252 i 0.0921 22 t1/2 0.2259 i 0.1331 (8) 4.08 :t 2.12 (8) 3.45 i 1.29 (8) 4.54 1.98 (8) 3.46 1.08 (8) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M12 After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment, and Matched Controls. Reference ID: 3403865 ESRD vs. Matched Controls Severe vs. Matched Controls Ctonrtric Mean Ratio? Geonrtric Mean Ratio? Paranrter Estinnte 90% Con?dence Interval Estinnte 90% Con?dence Interval 93.30 70.96 122.67 127.86 92.10 177.53 82.64 54.43 125.45 138.10 88.80 214.75 AUC(int) 83.49 54.87 12704 139.81 89.01 219.62 t?/z 110.58 70.80 172.73 127.83 90.29 180.98 67 Metabolite M13 Summary of Pliarmacokinetic Parameters for Metabolite Ml3 After Administration of Single 20 mg Doses of Iasimelteon to Subjects with ESRD, Subjects with Severe Impairment. and Matched Controls. ESRD Severe Impairment Pararmeter* Patients Controls Patients Controls Cmax?ng2'n1L} 235 2 20.2 (3) 213 30.3 (3) 292 2 122 (3) 239: 39.2 (3) Tues (11) 0.50 (3) 0.50 (3) 0.50 (3) 0. 25 (3) (1an g2n1L} 304 2 33.3 (3) 295 21141 (3) 20:30:11) 308 i 90.8 (8) 299 21142 (8) 2.2121511) 0.6286 3: 0.3243 (8) 0.6243 3: 0.4024 (8) 0.4301 3: 0.1421 0.5243 3: 0.2483 (8) 0201) 1.41 20.23 (3) 1.3120.54(3) 1.332 0.32 (3) 1.3220.50(3) DSitarithmetic mean :t standard deviation (N) except Tum for which the median (N) is reported. Statistical Comparison of Pharmacokinetic Parameters for Metabolite Ml3After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment, and Matched Controls. ESRD vs. Matched Controls Severe Impairment vs. Matched Controls Geometric Mean Ratio Geometric Mean Ratio Parameter Estimate 90% Con?dence Interval Estimate 90% Con?dence Interval Cmax 109.33 30.46 150.05 102.92 63.29 ?2 132.56 102.2? 29.61 131.3? 92.61 65.32 ?2 145.36 102.06 29.30 131.35 93.02 65.32 145.93 112': 106.2? 66.91 120.3? 132.26 94.53 135.04 *Based on analysis of natural log-transformed parameters. Metabolite M9 Summary of Pharmacokinelic Parameters for Metabolite M9 After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD. Subjects with Severe Impairment, and Matched Controls. ESRD Severe Impairment Parameter? Patients Controls Patients Controls Cmax (mg mL} 325 10418} 194: 104 (31 313 122 162 50.8 Tmax {11) 1.25 0.50 (81 1.00 (8) 0.25 111D 3.335 60313} 312 91.? 1.422 49? (3) 301: 214.9(3) AUCIiinf) (hxng 111D 3.599 636 318 91.5 (81 1.443 3: 496 (8) 305 45. 2 20:11 11} 0.0246 0.0243 (31 0.512." 0.1226 (3) 0.2343 0.0323 0.4341 0.1363 tix?: (11} 9.92 2.21 1.51: 0.56 3.32 1.15 1.53 2 0.41 Statistical Comparison of Pharmacokinetic Parameters for Metabolite 319 After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects With ESRD, Subjects with Severe Impairment. and Matched Controls. ESRD vs. Matched Controls Severe Impairment vs. Matched Controls Geometric Mean Ratio (933* Geometrie Mean Ratio Parameter Estimate 90% Con?dence Interval Estimate 90% Con?dence Interval Cnex 222.40 141.63 349.24 182.85 133.60 250.22 1099.36 828.50 1325.26 455.92 362.42 523.68 1160.92 930.63 1,443.20 455.35 362.60 521.34 t'v'i 626.04 512.51 891.26 212.24 159.54 232.36 Reference ID: 3403865 Metabolite M1 1 Summary of Pharmacokinetic Parameters for Metabolite After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment. and Matched Controls. ESRD Severe In'pairnient Paramete?? Patients Controls Patients Controls Cmax 35.9 5.53 (3) 30.0 4.19 (3) 39.5 13.4 (3) 40.1: 14. 3 (3) T111ax 1.50 (3) 1.00 (3) 1.00 (3) 1.25 (3) 131 46.3 (3) 94.3 23.2 (3) 160: 110 (3) 123 3: 53.3 (3) AUCtinf) 135 31.2 (4) 1013: 32.5 (6) 123 3: 53.1 (3) 133 61.9 (3) 7:2(1711) 0.1269 0.0974 (4) 0.4296: 0.2063 (6) 0.2452 0.1829 (7) 0.3835 0.1142 (7) 11/301) 333: 6.09 (4) 1.33 0.53 (6) 4.35 2.93 (3) 1.96: 0.61 (3) *Aritlirnetic mean :t standard :1 eviation (N) except me for which the median (N) is reported. Statistical Comparison of Pharmacokinetic Parameters for Metabolite Ml 1 After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD. Subjects with Severe Impairment, and Matched Controls. ESRD vs. Matched Controls Severe Inpairment vs. Matched Controls Geometric Mean Ratio Geonrtric Mean Ratio Parameter Estimate 90% Con?dence Interval Estimate 90% Con?dence Interval 119.32 104.41 136.36 97.10 69.09 136.45 136.70 101.94 133.30 114.48 73.66 177.91 130.12 124.74 260.11 97.13 65.18 144.73 11/: 392.09 199.69 769.37 187.79 110.34 313.16 *Based on analysis of natural log?transformed parameters. Metabolite M14 Summalj' of Pharmacokinetic Parameters for Metabolite Ml4 After Oral Administration of Single 20 mg Doses of Tasimelteon to Subjects with ESRD. Subjects with Severe Impairment, and Matched Controls. [h 7.2 (1711) W: 13.33: 14.0 (3) 0.46433: 0.2053 (3) 1.393: 1.11 (3) 19.5 314.1 (6) 0.5423 3: 0.4433 (6) 2.033: 166(6) ESRD Severe Inpairment Parameter* Patients Controls Patients Controls Cnnx?ngs'mL) 5.173: 1.53 5273:332 (3) 7.043: 3.17 (3) 4.15 3:212 (3) Turn; 0.52 (3) 0.50 (8) 0.50 (3) 1.00 (3) 15.4 3: 12.0 (3) 14.3 3: 9.33 (3) 23.3 3: 23.1 (3) 13.3 3: 10.5 (3) 30.13 24.4 (3) 3.033: 1.90 (3) 0.2933 3: 0.1533 (3) 15.43: 11.0(3) 03634301431 (3) 2.11 3:0.63 (3) *Arithmetic mean :t standard leviation (N) except me for which the median (N) is reported. Statistical Comparison of Pharmacokinetic Parameters for Metabolite Ml4 After Oral Administration of single 20 mg Doses of Tasimelteon to Subjects with ESRD, Subjects with Severe Impairment, and Matched Controls. ESRD vs. Matched Controls Severe Itrpairn?ent vs. Matched Controls Geometric Mean Ratio Geometric Mean Ratio Parameter Estimate 90% Con?dence Interval Estimate 90% Con?dence Interval C'Imx 109.09 69.89 ?9 170.23 177.47 1 13.51 265.78 AUCKCLI) 105.03 55.97 197.1 1 202.28 109.78 3 72.73 100.67 43.52 203.86 190.61 106.09 342.46 t1/2 101.97 53.34 194.95 132.95 87.3 7 202.30 *Based on analysis of natural log?transformed parameters. Metabolite M3 Reference ID: 3403865 69 Metabolites M3 and M9 are dialyzable. Tasimelteon, M11, M12, and M14 are dialyzable but to a lesser extent. However M13 was not removed by hemodialysis. There were no changes in plasma protein binding in RI subjects when compared to healthy controls. Renal impairment does not affect the protein binding of tasimelteon, M9, M11, M12, and M13. Reviewer’s Comment: The difference between ESRD subjects and subjects with severe renal impairment may be a may be due to small sample size. CONCLUSIONS:    Subjects with severe impairment had, on average, a 30% lower CL/F. Subjects with ESRD had a comparable CL/F with a GMR of 97.8%. Mean plasma concentrations and arithmetic mean values for Cmax and AUC (inf) were comparable with a large variability characterized by wide 90%CIs. Plasma protein binding in severe RI patients and ESRD patients was similar to matched controls. 70 Reference ID: 3403865 1.7 VP-VEC-162-1105: An Open-Label, Single-Dose, Parallel-Group Study to Compare the Pharmacokinetics of Tasimelteon in Subjects with Mild or Moderate Hepatic Impairment with that in Matched Healthy Control Subjects. Objectives: To assess plasma concentrations and pharmacokinetics (PK) of tasimelteon and its major metabolites in subjects with mild or moderate hepatic impairment compared to healthy subjects with normal hepatic function. Study Design Study Population Sampling: Analysis The study employed an open-label, parallel-group design. Twenty-nine subjects were enrolled in 3 groups: Group 1 consisted of 8 subjects with mild hepatic impairment; Group 2 consisted of 8 subjects with moderate hepatic impairment; and Group 3 consisted of 13 healthy subjects matched by gender, age, smoking status, and body mass index (BMI), to Groups 1 and/or 2. Healthy subjects and patients with hepatic impairment (23 male and 6 female) Age: 45-62 years BMI: 18 to 35 kg/m2. Thirty two subjects were enrolled and 32 completed the study. Plasma PK samples were collected at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours after dosing. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Quality Control Samples 0.9, 135, and 270 ng/mL 2.3% to 11.4% Standard Curve Samples 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 1.9 to 4.0 -6.4% to 3.2%. -5.7 to 5.1 Weighted linear equation (1/X2), mean r= 0.998 0.3 to 300 ng/mL 0.3 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Comparison of the pharmacokinetic parameters was done by analysis of variance. Safety was assessed by adverse event (AE) and serious adverse event (SAE) monitoring. Changes in clinical laboratory parameters that were relevant to safety. Influence of trial medication on vital signs and electrocardiogram (ECG) parameters. 71 Reference ID: 3403865 Statistical Methods Pharmacokinetic: Plasma concentration-time data for tasimelteon, M9, M11, M12, M13, and M14 were presented in descriptive summary tables, individual listings, mean profile plots, and individual profile plots, on linear and semi-logarithmic axes. Semi-logarithmic graphs of individual subject concentration versus time include a line segment indicating the range of data used to estimate the elimination rate constant. Descriptive statistics (number of nonmissing observations [n], arithmetic mean, standard deviation [SD], coefficient of variation [CV%], geometric mean, geometric CV, median, minimum, and maximum) were presented for plasma concentrations. Below quantifiable limit (BQL) concentrations were treated as zero for descriptive statistics. Mean concentrations that were BQL were presented as BQL, and the SD and CV% were reported as not applicable. Descriptive summaries of PK parameters include n, arithmetic mean, SD, CV%, median, minimum and maximum values. The Tmax was summarized only with n, mean, SD, CV%, median, minimum, and maximum. RESULTS: Following figure illustrates PK profile of tasimelteon in healthy subjects and in subjects with hepatic impairment. Arithmetic Mean Plasma Concentrations of Tasimelteon After Oral Administration of 20 mg Tasimelteon to Subjects With Mild (top panel) or Moderate Hepatic Impairment (bottom panel) and Healthy Matched Controls 72 Reference ID: 3403865 Summary of pharmacokinetic parameters for tasimelteon after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. Parameter* Cmax (ng/mL) Tmax (h) AUC(0-t) (h×ng/mL) AUC(inf) (h×ng/mL) λz (h-1) t1/2 (h) CL/F (mL/min) Vz/F (L) Mild Hepatic Impairment Patients Controls 366 ± 182 (8) 0.50 ( 8) [0.25 – 1.00] 556 ± 400 (8) 560 ± 401 (8) 0.4593 ± 0.2679 ( 8 1.84 ± 0.73 (8) ) 850 ± 521 (8) 118 ± 58.5 (8) 272 ± 58.8 ( 8) 0.50 ( 8) [0.25 – 1.00] 357 ± 124 (8) 358 ± 124 (8) 0.5523 ± 0.1265 ( 8 1.31 ± 0.27 (8) ) 1,128 ± 709 (8) 117 ± 44.1 (8) Moderate Hepatic Impairment Patients Controls 381 ± 289 ( 8) 0.50 ( 8) [0.25 – 1.00] 880 ± 966 (8) 893 ± 990 (8) 0.3819 ± 0.1732 ( 8 2.17 ± 1.07 (8) ) 721 ± 505 (8) 107 ± 58.3 (8) 284 ± 109.8 (8) 0.38 ( 8) [0.25 – 0.58] 332 ± 195 (8) 334 ± 195 (8) 0.5556 ± 0.1442 ( 8 1.32 ± 0.34 ( 8)) 1,318 ± 744 (8) 137 ± 51.6 (8) Statistical comparison of pharmacokinetic parameters for tasimelteon after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. 73 Reference ID: 3403865 Metabolite M12 Summary of pharmacokinetic parameters for Metabolite M12 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. Statistical comparison of pharmacokinetic parameters for Metabolite M12 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and 74 Reference ID: 3403865 healthy matched controls. Metabolite M13 Summary of pharmacokinetic parameters for Metabolite M13 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. Statistical comparison of pharmacokinetic parameters for Metabolite M13 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. 75 Reference ID: 3403865 Metabolite M14 Summary of pharmacokinetic parameters for Metabolite M14 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. Statistical comparison of pharmacokinetic parameters for Metabolite M14 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and 76 Reference ID: 3403865 healthy matched controls. Metabolite M9 Summary of pharmacokinetic parameters for Metabolite M9 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. Statistical comparison of pharmacokinetic parameters for Metabolite M9 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. 77 Reference ID: 3403865 Metabolite M11 Summary of pharmacokinetic parameters for Metabolite M11 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. ! Statistical comparison of pharmacokinetic parameters for Metabolite M11 after oral administration of 20 mg of tasimelteon to subjects with mild or moderate hepatic impairment and healthy matched controls. 78 Reference ID: 3403865 Note: Based on IC50 and Ki, the rank order of potency for human melatonin receptors MT1 and MT2 was tasimelteon followed by M13, M11 and M9, with consistent higher potency for MT2. Potency of tasimelteon and metabolites M9, M11, and M13 for human melatonin MT1 and MT2 receptors MT1 receptor: The potency of M13 compared to tasimelteon was 13 fold lower, M11 was 820 fold lower. MT2 receptor: The potency of M13 compared to tasimelteon was 13 fold lower, M11 was 50 fold lower and M9 was a 1000 fold lower. CONCLUSIONS:    1.8 The overall exposure (AUC) of tasimelteon increased by 43% and 90% in patients with mild and moderate HI respectively. Whereas, increase in Cmax was about 20% in both mild and moderate HI when compared to healthy subjects. The overall exposure (AUC) to metabolites (M9, M11 and M13) of tasimelteon decreased in mild and moderate HI by 6% to 30%. With an exception to Metabolite 14, where-in AUC increased by 2 fold in moderate HI. The maximum concentration of tasimelteon metabolites (M9, M11, M13 and M14) (Cmax) decreased in mild and moderate HI by 10% to 60%. With an exception to Metabolite 14, the AUC increase was 2 fold in moderate HI. VP-VEC-162-1111: An open-label, single-sequence study in healthy subjects to evaluate the single-dose pharmacokinetics of 79 Reference ID: 3403865 tasimelteon alone and in combination with a CYP1A2 inhibitor, fluvoxamine. Objectives:  To evaluate the single-dose pharmacokinetics (PK) of tasimelteon 5 mg alone and in combination with a CYP1A2 inhibitor, fluvoxamine, at steady state.  To evaluate the single-dose pharmacokinetics of tasimelteon metabolites (M9, M11, M12, M13, and M14) alone and in combination with a CYP1A2 inhibitor, fluvoxamine, at steady state. Study Design Study Population Duration of Treatment Sampling: Analysis This was an open-label, single-sequence study conducted at one site. Healthy male and female subjects Age: 18-55 years BMI: 18 to 35 kg/m2. Twenty four subjects were enrolled and 24 completed the study. A single-sequence of the following treatments:  Single oral dose of tasimelteon 5 mg on Day 1  Six days of fluvoxamine 50 mg daily (QD) (Days 2- 7)  Single doses of tasimelteon 5 mg and fluvoxamine 50 mg on Day 8 Blood samples for determining drug concentration of tasimelteon and its metabolites were obtained for each subject as follows: Days 1 and 6: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12 and 24 hours post-dose Day 8 Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 12 and 24 hours postdose The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) Quality Control Samples 0.9, 135, and 270 ng/mL 1.6 to 2.6 Standard Curve Samples 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 2.9 to 4.3 2.5 to 3.9 -2.9 to 4.1 Weighted linear equation (1/X2), mean r= 0.998 0.3 to 300 ng/mL 0.3 ng/mL The plasma samples were analyzed for the concentration of fluvoxamine by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for fluvoxamine. Parameter Quality Control Standard Curve 80 Reference ID: 3403865 Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods Samples 0.5, 1.5, 75 and 375 ng/mL 4.1 to 16 Samples 0.5, 1, 5, 25, 50 100, 400 and 500 ng/mL 1.0 to 7.3 -3.8 to 5.2 -4.5 to 4.7 Weighted linear equation (1/X2), mean r= 0.997 0.5 to 500 ng/mL 0.5 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-12, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Comparison of the pharmacokinetic parameters was done by analysis of variance. Confidence intervals (CI) (90%) were constructed for the ratios of tasimelteon + fluvoxamine-to-tasimelteon alone of all applicable parameters using the log transformed data and the two one-sided t-tests procedure. The point estimates and CIs were exponentiated back to the original scale. Adverse event (AE) and serious adverse event (SAE) monitoring,  Changes in clinical laboratory parameters that were relevant to safety  Influence of trial medication on vital signs and electrocardiogram (ECG) parameters  The Columbia-Suicide Severity Rating Scale (C-SSRS) was used to assess suicidal behavior and ideation. Pharmacokinetic: The 90% confidence intervals (CI) of the geometric mean ratio of AUC0-∞ and Cmax values between the 2 treatments were calculated. The log-transformed data was analyzed using an analysis of variance model with factors for sequence, subjects within sequence, period, and treatment groups. The sequence effects were tested using the intersubject variation and differences between periods or treatments were compared using intrasubject variation estimated from the analysis of variance model. Note: Because of expected increase in exposure in the presence of fluvoxamine, tasimelteon dose evaluated in this study is 4 fold lower compared to the proposed prescription dose (20 mg). The pharmacokinetics of tasimelteon were dose-proportional and linear over the dose range of 3 mg to 300 mg. RESULTS: Following figure depicts PK profile of tasimelteon after oral administration of single 5 mg doses of tasimelteon alone and after dosing with fluvoxamine 50 mg QD × 6 days Figure: Mean Plasma Concentrations of Tasimelteon After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing with Fluvoxamine 50 mg QD × 6 days 81 Reference ID: 3403865 Following table represents PK parameters of tasimelteon alone or in combination with fluvoxamine. Summary of Pharmacokinetic Parameters for Tasimelteon After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD × 6 Days Statistical Comparison of Pharmacokinetic Parameters for Tasimelteon After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing with Fluvoxamine 50 mg QD × 6 Days Parameter* Geometric Mean Ratio (%)* Estimate 90% Confidence Interval 82 Reference ID: 3403865 Cmax 232.74 202.63, 267.33 AUC(0-t) 651.06 524.43, 808.28 AUC(inf) 653.36 527.12, 809.82 t1/2 211.82 194.07, 231.21 CL/F 15.31 12.35, 18.97 Vz/F 32.42 27.36, 38.41 Note: Fluvoxamine in addition to strongly inhibiting CYP1A2, fluvoxamine also strongly inhibits CYP2C19 and weakly inhibits CYP2C8, CYP2C9, and CYP3A4. Metabolite M12 Summary of Pharmacokinetic Parameters for Metabolite M12 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD x 6 Days Parameter Treatment Tasimelteon 5 mg Tasimelteon 5 mg + Fluvoxamine 50 mg 31.0 ± 7.23 (24) 30.8 ± 17.6 (24) 0.88 (24) 3.00 (24) AUC(0-t) (h · ng/mL) 183 ± 86.8 (24) 392 ± 86.1 (24) AUC(inf) (h · ng/mL) 189 ± 90.8 (23) 435 ± 109.3 (19) 0.2524 ± 0.0749 (23) 0.1220 ± 0.0579 (19) 3.03 ± 1.02 (23) 7.03 ± 3.27 (19) Cmax (ng/mL) Tmax (h) λZ (1/h) t1/2 (h) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M12 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD X 6 Days Parameter Geometric Mean Ratio (%) Estimate 90% Confidence Interval 92.74 81.10, 106.05 AUC(0-t) 229.24 205.19, 256.10 AUC(inf) 274.81 251.47, 300.31 t1/2 241.02 201.62, 288.12 Cmax 83 Reference ID: 3403865 Metabolite 13 Summary of Pharmacokinetic Parameters for Metabolite M13 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD X 6 Days Parameter Treatment Tasimelteon 5 mg Tasimelteon 5 mg + Fluvoxamine 50 mg 87.5 ± 24.4 (24) 63.6 ± 24.6 (24) 0.50 (24) 0.50 (24) AUC(0-t) (h · ng/mL) 104 ± 32.4 (24) 117 ± 28.7 (24) AUC(inf) (h · ng/mL) 106 ± 32.6 (24) 133 ± 32.9 (22) 0.7517 ± 0.2146 (24) 0.2172 ± 0.0693 (22) 1.00 ± 0.30 (24) 3.51 ± 1.18 (22) Cmax (ng/mL) Tmax (h) λZ (1/h) t1/2 (h) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M13 Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD X 6 Days Parameter Geometric Mean Ratio (%) Estimate 90% Confidence Interval 69.31 59.43, 80.84 AUC(0-t) 114.40 107.12, 122.18 AUC(inf) 125.05 118.94, 131.47 t1/2 349.81 322.81, 379.06 Cmax Metabolite 9 Summary of Pharmacokinetic Parameters for Metabolite M9 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD X 6 Days Parameter Cmax (ng/mL) Tmax (h) Treatment Tasimelteon 5 mg Tasimelteon 5 mg + Fluvoxamine 50 mg 67.6 ± 19.1 (24) 47.4 ± 24.2 (24) 0.50 (24) 0.75 (24) 84 Reference ID: 3403865 AUC(0-t) (h · ng/mL) 102 ± 30.0 (24) 113 ± 27.1 (24) AUC(inf) (h · ng/mL) 104 ± 30.0 (24) 126 ± 29.6 (23) 0.6465 ± 0.1748 (24) 0.2034 ± 0.0720 (23) 1.14 ± 0.29 (24) 3.83 ± 1.34 (23) λZ (1/h) t1/2 (h) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M9 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing with Fluvoxamine 50 mg QD X 6 Days Parameter Geometric Mean Ratio (%) Estimate 90% Confidence Interval 64.94 56.21, 75.01 AUC(0-t) 113.05 105.47, 121.16 AUC(inf) 122.56 115.33, 130.24 t1/2 328.02 294.95, 364.79 Cmax Metabolite 11 Summary of Pharmacokinetic Parameters for Metabolite M11 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD × 6 Days Statistical Comparison of Pharmacokinetic Parameters for Metabolite M11 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD × 6 Days Parameter Cmax Geometric Mean Ratio (%) Estimate 90% Confidence Interval 68.71 61.38, 76.93 85 Reference ID: 3403865 AUC(0-t) 115.01 106.96, 123.66 AUC(inf) 16.03 118.24, 134.33 248.35 215.41, 286.32 t1/2 Metabolite 14 Summary of Pharmacokinetic Parameters for Metabolite M14 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD X 6 Days Parameter Treatment Tasimelteon 5 mg Tasimelteon 5 mg + Fluvoxamine 50 mg 1.20 ± 0.40 (23) 3.20 ± 1.49 (24) 0.75 (23) 4.00 (24) AUC(0-t) (h · ng/mL) 2.67 ± 1.83 (23) 37.8 ± 26.1 (24) AUC(inf) (h · ng/mL) 4.54 ± 2.39 (17) 42.6 ± 27.3 (22) 0.3691 ± 0.1447 (17) 0.1620 ± 0.0669 (22) 2.18 ± 0.97 (17) 4.98 ± 1.89 (22) Cmax (ng/mL) Tmax (h) λZ (1/h) t1/2 (h) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M14 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD x 6 Days Parameter Geometric Mean Ratio (%) Estimate 90% Confidence Interval Cmax 264.58 227.03, 308.34 AUC(0-t) 1500.19 1119.93, 2009.55 AUC(inf) 944.73 684.71, 1303.49 t1/2 243.34 188.00, 314.99 Metabolite 3 Summary of Pharmacokinetic Parameters for Metabolite M3 After Oral Administration of Single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD × 6 Days 86 Reference ID: 3403865 Statistical Comparison of Pharmacokinetic Parameters for Metabolite M3 After Oral Administration of single 5 mg Doses of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg QD × 6 Days Parameter Geometric Mean Ratio (%) Estimate 90% Confidence Interval Cmax 62.53 50.58, 77.31 AUC(0-t) 90.14 84.06, 96.66 AUC(inf) 97.69 88.99, 107.24 154.31 125.64, 189.53 t1/2 CONCLUSIONS:  Inhibition of CYP1A2 by treatment with fluvoxamine 50 mg QD × 6 days resulted in an 85% decrease in tasimelteon CL/F leading to a 6.5-fold increase in exposure. There was a 2-fold increase in t1/2.  There was about 3-fold increase in exposure to Metabolite M12, and a 25% increase in Metabolite M13 which are formed from tasimelteon by CYP1A2.  There were relatively small changes in exposure to Metabolites M9 and M11, formed from M13 by CYP1A2.  There was about 9.5-fold increase in exposure to Metabolite M14. 1.9 VP-VEC-162-1112: An open-label, single-sequence study in two cohorts of healthy subjects to evaluate the single-dose pharmacokinetics of tasimelteon alone and in combination with a CYP3A4 inhibitor, ketoconazole, or a CYP3A4 inducer, rifampin. 87 Reference ID: 3403865 Objectives:  To evaluate the single-dose pharmacokinetics of tasimelteon 20 mg alone and in combination with a CYP3A4 inhibitor (ketoconazole) or CYP3A4 inducer (rifampin), at steady state.  To evaluate the single-dose pharmacokinetics of tasimelteon metabolites (M9, M11, M12, M13, and M14) alone and in combination with a CYP3A4 inhibitor or inducer, at steady state. Study Design Study Population Duration of Treatment Sampling: Analysis This study was an open-label, single-sequence study conducted at one site. In one Cohort of 24 subjects, the potential effect of administration of a potent CYP3A4 inhibitor, ketoconazole, on tasimelteon’s pharmacokinetics was evaluated. In the second Cohort of 24 healthy volunteers, the potential effect of administration of a potent CYP3A4 inducer, rifampin, on tasimelteon’s pharmacokinetics was evaluated. Healthy male and female subjects Age: 18-55 years BMI: 18 to 35 kg/m2. Forty eight subjects were and 47 completed the study. Cohort 1 Single oral dose of tasimelteon 20 mg on Day 1 Four days of ketoconazole 400 mg QD (Days 2- 5)  Single doses of tasimelteon 20 mg and ketoconazole 400 mg on Day 6 Cohort 2  Single oral dose of tasimelteon 20 mg on Day 1!!  Ten days of rifampin 600 mg QD (Days 2- 11)  Single dose of tasimelteon 20 mg on Day 12 Blood samples for determining drug concentration of tasimelteon and its metabolites were obtained for each subject as follows: Cohort 1: Days 1 and 6: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose Days 2 and 7: 24 hours post- dose Day 7: 36 hours post-dose Cohort 2: Days 1 and 12: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose Days 2 and 13: 24 hours post-dose Days 13: 36 hours post-dose The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Quality Control Samples 0.9, 135, and 270 ng/mL Standard Curve Samples 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 88 Reference ID: 3403865 Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods 2.6 to 3.9 1.9 to 3.3 -1.5 to 3.7 -4.9 to 5.1 Weighted linear equation (1/X2), mean r= 0.997 0.3 to 300 ng/mL 0.3 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-12, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. • Plasma concentrations and pharmacokinetic parameters of tasimelteon were compared when given alone and in combination with a CYP3A4 inhibitor, ketoconazole, at steady state. • Plasma concentrations and pharmacokinetic parameters of tasimelteon were compared when given alone and in combination with a CYP3A4 inducer, rifampin, at steady state. • Plasma concentrations and pharmacokinetic parameters of tasimelteon metabolites M9, M11, M12, M13, and M14 were compared when given alone and in combination with a CYP3A4 inhibitor, ketoconazole and CYP3A4 inducer, rifampin, at steady state. Adverse event (AE) and serious adverse event (SAE) monitoring, physical examination and weight, vital signs measurement, clinical laboratory analysis (hematology, blood chemistry, coagulation [PT, PTT], urinalysis, beta-2 microglobulin, microalbumin), 12-lead electrocardiogram (ECG). Pharmacokinetic: The 90% confidence intervals (CI) of the geometric mean ratio of AUC0-∞ and Cmax values between the 2 treatments were calculated. The log-transformed data was analyzed using an analysis of variance model with factors for sequence, subjects within sequence, period, and treatment groups. The sequence effects were tested using the intersubject variation and differences between periods or treatments were compared using intrasubject variation estimated from the analysis of variance model. RESULTS: Following figure depicts PK profile of tasimelteon after oral administration of single 20 mg doses of tasimelteon alone and after dosing with ketoconazole 400 mg. Figure: Mean Plasma Concentrations of Tasimelteon After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days 89 Reference ID: 3403865 Following figure depicts PK profile of tasimelteon after oral administration of single 20 mg doses of tasimelteon alone and after dosing with rifampin 600 mg. Mean Plasma Concentrations of Tasimelteon After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Rifampin 600 mg QD for 10 Days 90 Reference ID: 3403865 Table: Summary of Pharmacokinetic Parameters for Tasimelteon After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter* Cohort 1 Cohort 2 Alone (Day 1) + Ketoconazole (Day 6) Alone (Day 1) + Rifampin (Day 12) 243 ± 129 (24) 337 ± 188 (24) 240 ± 119 (24) 54.7 ± 49.4 (24) Tmax (h) 0.50 (24) [0.25 – 2.00] 0.50 (24) [0.25 – 2.00] 0.63 (24) [0.50 – 1.00] 0.50 (23) [0.25 – 0.75] AUC(0-t) (h·ng/mL 453 ± 350 (24) 767 ± 617 (24) 481 ± 340 (24) 66.2 ± 71.7 (23) AUC(inf) (h·ng/mL ) λz (1/h) 457 ± 356 (24) 662 ± 562 (21) 484 ± 342 (24) 67.3 ± 72.0 (23) 0.5868 ± 0.2034 (24) 0.4566 ± 0.1635 (21) 0.5045 ± 0.1266 (24) 0.6497 ± 0.2087 (23) t1/2 (h) 1.31 ± 0.42 (24) 1.88 ± 1.38 (21) 1.48 ± 0.46 (24) 1.07 ± 0.27 (23) CL/F (ml/min) 307 ± 225 (24) 227 ± 191 (21) 288 ± 292 (24) 3493 ± 4702 (23) Vz/F (L) 29.7 ± 16.8 (24) 35.7 ± 49.7 (21) 31.5 ± 23.4 (24) 258 ± 258 (23) Cmax (ng/mL) * Arithmetic mean ± standard deviation (N) except Tmax for which the median (N) is reported. Following table summarizes statistical analysis conducted on PK parameters of tasimelteon.! ! Table: Statistical Comparison of Pharmacokinetic Parameters for Tasimelteon After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter* Geometric Mean Ratio(%)* Cohort 1 Cohort 2 Estimate 90% Confidence Interval Estimate 90% Confidence Interval Cmax 133.06 116.73 - 151.68 17.22 13.29 - 22.31 AUC(0-t) 161.14 141.49 - 183.53 10.48 8.11 - 13.55 AUC(inf) 153.95 137.75 - 172.07 10.75 8.36 - 13.82 t1/2 134.29 110.53 - 163.15 72.66 67.56 - 78.13 CL/F 64.95 58.12 - 72.60 930.50 723.47 - 1196.77 Vz/F 87.23 72.82 - 104.48 676.05 528.79 - 864.33 * Arithmetic mean ± standard deviation (N) except Tmax for which the median (N) is reported. Metabolite M14 91 Reference ID: 3403865 Table: Summary of Pharmacokinetic Parameters for Metabolite M14 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter* Cohort 1 Cohort 2 Alone (Day 1) + Ketoconazole (Day 6) Alone (Day 1) + Rifampin (Day 12) 6.70 ± 3.47 (24) 2.12 ± 1.04 (24) 6.17 ± 3.83 (24) 16.2 ± 8.48 (22) Tmax (h) 0.75 (24) [0.25 – 3.00] 0.75 (24) [0.25 – 8.12] 0.93 (24) [0.50 – 2.00] 0.50 (23) [0.25 – 1.50] AUC(0-t) (h·ng/mL 22.7 ± 20.6 (24) 12.5 ± 13.0 (24) 24.9 ± 24.0 (24) 27.2 ± 21.4 (23) AUC(inf) (h·ng/mL ) λz (1/h) 22.5 ± 21.5 (21) 13.7 ± 14.8 (14) 26.5 ± 25.7 (22) 28.1 ± 21.6 (23) 0.3922 ± 0.1514 (21) 0.2306 ± 0.0974 (14) 0.3406 ± 0.1377 (22) 0.7615 ± 0.2272 (23) 2.05 ± 0.85 (21) 3.60 ± 1.59 (14) 2.44 ± 1.21 (22) 0.99 ± 0.28 (23) Cmax (ng/mL) t1/2 (h) * Arithmetic mean ± standard deviation (N) except Tmax for which the median (N) is reported. Table: Statistical Comparison of Pharmacokinetic Parameters for Metabolite M14 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter Geometric Mean Ratio (%) Cohort 1 Cohort 2 Estimate 90% Confidence Interval Estimate 90% Confidence Interval Cmax 32.66 27.10 → 39.36 270.14 227.87 → 320.25 AUC(0-t) 46.86 38.45 → 57.11 119.94 101.17 → 142.19 AUC(inf) 55.36 43.12 → 71.08 115.22 96.46 → 137.62 180.19 146.83 → 221.13 41.96 37.98 → 46.36 t1/2 Metabolite M12 Summary of Pharmacokinetic Parameters for Metabolite M12 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter Cmax (ng/mL) Cohort 1 Cohort 2 Alone (Day 1) + Ketoconazole (Day 6) Alone (Day 1) + Rifampin (Day 12) 89.0 ± 30.1 (24) 97.2 ± 27.7 (24) 86.3 ± 23.3 (24) 49.9 ± 23.9 (23) 92 Reference ID: 3403865 Tmax (h) 1.50 (24) [0.25 – 4.00] 2.00 (24) [0.75 – 8.00] 1.50 (24) [0.50 – 4.00] 0.75 (23) [0.25 – 1.50] AUC(0-t) (h·ng/mL 654 ± 389 (24) 1044 ± 586 (24) 657 ± 324 (24) 133 ± 110 (23) AUC(inf) (h·ng/mL ) λz (1/h) 678 ± 419 (24) 1067 ± 611 (24) 683 ± 364 (24) 124 ± 100 (22) 0.2270 ± 0.0772 (24) 0.1676 ± 0.0531 (24) 0.2154 ± 0.0755 (24) 0.5635 ± 0.1368 (22) 3.43 ± 1.25 (24) 4.69 ± 1.62 (24) 3.65 ± 1.46 (24) 1.31 ± 0.35 (22) t1/2 (h) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M12 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days Parameter Geometric Mean Ratio (%) Cohort 2 90% Confidence Estimate Interval Cohort 1 Estimate 90% Confidence Interval Cmax 111.94 103.80 → 120.72 53.37 47.43 → 60.06 AUC(0-t) 162.35 150.96 → 174.61 17.16 14.98 → 19.65 AUC(inf) 160.79 148.99 → 173.54 16.65 14.59 → 18.99 t1/2 134.42 124.58 → 145.03 37.62 34.65 → 40.85 Metabolite M13 Summary of Pharmacokinetic Parameters for Metabolite M13 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter Cohort 1 Cohort 2 Alone (Day 1) + Ketoconazole (Day 6) Alone (Day 1) + Rifampin (Day 12) 298 ± 73.7 (24) 251 ± 85.7 (24) 279 ± 93.9 (24) 339 ± 148 (23) Tmax (h) 0.50 (24) [0.25 – 2.00] 0.50 (24) [0.25 – 2.00] 0.75 (24) [0.50 – 1.00] 0.50 (23) [0.25 – 1.00] AUC(0-t) (h·ng/mL ) AUC(inf) (h·ng/mL 437 ± 152 (24) 428 ± 155 (24) 442 ± 168 (24) 317 ± 134 (23) 441 ± 153 (24) 427 ± 157 (23) 448 ± 168 (24) 320 ± 135 (23) λz (1/h) 0.6169 ± 0.2401 (24) 0.5295 ± 0.2418 (23) 0.5585 ± 0.2008 (24) 0.9623 ± 0.3803 (23) 1.28 ± 0.46 (24) 1.54 ± 0.63 (23) 1.41 ± 0.56 (24) 0.86 ± 0.38 (23) Cmax (ng/mL) t1/2 (h) 93 Reference ID: 3403865 Statistical Comparison of Pharmacokinetic Parameters for Metabolite M13 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter Geometric Mean Ratio (%) Cohort 1 Cohort 2 Estimate 90% Confidence Interval Estimate 90% Confidence Interval Cmax 82.29 72.93 → 92.86 118.05 102.86 → 135.48 AUC(0-t) 97.53 93.86 → 101.36 70.82 64.07 → 78.28 AUC(inf) 97.74 94.05 → 101.56 70.44 63.80 → 77.77 116.88 110.90 → 123.18 58.73 51.67 → 66.75 t1/2 Metabolite M9 Summary of Pharmacokinetic Parameters for Metabolite M9 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter Cohort 1 Cohort 2 Alone (Day 1) + Ketoconazole (Day 6) Alone (Day 1) + Rifampin (Day 12) 228 ± 88.1 (24) 182 ± 49.2 (24) 211 ± 70.3 (24) 372 ± 109 (23) Tmax (h) 0.75 (24) [0.25 – 2.00] 0.75 (24) [0.50 – 2.00] 0.75 (24) [0.50 – 1.03] 0.50 (23) [0.25 – 1.00] AUC(0-t) (h·ng/mL 360 ± 88.6 (24) 362 ± 110 (24) 388 ± 112 (24) 362 ± 91.4 (23) AUC(inf) (h·ng/mL ) λz (1/h) 365 ± 89.1 (24) 371 ± 119 (24) 395 ± 113 (24) 365 ± 91.8 (23) 0.5134 ± 0.1274 (24) 0.4215 ± 0.1489 (24) 0.4846 ± 0.1149 (24) 0.6019 ± 0.0848 (23) 1.43 ± 0.36 (24) 2.00 ± 1.39 (24) 1.52 ± 0.42 (24) 1.17 ± 0.17 (23) Cmax (ng/mL) t1/2 (h) Statistical Comparison of Pharmacokinetic Parameters for Metabolite M9 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter Geometric Mean Ratio (%) Cohort 1 Cohort 2 Estimate 90% Confidence Interval Estimate 90% Confidence Interval Cmax 82.17 72.77 → 92.79 157.92 139.57 → 178.67 AUC(0-t) 99.58 96.14 → 103.15 95.30 91.81 → 98.92 94 Reference ID: 3403865 AUC(inf) 100.59 97.03 → 104.29 94.53 91.07 → 98.13 t1/2 127.49 110.57 → 147.00 77.93 70.48 → 86.16 Metabolite M11 Summary of Pharmacokinetics Parameters for Metabolite M11 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter* Cohort 1 Cohort 2 Alone (Day 1) + Ketoconazole (Day 6) Alone (Day 1) + Rifampin (Day 12) 51.6 ± 13.4 (24) 45.9 ± 12.8 (24) 48.9 ± 15.0 (24) 39.8 ± 15.4 (23) 1.00 (24) [0.50 – 3.00] 1.50 (24) [0.75 – 2.00] 1.27 (24) [0.75 – 2.00] 0.75 (23) [0.25 – 1.50] AUC(0-t) (h·ng/mL) 160 ± 65.8 (24) 189 ± 82.2 (24) 164 ± 66.6 (24) 84.0 ± 37.0 (23) AUC(inf) (h·ng/mL) 167 ± 65.8 (23) 196 ± 86.3 (21) 167 ± 67.1 (24) 81.4 ± 36.6 (17) 0.3293 ± 0.0802 (23) 0.2969 ± 0.1091 (21) 0.3564 ± 0.0926 (24) 0.3087 ± 0.1272 (17) 2.21 ± 0.47 (23) 2.84 ± 1.79 (21) 2.08 ± 0.59 (24) 2.82 ± 1.78 (17) Cmax (ng/mL) Tmax (h) λ z (1/h) t1/2 (h) * Arithmetic mean ± standard deviation (N) except Tmax for which the median (N) is reported. Table: Statistical Comparison of Pharmacokinetic Parameters for Metabolite M11 After Oral Administration of Single 20 mg Doses of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg QD for 5 Days or Rifampin 600 mg QD for 10 Days Parameter* Geometric Mean Ratio (%) Cohort 1 Cohort 2 Estimate 90% Confidence Interval Estimate 90% Confidence Interval Cmax 88.89 82.69 → 95.56 80.11 73.14 → 87.76 AUC(0-t) 117.36 112.30 → 122.65 50.65 45.85 → 55.96 AUC(inf) 115.41 109.95 → 121.15 51.92 46.40 → 58.10 t1/2 105.09 93.74 → 117.82 127.16 102.67 → 157.48 Forest plot showing impact of concomitant administration of ketoconazole (left) and rifampin (right) with tasimelteon. 95 Reference ID: 3403865 Impact of Ketoconazole Coadministration With Tasimelteon Impact of Rifampin oadministration With Tasimelteon Analylc PK Fold Change and 90% Cl Analyte PK Fold Change and 00% Cl Cmax max Tasimelteon Tasimelteon Metabolite 9 Metabolite 9 l?-l Metabolite 11 Metabolite 11 Metabolite 12 rl?J?i Metabolite 12 Hi Metabolite l3 Metabolite 13 Metabolite 14 Metabolite l4 AUC AUC Tasimelteon Tasimelteon ll Metabolite 9 0H Metabolite 9 Metabolite 11 hictulmlitc 11 Metabolite 12 Metabolite 12 Metabolite 13 "l '3 Metabolite 14 Fl-Fl I Metalwme elat'v Wit out R'a Change rclatlvc: Without ng I It Discussion The major metabolites M12, M13, M9, M11 and M14 are eliminated at similar rate when compared to tasimelteon. The parent to metabolite ratio is 1.6, 0.96, 0.92, 0.38 and 0.05 for M12 M13, M9, M11 and M14 ,respectively. Metabolite M12, which shows higher parent to metabolite ratio (1.6), is inactive. M13 (parent to metabolite ratio, 0.92) is approximately l3-times lower in potency at and MT2 receptors. M11 (parent to metabolite ratio, 0.38) is approximately 800-times lower in potency at and 50 times lower at MT2 receptors as shown in the table below. Following table indicates activities of tasimelteon and its major active metabolites at and MT2 receptors. Potency of tasimelteon and metabolites M9, M11, and M13 for human melatonin and MT2 receptors 96 Reference ID: 3403865 Reviewer’s Comment: The potency of the major metabolites is much lower when compared to parent for most of the metabolites. Moreover, parent to metabolite ratio are similar or lower for most active metabolites. Change in concentration of the M13, which is most active, does not contribute to overall activity and impact of rifampin on tasimelteon. Tasimelteon is tolerated upto 300 mg in single ascending dose and upto 150 mg in multiple ascending dose tolerability studies, no dose adjustment is necessary for increase in exposure (approximately 50%) when tasimelteon is coadministered with ketoconazole. Reviewer’s Comment: The sponsor’s rationale appears reasonable. Labeling statements should be discussed with Clinical Division for the assessment of safety data including treatment related AE’s. CONCLUSIONS: • • • 1.10 The Cmax and AUC of tasimelteon increased by 33% and 53% respectively in the presence of ketoconazole, a strong inhibitor of CYP3A4. Rifampin, a strong CYP3A4 and moderate CYP2C19 inducer, reduced the Cmax and AUC of tasimelteon by approximately 90%. Decrease in exposure to tasimelteon in the presence of rifampin may reduce the efficacy when tasimelteon is concomitantly used with strong CYP enzyme inducers such as rifampin. VP-VEC-162-1108: A randomized, double-mask, four period crossover study in healthy subjects to evaluate the pharmacodynamic and pharmacokinetic interactions of tasimelteon and ethanol Objectives: • To assess the effect of 20 mg tasimelteon on sustained attention test, cognition, postural stability and motor control alone and in combination with ethanol; 97 Reference ID: 3403865 • • To assess the effect of 20 mg tasimelteon on subjective ethanol-related effects such as intoxication, dizziness, and drowsiness; To evaluate the single-dose pharmacokinetics (PK), safety and tolerability of 20 mg tasimelteon and ethanol alone and in combination Study Design Study Population Sampling: Analysis This was a single-center, randomized, double-masked, 4-period crossover study conducted in healthy subjects to evaluate the pharmacodynamic (PD) and PK interactions of tasimelteon and ethanol. The study consisted of a qualification period and 4 treatment periods: Qualification Period: Single oral dose of 0.6 g/kg (females) or 0.7 g/kg (males) of ethanol. Treatment Period: • 20 mg tasimelteon + placebo ethanol (with about 1 mL supernatant of ethanol), • 0.6 g/kg (female) or 0.7 g/kg (male) ethanol + placebo tasimelteon, • 20 mg tasimelteon + 0.6 g/kg (female) or 0.7 g/kg (male) ethanol, Placebo tasimelteon + placebo ethanol (with about 1 mL supernatant of ethanol). Healthy male and female subjects Age: 19-75 years BMI: 18 to 35 kg/m2. Twenty eight subjects were enrolled and 25 completed the study Blood samples for the determination of tasimelteon and ethanol in plasma were taken for each subject before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 and 24 hours after dosing The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments PD Quality Control Samples 0.9, 135, and 270 ng/mL 2.0 to 6.0 Standard Curve Samples 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 1.6 to 6.0 -6.7 to 0.7 -4.4 to 3.3 Weighted linear equation (1/X2), mean r= 0.998 0.3 to 300 ng/mL 0.3 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Plasma concentrations and PK parameters of tasimelteon, metabolites M9, M11, M12, M13, and M14, and ethanol were compared among the 4 different groups. Peak change from pre-dose in Digit Vigilance (DV) • Peak change from pre98 Reference ID: 3403865 Assessments Safety Assessments Statistical Methods dose in Digit Symbol Substitution Test (DSST) • Peak change from pre-dose in Hopkins Verbal Learning Test- Revised (HVLT-R) • Peak change from predose in Divided Attention Test (DAT) • Peak change from pre-dose in Balance Platform Test • Peak change from pre-dose in Choice Reaction Time (CRT) • Peak change from pre-dose in Visual Analog Scales (VASs) Subjective tolerability from spontaneous reporting of adverse events (AEs) • Changes in laboratory parameters that were relevant to safety • Influence of trial medication on vital signs and electrocardiogram (ECG) parameters • The Columbia Suicide Severity Rating Scale assessed suicidal behavior and ideation Pharmacokinetics: Plasma concentration data for tasimelteon and ethanol were summarized using descriptive statistics (arithmetic mean, standard deviation [SD], and coefficient of variation [CV]; geometric mean and CV; and median, minimum, and maximum). Pharmacodynamics: For each PD variable, descriptive and graphical data were presented for each time point. Peak change from baseline (either maximum [CFBmax] or minimum [CFBmin] effect, depending on the variable) were also calculated and summarized using standard descriptive statistics. CFBmax or CFBmin for each variable was analyzed inferentially using a mixed-effect model with fixed effects for treatment, period, and sequence and subject nested within sequence as a random effect. The least squares means for CFBmax/CFBmin were calculated for each treatment condition. Least squares mean differences and 95% confidence intervals (CI) for the differences were calculated for the following comparisons: • Ethanol alone vs. placebo • Ethanol alone vs. tasimelteon + ethanol • Tasimelteon alone vs. placebo • Tasimelteon alone vs. tasimelteon + ethanol RESULTS: Following figure depicts PK profile of tasimelteon after oral administration of single 20 mg doses of tasimelteon alone and when coadministered with ethanol. Plasma Tasimelteon Mean Concentration Curves (ng/mL) 99 Reference ID: 3403865 Mean (%CV) Pharmacokinetic Parameters of Tasimelteon - Tasimelteon Alone and In Combination with Ethanol Treatment A (Tasimelteon Alone) (N = 26) Cmax (ng/mL) 39.74 (30.52) Treatment C (Tasimelteon + Ethanol) (N = 25) Contrasts (Differences) Treatment C (Tasimelteon + Ethanol) vs. Treatment A (Tasimelteon Alone) Least Squares Mean (SE) 90% CI P-value Estimated Ratio % (90% CI for Ratio) 51.98 (64.56) 0.27 (0.06) (0.170.37) <0.001 130.70 (118.50– 144.15) Tmax (h) 1.43 (0.62–4.42) 1.47 (0.50–4.38) — — — — AUC0-t (h*ng/mL) 138.9 (43.87) 197.4 (85.93) 0.27 (0.14) (0.03– 0.50) 0.065 130.71 (103.22– 165.51) AUC0-inf (h*ng/mL) 142.6 (44.70) 207.4 (70.49) 0.30 (0.13) (0.08– 0.53) 0.030 135.53 (108.18– 169.80) T1/2 (h) 1.72 (0.86–4.58) 1.73 (0.32–13.38) — — — — Xz (1/h) 0.42 (30.11) 0.45 (68.55) — — — — Metabolite M9 Mean (%CV) Pharmacokinetic Parameters of M9 - Tasimelteon Alone and iIn combination with Ethanol (PK Population) 100 Reference ID: 3403865 Contrasts (Differences) Treatment A (Tasimelteon Alone) a (N = 26 ) Treatment C (Tasimelteon + Ethanol) vs. Treatment A (Tasimelteon Alone) Treatment C (Tasimelteon + Ethanol) a (N = 25 ) Least Squares Mean (SE) 90% CI Estimated Ratio % (90% CI for Ratio) Pvalue -1.50 (0.08) (-1.64 – -1.36) <0.001 22.39 (19.49–25.73) — — — 112.5 (81.98) -1.17 (0.16) (-1.44 – -0.89) <0.001 31.10 (23.63–40.93) 355.9 (41.07) 114.9 (74.87) -1.17 (0.17) (-1.45 – -0.89) <0.001 30.99 (23.39–41.06) T1/2 (h) 1.37 (0.85– 8.06) 2.21 (0.40– 4.14) — — — — λz (1/h) 0.52 (47.93) 0.41 (49.71) — — — — Cmax (ng/mL) 157.5 (30.80) 34.92 (68.21) Tmax b (h) 0.89 (0.50– 4.42) 0.98 (0.50– 8.35) AUC0-t (h*ng/mL) 330.7 (34.41) AUC0-inf (h*ng/mL) — Metabolite M11 Mean (%CV) Pharmacokinetic Parameters of M11 - Tasimelteon Alone and In Combination with Ethanol (PK Population) Contrasts (Differences) Treatment A (Tasimelteon Alone) (N = 26) Treatment C (Tasimelteon + Ethanol) vs. Treatment A (Tasimelteon Alone) Treatment C (Tasimelteon + Ethanol) (N = 25a) Least Squares Mean (SE) 90% CI P-value Estimated Ratio % (90% CI for Ratio) Cmax (ng/mL) 39.74 (30.52) 51.98 (64.56) 0.27 (0.06) (0.17–0.37) <0.001 130.70 (118.50– 144.15) Tmax (h) 1.43 (0.62– 4.42) 1.47 (0.50– 4.38) — — — — 101 Reference ID: 3403865 AUC0-t (h*ng/mL) 138.9 (43.87) 197.4 (85.93) 0.27 (0.14) (0.03–0.50) 0.065 130.71 (103.22– 165.51) AUC0-inf (h*ng/mL) 142.6 (44.70) 207.4 (70.49) 0.30 (0.13) (0.08–0.53) 0.030 135.53 (108.18– 169.80) T1/2 (h) 1.72 (0.86– 4.58) 1.73 (0.32– 13.38) — — — — Xz (1/h) 0.42 (30.11) 0.45 (68.55) — — — — Metabolite M13 Mean (%CV) Pharmacokinetic Parameters of M13 - Tasimelteon Alone and In Combination with Ethanol (PK Population) Treatment A Treatment C (Tasimelteon Alone) (Tasimelteon + Ethanol) (N = 26) Cmax (ng/mL) 257.9 (32.33) Tmax a (h) (N = 25) 300.6 (64.19) Contrasts (Differences) Treatment C (Tasimelteon + Ethanol) vs. Treatment A Least Squares Mean (SE) Pvalue 90% CI Estimated Ratio % (90% CI for Ratio) 120.33 (106.08– 136.48) 0.19 (0.07) (0.06–0.31) 0.53 (0.48–4.38) 0.92 (0.25– — — AUC0-t (h*ng/mL) 505.5 (50.38) 673.3 (68.05) 0.29 (0.16) (0.02–0.56) 0.077 134.03 (102.28– 175.64) AUC0-inf (h*ng/mL) 513.4 (50.24) 680.8 (67.56) 0.29 (0.16) (0.016–0.56) 0.083 133.37 (101.63– 175.02) T1/2a (h) 1.27 (0.70–3.44) 1.19 (0.39– 2.16) — — — — Xz (1/h) 0.61 (42.16) 0.65 (31.16) — — — — 0.020 — — Metabolite M14 Mean (%CV) Pharmacokinetic Parameters of M14 - Tasimelteon Alone and In combination with Ethanol (PK Population) 102 Reference ID: 3403865 Treatment A (Tasimelteon Alone) (N = 26) Treatment C (Tasimelteon + Ethanol) Contrasts (Differences) Treatment C (Tasimelteon + Ethanol) vs. Treatment A (Tasimelteon Alone) (N = 25) Least Squares Mean (SE) 90% CI Cmax (ng/mL) 4.07 (38.99) 4.01 (77.02) -0.10 (0.09) (-0.25–0.05) Tmax b (h) 0.92 (0.50– 4.42) 1.08 (0.48– 8.35) — — P-value 0.254 — Estimated Ratio % (90% CI for Ratio) 90.36 (77.86104.86) — 83.47 (62.44111.58) 108.10 (92.15126.80) AUC0-t (h*ng/mL) 16.52 (76.85) 16.88 (151.0) -0.18 (0.17) (-0.47–0.11) 0.297 AUC0-inf (h*ng/mL) 20.06 (80.45) 21.21 (92.02) 0.08 (0.09) (-0.08–0.24) 0.410 T1/2b (h) 2.15 (0.81– 6.72) 2.28 (0.73– 6.81) — — — — Xz (1/h) 0.37 (58.05) 0.35 (48.76) — — — — Plasma Ethanol Mean Concentration Curves (ng/mL) Mean (%CV) Pharmacokinetic Parameters of Ethanol - Ethanol Alone and In Combination with Tasimelteon (PK Population) 103 Reference ID: 3403865 Treatment C Treatment B (Ethanol Alone) (Tasimelteon + Ethanol) Contrasts (Differences) Treatment C (Tasimelteon + Ethanol) vs. Treatment B (Ethanol Alone) Least Squares Mean (SE) (N = 25) (N = 27) 90% CI Cmax (mmol/L) 24.74 (16.49) 25.49 (24.31) 0.02 (0.04) (-0.05–0.08) Tmax b (h) 0.72 (0.42–1.68) 0.67 (0.42– 2.85) — — P-value 0.652 — Estimated Ratio % (90% CI for Ratio) 101.67 (95.55– 108.18) — AUC0-t (h*mmol/L) 83.22 (17.05) 79.68 (19.14) -0.06 (0.04) (-0.12–0.00) 0.108 94.27 (88.73– 100.15) AUC0-inf (h*mmol/L) 140.9 (23.35) 156.4 (38.35) 0.01 (0.07) (-0.10–0.12) 0.896 100.86 (90.23– 112.74) T1/2b(h) 3.44 (1.29–6.73) 3.68 (1.49– 16.51) — — — — Xz (1/h) 0.23 (38.91) 0.20 (47.46) — — — — Pharmacokinetic Summary • Ethanol 0.6 g/kg (female) or 0.7 g/kg (male) had no effect on the PK profile of tasimelteon. The 90% CIs for the ratio between tasimelteon alone and in combination with ethanol were not within 80%-125% range for all PK parameters (AUC0-inf, AUC0-t, and Cmax). The magnitude of increase in exposure ranged from approximately 30% to 25%. • Exposure to the metabolite M9 was significantly lower in the presence of ethanol and the magnitude of decrease in exposure ranged from approximately 70%–75% in the presence of ethanol. Exposure to the metabolite M12 and M14 was relatively small in the presence of ethanol. • Exposure to the metabolites M11 and M13 was significantly higher in the presence of ethanol and the magnitudes of increase in exposure ranged from approximately 30% to 35% and 20% to 35%, respectively. • Tasimelteon 20 mg had no effect on the PK profile of ethanol. Pharmacodynamic Results There was no trend in PD parameters evaluated (see below) when tasimelteon was concomitantly administered with ethanol. Most of the impairments on PD measures were related to ethanol and not to the addition of tasimelteon as shown in figure below. Mean Hit Reaction Time – DV 104 Reference ID: 3403865 122"]- 1150- Mean Reaction TIITIE [FtT:n 1350 - F'Schedule-d Tirr'e Poin'. FH- 2 2Img of tasin'relteon plaoebo ethanol 'l?H placebo tasin're lteon ethanol 20mg of tasin'relteon ethanol placebo tasin're lteon plaoe ho ethanol Mean (1 Prime Scheduled Tirne Point lhr] 2 2Irng of tasin'relteon plaoe ho ethanol 20mg of tasin'relteon ethanol placebo tasin're lteon ethanol placebo tasin're lteon plaoe ho ethanol DIV digit vigilance Mean Intoxication VAS Scores Over Time Reference ID: 3403865 105 Mean Alertness/Drowsiness VAS Scores Over Time (PD Population) Digit Symbol Substitution Test (DSST) Mean Number of Symbols Completed Over Time – DSST 106 Reference ID: 3403865 Mean Number of Incorrect Symbols Over Time – DSST CONCLUSIONS: • Concomitant administration of ethanol resulted in relatively small increase in exposure (AUC0-inf, AUC0-t, and Cmax) to tasimelteon. The magnitude of increase in exposure ranged from 10% to 25%. • Tasimelteon 20 mg had no effect on the PK profile of ethanol. • Pharmacodynamic parameters evaluated on subjective measures, or on sustained attention, cognition, balance or psychomotor performance in this study did not show 107 Reference ID: 3403865 any trend when tasimelteon was concomitantly administered with ethanol. Most of the impairments on PD measures were related to ethanol and not to the addition of tasimelteon. 1.11 VP-VEC-162-1107: An open-label, single dose, parallel group study to assess the effect of smoking status, age and body size on the pharmacokinetics, safety, and tolerability of tasimelteon in healthy volunteers. Objectives: Primary: • To assess plasma concentrations and pharmacokinetics of tasimelteon in subjects who smoke compared to subjects who do not smoke. • To assess the effect of weight, body mass index (BMI), and age on the pharmacokinetic profile of tasimelteon. Secondary: • To assess effect of smoking, weight, BMI, and age on the pharmacokinetic profile of tasimelteon metabolites (M9, M11, M12, M13, and M14). • To assess the safety and tolerability of a single 20-mg oral dose of tasimelteon. Study Design Study Population This was an open-label, parallel-group design study. Sixty (60) healthy subjects were enrolled into the study. Part 1 Group 1: Twenty-four (24) male and female subjects between the ages of 18 and 55 years of age, inclusive, who smoked at least 10 tobacco cigarettes per day for at least 6 months prior to Screening and had a positive test for cotinine at Screening and Baseline. a. 8 underweight/normal [BMI ≤24.99], b. 8 overweight [BMI 25.00 to 29.99], and c. 8 obese [BMI ≥ 30.00]) Group 2: Twenty-four (24) male and female subjects between 18 and 55 years of age, inclusive, who had not consumed tobacco for 6 months before the start of the study and were similar in the distribution of the matching variables (gender, age (±10 years), and BMI category (underweight/normal, overweight and obese)) to Group 1. Sampling: Part 2 Group 3: Twelve (12) non-smoker subjects over 65 years of age were enrolled into the study. An approximately equal number of male and female volunteers were enrolled into each study group. Plasma PK samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 108 Reference ID: 3403865 Analysis 6, 8, 12, and 24 hours after dosing. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods Quality Control Samples 0.9, 135, and 270 ng/mL 1.9% to 3.3% Standard Curve Samples 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 1.5 to 4.3 -5.7% to 5.0%. -3.7 to 4.0 Weighted linear equation (1/X2), mean r= 0.996 0.3 to 300 ng/mL 0.3 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-12, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Comparison of the pharmacokinetic parameters was done by analysis of variance. Plasma concentrations and PK parameters of tasimelteon were compared between subjects who were current smokers and matched controls that did not smoke. Plasma concentrations and PK parameters of tasimelteon were also compared amongst subjects with different BMIs and ages. Secondary Endpoints • Plasma concentrations and PK parameters of tasimelteon metabolites M3 (Groups 1A, 1B, 2A, and 2B only), M9, M11, M12, M13, and M14 were compared between subjects who were current smokers and match controls that did not smoke. • Plasma concentrations and PK parameters of tasimelteon metabolites M9, M11, M12, M13, and M14 were compared amongst subjects with different BMIs and ages. Safety was assessed by adverse event (AE) and serious adverse event (SAE) monitoring. Changes in clinical laboratory parameters that were relevant to safety. Influence of trial medication on vital signs and electrocardiogram (ECG) parameters. Pharmacokinetic: The effects of gender, smoking, age, and BMI were also examined using the data from all subjects in the study by a stepwise general linear models approach. For tasimelteon, the parameters examined were CL/F, Vz/F, and t½; for the metabolites, the parameters examined were AUC(inf) and t½. Parameters were natural log-transformed prior to the stepwise analysis. RESULTS: Following figure depicts PK profile of tasimelteon in young smokers and young non-smokers. 109 Reference ID: 3403865 Mean Plasma Concentrations of Tasimelteon after Oral Administration of Single 20 mg Doses of Tasimelteon to Young Smokers and Young Non-Smokers Following Table Summarizes PK Parameters of of Tasimelteon after Oral Administration of Single 20 mg Doses of Tasimelteon to Young Smokers and Young Non-Smokers. Parameter* Cmax (ng/mL) Tmax (h) AUC(0-t) (h× ng/mL) AUC(inf) (h× ng/mL) λ z (1/h) t1/2 (h) CL/F (mL/min) Vz/F (L) Young Smokers Young Non-Smokers 136 ± 59.5 (24) 0.75 (24) 204 ± 151 (24) 205 ± 152 (24) 0.7208 ± 0.1234 (24) 0.99 ± 0.18 (24) 2,290 ± 1,232 (24) 189 ± 94.2 (24) 239 ± 177 (24) 0.50 (24) 386 ± 427 (24) 389 ± 429 (24) 0.6433 ± 0.1737 (24) 1.18 ± 0.46 (24) 1,482 ± 1,008 (24) 133 ± 83.0 (24) Following figure depicts the impact of smoking on tasimelteon Cmax and AUC. Impact of smoking on tasimelteon 110 Reference ID: 3403865 Following figure depicts PK profile of tasimelteon in young and elderly non-smokers . Mean Plasma Concentrations of Tasimelteon after Oral Administration of Single 20 mg Doses of Tasimelteon to Young and Elderly Non-Smokers Following figure depicts relationship between tasimelteon clearance and BMI. Relationship between Tasimelteon CL/F and BMI after Oral Administration of Single 20 mg doses of Tasimelteon to Young and Elderly Non-Smokers. 111 Reference ID: 3403865 Summary of Pharmacokinetic Parameters for Tasimelteon after Oral Administration of Single 20 mg Doses of Tasimelteon to Young and Elderly Non-Smokers. Parameter* Cmax (ng/mL) Tmax (h) AUC(0-t) (h×ng/mL) AUC(inf) (h×ng/mL) λz (1/h) t1/2 (h) CL/F (mL/min) Vz/F (L) Elderly Non-Smokers Young Non-Smokers 365 ± 211 (12) 0.50 (12) 649 ± 399 (12) 653 ± 402 (12) 0.4562 ± 0.0963 (12) 1.59 ± 0.40 (12) 737 ± 471 (12) 92.8 ± 50.9 (12) 239 ± 177 (24) 0.50 (24) 386 ± 427 (24) 389 ± 429 (24) 0.6433 ± 0.1737 (24) 1.18 ± 0.46 (24) 1,482 ± 1,008 (24) 133 ± 83.0 (24) CONCLUSIONS: • • 1.12 Cigarette smoking resulting in induction of CYP1A2, increased the clearance of tasimelteon and decreased exposure about 40%. The clearance of tasimelteon is inversely related to age and BMI. VP-VEC-162-1110: An open-label, single-sequence study to assess the effect of multiple doses of tasimelteon on the cytochrome P450 3A4 and 2C8 enzymes using midazolam and rosiglitazone as substrates in healthy subjects. Objectives: To characterize the effect of repeat 20 mg tasimelteon dosing on CYP3A4 and CYP2C8 activity at steady state. Midazolam and rosiglitazone were used as markers for CYP3A4 and CYP2C8 activity respectively. 112 Reference ID: 3403865 Study Design Study Population Duration of Treatment Sampling: Analysis This was an open-label, single-sequence study conducted at one site. Approximately 24 subjects were enrolled in this study. Healthy male and female subjects Age: 18-55 years BMI: 18 to 35 kg/m2. Twenty four subjects were enrolled and 24 completed the study. A single-sequence of the following treatments: • Single oral dose of midazolam 10 mg on Day 1 • Single oral dose of rosiglitazone 4 mg on Day 3 • Tasimelteon 20 mg QD for 13 days on Days 5-17 • Single oral doses of tasimelteon 20 mg and midazolam 10 mg on Day 18 • Single oral doses of tasimelteon 20 mg on Day 19 • Single oral doses of tasimelteon 20 mg and rosiglitazone 4 mg on Day 20. Blood samples for determining drug concentration of midazolam, tasimelteon and its metabolite were obtained for each subject as follows: Days 1 and 18: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours postdose Blood samples for determining drug concentration of rosiglitazone, tasimelteon were obtained for each subject as follows: Days 3 and 20: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours postdose Predose tasimelteon concentrations were determined on days 5, 8, 11, 14. The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.3 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) Quality Control Samples 0.9, 135, and 270 ng/mL 2.3% to 11.4% Standard Curve Samples 0.3, 0.9, 3, 9, 30, 90, 225 and 300 ng/mL 1.9 to 4.0 -6.4% to 3.2%. -5.7 to 5.1 Weighted linear equation (1/X2), mean r= 0.998 0.3 to 300 ng/mL 0.3 ng/mL The plasma samples were analyzed for the concentration of midazolam and 1OH midazolam by using LC-MS/MS method. Midazolam Parameter Quality Control or Standard Curve Concentration (ng/mL) Quality Control Samples 0.3, 5, 30, and 75 ng/mL Standard Curve Samples 0.1, 0.2, 0.5, 1.5, 5, 15, 40, 80 and 100 113 Reference ID: 3403865 Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) 1-OH midazolam Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Methods 3.4% to 5.9% ng/mL 3.1 to 6.6 -4.0% to 2.7%. -7.0 to 3.4 Weighted linear equation (1/X2), mean r= 0.997 0.1 to 100 ng/mL 0.1 ng/mL Quality Control Samples 0.3, 5, 30, and 75 ng/mL 2.0% to 4.4% Standard Curve Samples 0.1, 0.2, 0.5, 1.5, 5, 15, 40, 80 and 100 ng/mL 1.0 to 7.3 -1.3% to 2.3%. -4.5 to 4.7 Weighted linear equation (1/X2), mean r= 0.997 0.1 to 100 ng/mL 0.1 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentrationtime data using noncompartmental analysis. Comparison of the pharmacokinetic parameters was done by analysis of variance. • Plasma concentrations and pharmacokinetic parameters of midazolam were compared between Day 1 and Day 18. • Plasma concentrations and pharmacokinetic parameters of rosiglitazone were compared between Day 3 and Day 20.! • Plasma concentrations and pharmacokinetic parameters of tasimelteon and tasimelteon metabolites M9, M11, M12, M13, and M14, at Days 5, 8, 11, 14 (Group 1 only), and Days 17 and 19 (Groups 1 and 2). Safety of multiple oral doses of 20 mg of tasimelteon alone and in combination with 10 mg of midazolam as measured by adverse event (AE) and serious adverse event (SAE) monitoring. Changes in clinical laboratory parameters that were relevant to safety. Influence of trial medication on vital signs and electrocardiogram (ECG) parameters Pharmacokinetic: The 90% confidence intervals (CI) of the geometric mean ratio of AUC0-∞ and Cmax values between the 2 treatments were calculated. The log-transformed data was analyzed using an analysis of variance model with factors for sequence, subjects within sequence, period, and treatment groups. The sequence effects were tested using the intersubject variation and differences between periods or treatments were compared using intrasubject variation estimated from the analysis of variance model. 114 Reference ID: 3403865 RESULTS: Following figure represents PK profile of midazolam alone or in combination with tasimelteon. Figure: Mean plasma concentrations of midazolam after oral administration of 10 mg alone and after dosing with tasimelteon 20 mg QD for 14 days. Following table represents PK parameters of midazolam alone or in combination with tasimelteon. Summary of pharmacokinetic parameters for midazolam after oral administration of 10 mg alone and after dosing with tasimelteon 20 mg QD for 14 days. Parameter* Cmax (ng/mL) Tmax (h) AUC(0-t) (h x ng/mL) AUC(inf) (h x ng/mL) λ z (h -1 ) t1/2 (h) Day 1 Midazolam Alone Day 18 Midazolam + Tasemelteon 59.3 ± 23.5 (23) 0.50 (23) [0.25 – 1.00] 152 ± 37.8 (23) 155 ± 39.4 (23) 55.8 ± 13.9 (23) 0.50 (23) [0.25 – 1.00] 135 ± 38.8 (23) 139 ± 39.9 (23) 0.1454 ± 0.0561 (23) 5.25 ± 1.47 (23) 0.1405 ± 0.0443 (23) 5.36 ± 1.57 (23) Following table summarizes statistical comparison of PK parameters of midazolam alone or in combination with tasimelteon. Statistical comparison of pharmacokinetic parameters for midazolam after oral administration of 10 mg alone and after dosing with tasimelteon 20 mg QD for 14 days. 115 Reference ID: 3403865 Mean plasma concentrations of 1-OH-midazolam after oral administration of 10 mg alone and after dosing with tasimelteon 20 mg QD x 14 days Statistical comparison of pharmacokinetic parameters for 1-OH-midazolam after oral administration of 10 mg alone and after dosing with tasimelteon 20 mg QD for 14 days. Rosiglitazone Following figure represents PK profile of rosiglitazone alone and in combination with tasimelteon. Mean plasma concentrations of rosiglitazone after oral administration of 4 mg alone and after dosing with tasimelteon 20 mg QD x 16 days. 116 Reference ID: 3403865 Following table represents PK parameters of rosiglitazone alone or in combination with tasimelteon. Summary of pharmacokinetic parameters for rosiglitazone after oral administration of 4 mg alone and after dosing with tasimelteon 20 mg QD for 16 days. Statistical comparison of pharmacokinetic parameters for rosiglitazone after oral administration of 4 mg alone and after dosing with tasimelteon 20 mg QD for 16 days. 117 Reference ID: 3403865 Summary of pharmacokinetie parameters for tasimelteon on Days 18 and 20 after oral administration of 20 mg QD (Day 5 through Day 20). Pa1'a111ete1133 (23) 238 i 126 (23) 1111a1;(11) 0.50 (23) 0.50 (23) (lung/111D 360 i 226 (23) 341 i 211 (23) (lung/11111) 360 226 (23) 363 207 (21) 312 (11'1) 0.6039 0.1878 (23) 0.5659 3: 0.1605 (21) 0.601) 1.26 0.39 (23) 1.31 0.33 (21) Metabolite M9 Summary of pharmaeokinelie parameters for Metabolite on Days 18 and 20 after oral administration of 20 mg QD (Day 5 through Day 20). Parameter?: Day 18 Day 20 C?maxmg 1111.) 232 d: 83.9 {23} 285 134 (23) T111ax (11} 0.50 {23) 0.50 (23) 420i 122 {23} 422 135 (23} 420i 122 {23} 423 135 (23) 1.: (111} 0.520? :t 0.1154 (23) 0.48414: 0.0858 (23} t1": (11} 1.38 :t 0.31 (23) 0.25 (23} Metabolite M11 Summary of pharmaeokinelie parameters for Metabolite on Days 18 and 20 after oral administration of 20 mg QD (Day 5 through Day 20). Parameter?: Day 18 Day 20 C'n1ax(ng 1111.) 49.5 :t 19.1 (23) 15.? (23} Tmax?l} 1.1111123) 1.00 (23) (11 -11g-111L) 154i 03.0 {23} 140i 02.0 (23) (11 -11g-111L) 149i 03.4 {20} 145 :t 03.5 (20) 1.2 0.3844 1 11.11111 (2o) 11.41194 1: {1.11125 t1": (11} 1.9? :t 0.00 (20) 0.4? (20} Metabolite M12 118 Reference ID: 3403865 Metabolite M13 CONCLUSIONS: • Oral administration of tasimelteon 20 mg daily for 14 days does not significantly change the overall exposure (AUC) of midazolam and 1-OH midazolam. Similarly there was no change in 1-OH midazolam Cmax. There was a relatively small increase (13%) in midazolam Cmax. • Tasimelteon 20 mg daily administration for 16 days did not significantly change the plasma concentrations and mean pharmacokinetic parameters of rosiglitazone. • There were no apparent changes in the pharmacokinetics of tasimelteon and metabolites M12 and M14 with dosing of 20 mg QD for 16 days. There were relatively small changes in concentration of Metabolites M9, M11, and M13. • There is no significant induction of CYP3A4/5 or CYP2C8, when 20 mg tasimelteon was administered daily for 14 or 20 days respectively. 119 Reference ID: 3403865 1.13 VP-VEC-162-1102: An Open-label, Two-period, Two-sequence, Randomized, Single Oral Dose, Crossover Study to Evaluate the Effect of Food on the Absorption of 100 mg VEC-162 in Healthy Subjects Objectives: Primary Objective: The primary objective of this study was to investigate the influence of food (highfat/ high-calorie meal) on the pharmacokinetics of 100 mg VEC-162 capsule in healthy subjects. Secondary Objective: The secondary objective of this study was to assess the implications of CYP2D6, CYP2C9, and CYP1A2 genotypes for VEC-162 metabolism and overall pharmacokinetics. Study Design Study Population Sampling: Analysis This was a 2-period, randomized, 2-sequence crossover design where each subject received 100 mg of VEC-162 either with or without food. Healthy male and female subjects Age: 18-50 years BMI: 18 to 35 kg/m2. Twenty six subjects were enrolled and 26 completed the study Blood samples for the determination of VEC-162 in plasma were taken for each subject before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16 and 24hours after dosing The plasma samples were analyzed for the concentration of tasimelteon by using LC-MS/MS method. The lower limit of quantification (LLOQ) was 0.1 ng/mL for tasimelteon. Parameter Quality Control or Standard Curve Concentration (ng/mL) Between Batch Precision (%CV) Between Batch Accuracy (%RE) Linearity Linear Range (ng/mL) Sensitivity (LLOQ, ng/mL) PK Assessments Safety Assessments Statistical Reference ID: 3403865 Quality Control Samples 0.3, 45, and 90 ng/mL 4.1 to 5.5 Standard Curve Samples 0.1, 0.3, 1, 3, 10, 30, 60 and 100 ng/mL 3.4 to 6.3 -1.5 to 3.5 -4.1 to 7.0 Weighted linear equation (1/X2), mean r= 0.994 0.1 to 100 ng/mL 0.1 ng/mL The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC(0-inf), apparent volume of distribution, CL, tlag and t1/2 were calculated from the plasma concentration-time data using noncompartmental analysis. Safety assessments included physical examinations, vital signs (systolic/diastolic blood pressure, pulse rate, respiration rate, and oral body temperature), clinical laboratory tests (hematology, chemistry, and urinalysis), 12-lead electrocardiograms, and reported or observed adverse events. Comparison of Cmax, AUC(0-t), and AUC(inf) with respect to the fed (test) 120 Methods and fasted (reference) treatments was done using an analysis of variance model with sequence, subject within sequence, treatment, and period as the classification variables. Confidence intervals (90%) were constructed for the treatment ratios (fed to fasted) of all 3 parameters using the log-transformed data and the 2 one-sided t-tests procedure. The point estimates and confidence limits were exponentiated back to the original scale. The 90% confidence intervals for the geometric mean ratios for Cmax, AUC(0-t), and AUC(inf) were calculated. RESULTS: Following figure illustrates PK profile of tasimelteon following single oral 100 mg doses under fasted and fed conditions. Mean Plasma Concentrations of VEC-162 after Single Oral 100 mg Doses Under Fasted and Fed Conditions Following table summarizes PK parameters of tasimelteon under fasted and fed conditions.! Summary of Pharmacokinetic Parameters for VEC-162 after Single Oral 100 mg Doses Under Fasted and Fed Conditions 121 Reference ID: 3403865 Following table summarizes statistical analysis conducted on PK parameters of tasimelteon.! Statistical Analysis of Pharmacokinetic Parameters for VEC-162 after Single Oral 100 mg Doses Under Fasted and Fed Conditions Geometric Mean Ratio (%) Parameter Estimate Cmax 90% Confidence Interval 55.82 49.71 – 62.67 AUC(0-t) 108.57 101.82 – 115.76 AUC(inf) 106.54 99.39 – 114.21 CONCLUSIONS: High fat, high calorie meal did not influence on the overall exposure (did not affect AUC) of tasimelteon but Cmax was reduced by 44%. The median Tmax was delayed from 0.75 hours to 2.5 hours by high-fat meal. In Vitro Study Reviews 1.14 In vitro determination of protein binding of [14C]BMS-214778 in human, monkey, rat, and mouse sera. Study Title Study number Study Period Study Director Objective In vitro determination of protein binding of [14C]BMS-214778 in human, monkey, rat, and mouse sera. 910073823 April 1999 (b) (4) This study was conducted to determine in vitro plasma protein binding of tasimelteon in human, monkey, rat, and mouse sera. 122 Reference ID: 3403865 METHODS Serum protein binding was determined by equilibrium dialysis for 4 hat 37°C at five concentrations. [14C]BMS-214778 was used to determine the time to reach equilibrium and the extent of protein binding in serum. Stability in Serum and Plasma The stability was determined by incubating BMS-214778 in human serum at 10 and 2,000 ng/mL in monkey, rat, and mouse plasma at 200 and 20,000 ng/mL at 37 °C. Samples were removed preincubation and at 3, 4, 6, and 24 h. All samples were stored at -20 °C until analyzed for BMS214778 by an LC/MS method. Peak area response ratios of BMS-214778 to the internal standard were determined. Stability was assessed based on the peak area response ratios at various times relative to the response ratio at preincubation. Equilibrium Dialysis Serum protein binding was determined by equilibrium dialysis using sodium phosphate buffer (0.134M, pH 7.4) and Spectra/POR molecular porous dialysis membranes with a 12:000-14,000 Dalton molecular weight cutoff. Dialysis cells were rotated at 20 rpms in a water bath at 37 °C. The time to reach equilibrium study was carried out at two nominal concentrations in human serum. After establishing the time to reach equilibrium, samples for all subsequent experiments were collected at that time. The serum protein binding experiments were carried out at five nominal concentrations ranging from 10 to 2,000 ng/mL in human serum and 200 to 20,000 ng/mL in monkey, rat, and mouse sera. RESULTS The results of plasma protein binding are summarized in the table below. Total Conc Mean (SD) Total Cone (ng/L) %Bound in Human (ng/mL) Mean (SD) % Percent Bound in Monkey Rat Mouse 79.7 (0.22) 84.8 (0.12) 77.6 (0.19) 1,000 78.2 (0.23) 83.5 (0.14) 77.5 (0.64) 89. 1 (0.46) 5,000 74.0 (0.49) 80.6 (0.25) 76.3 (0.08) 1,000 87.7 (0.19) 10,000 71.9 (0.51) 78.0 (0.97) 75.3 (0.31) 2,000 85.8 (0.27) 20,000 69.0 (0.75) 76.8 (0.58) 73.5 (0.31) 10 90.3 (0.50) 50 89.9 (0.26) 200 200 CONCLUSIONS 123 Reference ID: 3403865   1.15 Tasimelteon is moderately bound in human, monkey, rat, and mouse sera. The plasma protein binding ranged from 89.1% in human serum to 77.6% in mouse serum The extent of serum protein binding was concentration dependent with relatively small change over 200 fold increases in concentration in human serum and a 100-fold range in monkey, rat, and mouse sera. VEC-162/Tasimelteon: Cytochrome P450 Reaction Phenotyping Study Title Study number Study Period Study Director Objective VEC-162/Tasimelteon: Cytochrome P450 Reaction Phenotyping (b) (4) 08639 May 2009 (b) (4) This study was conducted to investigate the prominent Phase I metabolite profiles of VEC-162/tasimelteon in human liver microsomes and to characterize the cytochrome P450 enzymes responsible for the formation of the prominent metabolites. METHODS Metabolite Profiling [14C]VEC-162, at concentrations of 5 μM and 10 µM in 0.1-M potassium phosphate buffer (pH 7.4), was incubated with human liver microsomes (HLM) at 37 ºC for 1-hr. The incubations were carried out in the presence of 4 mM MgCl2 and 1 mM NADPH. After 1-hr, the metabolic reactions were terminated by mixing with 2 volumes of ice-cold methanol, followed by centrifugation. Metabolite profiling was accomplished by HPLC with radiochemical detection. Characterization and/or identification of the prominent metabolites were conducted by LC/MS/MS in conjunction with radioactivity detection. 7-Ethoxycoumarin (100 µM), as a positive control, was incubated concurrently to assess the metabolic capacity of the human liver microsomes used in the incubation. CYP Phenotyping The incubation mixture, prepared in 0.1 M potassium phosphate buffer (pH 7.4), contained human liver microsomes (HLM) (0.25 mg/mL) or a recombinant human CYP isozyme (rCYP, 50 pmol/mL) and tasimelteon (100µM) or a marker substrate. After a pre-incubation at 37 oC for 5 min in a shaking water bath, the reaction was initiated by the addition of NADPH (1 mM) solution. Samples were incubated aerobically in a shaking water bath at 37 oC. The incubation was terminated by the addition of the appropriate quench solution. After centrifugation, the supernatant was analyzed by LC/MS/MS. Positive control incubations containing marker substrates were incubated concurrently to assess the metabolic capacity of HLM and rCYP used in each assay. RESULTS 124 Reference ID: 3403865 P450 Mediated Metabolism of Tasimelteon in HLM Percentage Inhibition and Formation of M9, M11, M12, M13, and M14 in Human Liver Microsomes and rCYP Isoforms CYP Isofor m 1A2 2B6 Metabolite M9 Metabolite M11 b a % rCYP CIa 42.9 30.0 b % CI rCYP 487 (High) 40.9 23 (Very Low) d d 1.44 540 (High) NA Metabolite M12 a b % CI rCYP 47.3 49.3 171(High) NA Metabolite M13 a Metabolite M14 b % CIa rCYPb % CI rCYP 69.3 434 (High) NA e 42 (Low) d 67.6 ND 58.8 ND 2C8 83.1 5 (Very Low) 45.5 NA NA NA 37.6 6 (Very Low) NA ND 2C9 80.8 15 (Very Low) d 4.38 NA 29.4 NA NA 46 (Low) e 46.0 ND 2C19 41.9 117 (High) 21.2 130 (High) 4.50 NA 17.6 283 (High) 32.1 ND 2D6 13.5 98 (High) NA 149 (High) 2.39 NA 11.9 571 (High) 43.4 ND 2E1 48.9 NA 35.2 NA 52.3 NA 12.9 NA 87.0 ND 3A4 c 44.2 7 (Very Low) NA 0 74.3 287 (High) 7.28 NA 99.0 226 (High) 125 Reference ID: 3403865 a Percent inhibition of formation of tasimelteon metabolites by isoform-selective chemical inhibitor compared to noinhibitor control in human liver microsomes. b Formation of tasimelteon metabolites by recombinant human cytochrome P450 isoform. c Inhibition of formation of tasimelteon metabolites using 6β-hydroxy-testosterone as CYP3A4 substrate ND: Not detected. d Formation of metabolite ≤ 5% of the highest value e Formation of metabolite ≤ 10% but > 5% of the highest value CYP1A1 is expressed in human liver only in very low levels, metabolism of tasimelteon was tested only in the recombinant CYP1A1 system. Metabolite M12 was formed in the recombinant system, and significant chemical inhibition was observed with the CYP1A1 selective chemical inhibitor, alpha naphoflavone. CONCLUSIONS  CYP1A2 plays a major role in the Phase I metabolism of tasimelteon.  CYP2C19 plays a significant role, specifically in the formation of metabolite M9 and M11 and a minor role in the formation of M13.  CYP3A4 plays a significant role, specifically in the formation of M12 and M14, respectively. CYP2D6 may be involved to a lesser extent in the formation of M9 and M13. CYP1A1 may play a role in the formation of M12. 1.16 In Vitro Evaluation ofVEC-162 as an Inhibitor of Human Cytochrome P450 Enzymes Study Title Study number Study Period Study Director Objective In Vitro Evaluation ofVEC-162 as an Inhibitor of Human Cytochrome P450 Enzymes (b) (4) 065016 August 2006 (b) (4) This study was conducted to evaluate the ability of VEC-162 to inhibit in vitro the major CYP enzymes in human liver microsomes (namely CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 [using two different substrates]). METHODS To evaluate VEC-162 as a direct inhibitor of CYP activity, human liver microsomes from a pool of 16 individuals were incubated with marker substrates, at concentrations approximately equal to each marker substrate's Km, in the presence or absence of VEC-162. The target concentrations of VEC-162 ranged from 0.1 µM to 100 µM. In addition, VEC-162 was evaluated for its ability to function as a time-dependent inhibitor at the same concentrations mentioned above, in which case VEC-162 was pre-incubated with human liver microsomes and a NADPH-generating system for 30 minutes to allow for the generation of metabolites that might inhibit CYP activity. 126 Reference ID: 3403865 Known direct and metabolism-dependent inhibitors of CYP enzymes were included as positive controls. VEC-162 was evaluated for its ability to directly inhibit the following human CYP enzymes. VEC-162 was also evaluated for its ability to inhibit the following CYP enzymes in a timedependent manner. CYP1A2 Phenacetin 0-deethylation CYP2C8 Amodiaquine N-dealkylation CYP2C9 Diclofenac 4'-hydroxylation CYP2Cl9 S-Mephenytoin 4'-hydroxylation CYP2D6 Dextromethorphan O-demethylation CYP3A4/5 Testosterone 6β-hydroxylation CYP3A4/5 Midazolam 1' -hydroxylation RESULTS VEC-162 caused direct inhibition of CYP2C19 with an IC50 value of 80 µM. There was evidence of direct inhibition of CYP1A2, CYP2C8, CYP2D6, and CYP3A4/5 the IC50 values for these enzymes were greater than 100 µM. VEC-162 caused little or no direct inhibition of CYP2C9, and the IC50 value determined for this enzyme was > 100 µM). There was little or no evidence that VEC-162 has the potential to cause time-dependent inhibition of any of the CYP enzymes evaluated (table below). In Vitro Evaluation ofVEC-162 as an Inhibitor of Human CYP Enzymes 127 Reference ID: 3403865 Note: The Cmax of tasimelteon at the 20 mg therapeutic dose is approximately 0.2 µM. CONCLUSIONS Tasimelteon is less likely to cause direct inhibition or time-dependent inhibition of any of the CYP enzymes evaluated (i.e., CYP1A2, CYP2C8, CYP2C9, CYP2Cl9, CYP2D6, or CYP3A4/5) at therapeutic levels. 1.17 In Vitro Evaluation of M9, M12 and M13 as Potential Inhibitors of Cytochrome P450 (CYP) Enzymes in Human Liver Microsomes Study Title Study number Study Period Study Director Objective In Vitro Evaluation of M9, M12 and M13 as Potential Inhibitors of Cytochrome P450 (CYP) Enzymes in Human Liver Microsomes (b) (4) 12A024 November 2010 (b) (4) This study was conducted to investigate inhibition potential of metabolites M9, M12 and M13 METHODS The ability of M9, M12 and M13 to each directly inhibit human CYP enzymes was investigated with a pool of sixteen individual human liver microsomal samples. Each test article concentration was incubated with marker substrate and human liver microsomes in triplicate. To examine its ability to act as a time-dependent inhibitor of CYP enzymes, M9, M12 or M13 (at the same concentrations used to evaluate direct inhibition) was preincubated with human liver microsomes and an NADPH-generating system for 30 minutes to allow for the generation of intermediates that could inhibit human CYP enzymes. To evaluate its ability to inhibit the CYP2C9 and CYP2C19 in a time-dependent manner, experiments were designed to determine if any increase in inhibition in M12 observed after 128 Reference ID: 3403865 preincubation was NADPH-dependent (i.e., metabolism-dependent) and reversible by either microsomal re-isolation or by incubation with potassium ferricyanide prior to re-isolation. RESULTS M9 was not direct or time dependent inhibition of any CYP enzyme activity as shown in the figure below. Inhibition of CYP1A2 (phenacetin O-dealkylation) by M9: IC50 determination Metabolite M13 was a direct inhibitor of CYP3A4/5. The percent of control activity in the presence of 100 μM M13 was 69%. The IC50 value is reported as > 100 μM since less than 50% inhibition of enzyme activity was observed at the highest concentration of M13 examined as shown in the figure below. Inhibition of CYP3A4/5 (midazolam 1′-hydroxylation) by M13: IC50 determination There was no evidence of direct inhibition of any other CYP enzyme activity by M13. 129 Reference ID: 3403865 The IC50 values for M12 for CYP3A4/5 were 84 μM. Inhibition of CYP3A4/5 (midazolam 1′-hydroxylation) by M12: IC50 determination M12 was found to directly inhibit CYP2C8 and CYP2C19 with an IC50 value of >100 μM since less than 50% inhibition of enzyme activity was observed at the highest concentration of M12 examined. Summary of results: In vitro evaluation of M9, M12 and M13 as inhibitors of human CYP enzymes 130 Reference ID: 3403865 Discussion A drug is less likely to cause in vivo drug interactions if the R1 value is greater than 1, as calculated using the formula R1 = 1 + [I]/Ki. Based on human plasma Cmax for M12 of approximately 0.4 μM, R1 is calculated to be approximately 1.01 for CYP3A4/5 direct inhibition. The calculated R1 values for direct inhibition by M12 of other CYP enzymes as well as inhibition of all CYP enzymes by either M9 or M13 are less than 1.1. CONCLUSION The major metabolites of tasimelteon M9, M12 or M13 are less likely to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5 at therapeutic concentrations. 1.18 In Vitro Evaluation of Tasimelteon as an Inhibitor of CYP2B6 in Human Liver Microsomes Study Title Study number Study Period Study Director Objective In Vitro Evaluation of Tasimelteon as an Inhibitor of CYP2B6 in Human Liver Microsomes (b) (4) 065016 February 2013 to March 2013 (b) (4) This study was conducted to evaluate the ability of tasimelteon to inhibit, in vitro, CYP2B6 in human liver microsomes. 131 Reference ID: 3403865 METHODS The ability of tasimelteon to directly inhibit human CYP2B6 was investigated with a pool of sixteen individual human liver microsomal samples. Each test article concentration was incubated with marker substrate and human liver microsomes in duplicate. To examine its ability to act as a metabolism-dependent (i.e., time-dependent and NADPHdependent) inhibitor of CYP2B6, tasimelteon (at the same concentrations used to evaluate direct inhibition) was preincubated with human liver microsomes and an NADPH-generating system for up to 30 minutes to allow for the generation of intermediates that could inhibit human CYP2B6. To distinguish between time-dependent (i.e., NADPH-independent) and metabolismdependent inhibition, tasimelteon was also preincubated with human liver microsomes for 30 minutes without an NADPH-generating system, prior to incubation with the marker substrate. To further evaluate the ability of tasimelteon to inhibit CYP2B6 in a metabolism-dependent manner, experiments were designed to determine if the metabolism-dependent inhibition of CYP2B6 by tasimelteon was reversible by either microsomal re-isolation or by incubation with potassium ferricyanide prior to re-isolation. Another experiment was performed to determine the KI and kinact values associated with inactivation of CYP2B6 by tasimelteon. RESULTS Under the experimental conditions examined, tasimelteon was a direct inhibitor of CYP2B6 with an IC50 value of 550 µM. Furthermore, tasimelteon was a metabolism-dependent (i.e., timedependent and NADPH-dependent) inhibitor of CYP2B6 since the IC50 value shifted approximately 3.7-fold lower (i.e., from 550 μM to 150 μM) after tasimelteon was preincubated with NADPH-fortified human liver microsomes for 30 minutes. Inhibition of CYP2B6 (efavirenz 8-hydroxylation) by tasimelteon: IC50 Determination 132 Reference ID: 3403865 CONCLUSIONS Tasimelteon is less likely to cause direct inhibition or time-dependent inhibition of, CYP2B6 at therapeutic levels. 1.19 In vitro Evaluation of VEC-162 as an Inducer of Cytochrome P450 Expression in Cultured Human Hepatocytes Study Title Study number Study Period Study Director Objective In vitro Evaluation of VEC-162 as an Inducer of Cytochrome P450 Expression in Cultured Human Hepatocytes (b) (4) 063014 March 2007 (b) (4) This study was conducted to to investigate the effect of treating primary cultures of human hepatocytes with VEC-162 on the expression of several microsomal cytochrome P450 (CYP) enzymes, namely CYP1A2, 2C8, 2C9, 2C19, and 3A4/5. METHODS Three preparations of cultured human hepatocytes from three separate human livers were treated once daily for three consecutive days with dimethyl sulfoxide (DMSO, vehicle, 0.1% v/v), one of three concentrations of VEC-162 (1, 10 or 100 μM), or one of two known human CYP inducers namely omeprazole (100 μM) and rifampin (10 μM). After treatment, cells were harvested to prepare microsomes for the analysis of phenacetin O-dealkylation (marker for CYP1A2), paclitaxel 6α-hydroxylation (marker for CYP2C8), diclofenac 4´-hydroxylation (marker for CYP2C9), S-mephenytoin 4´-hydroxylation (marker for CYP2C19), and testosterone 6β133 Reference ID: 3403865 hydroxylation (marker for CYP3A4/5). Microsomes were also analyzed by Western immunoblotting to assess changes in the levels of CYP2C8, CYP2C9, CYP2C19 and CYP3A4. RESULTS Treatment with omeprazole caused a 34.3-fold increase in CYP1A2 activity whereas treatment with rifampin caused an 8.85-, 2.60-, 10.8- and 3.55-fold increase in CYP2C8, 2C9, 2C19 and 3A4/5 activity, respectively. Treatment of cultured human hepatocytes with VEC-162 had no effect on CYP1A2 activity. In all three hepatocyte preparations tested, treatment of hepatocytes with VEC-162 caused a statistically-significant and concentration-dependent increase in CYP2C8 activity (up to 4.43fold). VEC-162 was up to 60.3% as effective as rifampin at inducing CYP2C8 activity. The increase in activity was accompanied by a similar increase in immunoreactive CYP2C8 protein levels. In all three hepatocyte preparations, treatment with VEC-162 caused a statistically-significant and concentration-dependent increase in CYP3A4/5 activity (up to 2.27- fold). VEC-162 was up to 83.2% as effective as rifampin at inducing CYP3A4/5 activity. The increase in CYP3A4/5 activity was accompanied by a similar increase in CYP3A4 immunoreactive protein levels. The effect of treating cultured human hepatocytes with VEC-162 on markers of cytochrome P450: expressed as average fold-increase 134 Reference ID: 3403865 Note: VEC-162 did not increase CYP2C9 and CYP2C19 activity but actually decreased these activities without resulting in decrease in immunoreactive protein indicating metabolism dependent inhibition. However, there was no such inhibition when VEC-162 was evaluated a (b) (4) direct-acting and metabolism-dependent inhibitor of these enzymes, in Study 065016. CONCLUSION VEC-162 (1-100 μM) induces CYP2C8 and 3A4 in cultured human hepatocytes (up to 83% of that induced by rifampin) 1.20 In Vitro Evaluation of Tasimelteon and Metabolites M9, M12 and M13 as Inducers of Cytochrome P450 Expression in Cultured Human Hepatocytes Study Title Study number Study Period Study Director Objective In Vitro Evaluation of Tasimelteon and Metabolites M9, M12 and M13 as Inducers of Cytochrome P450 Expression in Cultured Human Hepatocytes (b) (4) 123078 Sept 2012 to Oct 2012 (b) (4) This study was conducted to investigate the effects of treating cultured human hepatocytes with tasimelteon and its most abundant metabolites (namely M9, M12 and M13) on the expression of cytochrome P450 (CYP) 1A2 and 2B6 enzymes. Tasimelteon’s potential for inducing (b) (4) CYP1A2 has been previously evaluated (Study 063014). It is not included in this study. METHODS Three preparations of cultured human hepatocytes from three separate livers were treated once daily for three consecutive days with one of the following: dimethyl sulfoxide (DMSO, 0.1% v/v, vehicle control), flumazenil (50 μM, negative control), one of three concentrations of tasimelteon (CYP2B6 analysis only), M9, M12 or M13 (1, 10 or 100 μM), omeprazole (50 μM, strong CYP1A2 inducer) or phenobarbital (750 μM, strong CYP2B6 inducer). After treatment, the cells were incubated in situ with the appropriate marker substrate and analyzed by LC/MS/MS. Following the in situ incubation, the same hepatocytes from the same treatment groups were harvested with Trizol to isolate RNA, which was analyzed by qRT-PCR to assess the effect of M9, M12 and M13 on CYP1A2 mRNA as well as the effect of tasimelteon, M9, M12 and M13 on CYP2B6 mRNA levels. RESULTS 135 Reference ID: 3403865 Omeprazole caused increases ranging from 19.1- to 73.6-fold and 9.35- to 88.1-fold in CYP1A2 activity and mRNA levels, respectively Phenobarbital caused increases ranging from 10.7- to 191-fold and 11.5- to 20.9-fold in CYP2B6 activity and mRNA levels, respectively. Treatment of human hepatocyte culture H835, H1123 and HC1-18 with up to 100 μM M9 or M13 caused little to no change in CYP1A2 activity and mRNA levels (less than 2-fold increase). Treatment with up to 10 μM M12 had little to no effect on CYP1A2 activity and mRNA levels (less than 2-fold increase), except for a 2.29-fold increase in CYP1A2 mRNA levels observed in one culture (H835). Treatment with 100 μM M12 caused a 2.71-fold increase in CYP activity in one hepatocyte culture (H835) and an increase in CYP1A2 mRNA levels in two of the hepatocyte preparations (3.40- and 4.64-fold increase). Mean fold increase: The effects of treating cultured human hepatocytes with tasimelteon, M9, M12, M13 or prototypical inducers on cytochrome P450 (CYP) enzyme activity and mRNA levels It should be noted that, at concentrations at or near the Sponsor reported average human maximum plasma concentrations at the 20 mg therapeutic dose) Cmax (1 to 2.5 μM) 136 Reference ID: 3403865 CONCLUSION Tasimelteon and its most abundant metabolites (namely M9, M12 and M13) do not incduce CYP1A2 or CYP2B6 enzymes at therapeutic concentration. 1.21 In vitro Interaction Studies of Tasimelteon and Metabolites M9, M12, and M13 with the Human BCRP ABC (Efflux) Transporter, and with Human OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 Uptake Transporters Study Title Study number Study Period Study Director Objective In vitro Interaction Studies of Tasimelteon and Metabolites M9, M12, and M13 with the Human BCRP ABC (Efflux) Transporter, and with Human OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 Uptake Transporters 12700 November 2012 (b) (4) This study was conducted to determine the inhibitory potential of tasimelteon and metabolites M9, M12 and M13 on the human OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 uptake transporters and the human BCRP efflux transporter. METHODS Uptake transporter inhibition and substrate assays The inhibiting potential of a test article on the transporter is assessed by incubating the test article and a probe substrate with transporter overexpressing cells in parallel with control cells. A test article is considered to have inhibition potential on the transporter if the accumulation of probe substrate in the cells is reduced in the presence of test article. By testing the inhibition potential of the test article at several concentrations, an IC50 was calculated if inhibition is observed. Uptake inhibition assay In the present study the in vitro interaction potential of tasimelteon, M9, M12 and M13 with the human OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 uptake transporters were investigated at 7 concentrations (0.14, 0.41, 1.2, 3.7, 11, 33 and 100 μM) in uptake transporter inhibition assays. Vesicular transport inhibition assays The inhibiting potential of a test article on the transporter is assessed by incubating the test article and a probe substrate with transporter expressing vesicles in the presence and absence of ATP. A test article is considered to have inhibition potential on the transporter if the accumulation of probe substrate in the vesicles is reduced in the presence of test article. By testing the inhibition potential of the test article at several concentrations, an IC50 was calculated if inhibition is observed. 137 Reference ID: 3403865 MDCKII monolayer efflux assays Madin-Darby Canine Kidney (MDCK) cell lines overexpressing efflux transporters are used to study interactions of compounds with the expressed transporter. A contribution of selected transporters to the drug permeability can be investigated in these MDCKII models by choosing the cell line expressing the transporter of interest. Interacting molecules display a difference in transport rates between apical to basolateral and reverse directions in cell monolayers expressing the transporter, whereas no, or significantly less, difference is observed in parental (control) cell monolayers. MDCKII-BCRP inhibition measurements were carried out at one concentration of the test articles in triplicate. RESULTS Inhibition of uptake transporters by tasimelteon and metabolites M9, M12, and M13. Discussion Tasimelteon and its metabolites M9, M12, and M13 were not actively transported by OATP1B1 and OATP1B3. Tasimelteon did not inhibit OATP1B1, OATP1B3, OAT1 and BCRP. However, OCT2 and OAT3 were inhibited with an estimated IC50 values of 60.1 and 34.5 M, respectively. The unbound Cmax at the 20 mg therapeutic dose is at least 350 times lower than the 34.5 µM IC50. The metabolite M9 did not inhibit OATP1B1, OATP1B3, OCT2 and OAT1. However, OAT3 and BCRP were inhibited with IC50 values of 6.8 M and 18.1 μM, respectively. The unbound Cmax of M9 is reported to be 25-fold lower than the determined IC50 for OAT3. M12 did not inhibit OATP1B1, OATP1B3, OAT1 and OAT. However, OCT2 was inhibited with an IC50 of 41.3 M, which is 585 times higher than the unbound Cmax. M13 did not inhibit OATP1B1, OATP1B3 and BCRP. However, OCT2, OAT1, and OAT3 were inhibited with an estimated IC50 value of 75.2, 72.3 and 37.2 M, respectively, a minimum of 380 times higher than the unbound Cmax. CONCLUSIONS Reference ID: 3403865 138   1.22 Tasimelteon and its metabolites M9, M12, and M13 were not actively transported by OATP1B1 and OATP1B3. Tasimelteon and its metabolites have low likelihood of in vivo inhibition of transporters, OATP1B1, OATP1B3, OAT1, BCRP, OCT2 and OAT3. P-gp Interaction Assessment of the Customer's Test Compound (VEC-162) and Metabolites Study Title Study number Study Period Study Director Objective P-gp Interaction Assessment of the Customer's Test Compound (VEC162) and Metabolites 10VNDAP1R1 September 2011 (b) (4) This study was conducted to to assess if the test compound is a Pglycoprotein (P-gp) substrate in Caco-2 cell monolayers; and 3) to assess the P-gp inhibitor potential towards digoxin transport of the test compound in Caco-2 cells. METHODS P-gp Inhibitor Assessment The bi-directional transport of digoxin was measured in the absence and presence of VEC-162, M9, M11, M12, M13, M14 or cyclosporine A (CsA). The purpose of this assay was to determine the effect of the test compound on digoxin efflux transport. CsA and ketoconazole are used as Pgp inhibitors. A 30-minute pre-incubation with test compound and 5 μM CsA solution was performed to preload the cells with test or control compounds. After this pre-incubation, the following procedure was performed: for AP to BL transport, 0.5 mL fresh dosing solutions of digoxin in the absence and presence of test compound or CsA were added to the AP side, and 1.5 mL of HBSSg alone, or containing test compound or CsA, was added to the BL side. For BL to AP transport, 1.5 mL dosing solutions of digoxin, in the absence and presence of test compound or CsA, were added to the BL side, and 0.5 mL of HBSSg alone, or containing test compound or CsA, was added to the AP side. Then, the Caco-2 plates were incubated in a humidified incubator (37 ± 1°C, 5 ± 1% CO2) for 120 minutes. Each determination was performed in triplicate. For receiver samples, aliquots (200 μL) were taken at 120 minutes. Aliquots (50 μL) were taken from the donor compartment at 5 and 120 minutes. P-gp Substrate Assessment The P-gp substrate assessment was performed with the bidirectional permeability. The experiment was conducted in three replicates (n=3) in each AP-to-BL and BL-to-AP direction. Each compound was tested with three concentrations. 139 Reference ID: 3403865 RESULTS P-gp Inhibitor Assessment Permeability and Recovery of Digoxin (VEC-162, M9, M11) Permeability and Recovery of Digoxin (M13) 140 Reference ID: 3403865 Treatment Dil'eetiens Parameters 1 R2 R3 Awrage Elf-I113: e44 - . 5.215 5.553 5.245 5.552 4 5.55 2112-1531- 92? 19 5351 1515555555- {555 25.5 55.5 53.2 55.5 4 5.5 12155555 5 24.1 11511511551? 15.2 15.5 25.5 15.3 4 5.5 ELL-154.45 1?1? 355555551555 32.5 35.5 24.2 355.255 5.555 5.455 5.545 4 5.21 2112?15431- (?mi-??123 15 5?21 35555555155} 55.3 55.1 5552.5 P1555 12.5 13.2 12.2 12.5 4 5.52 ??123 145555555555} 52.4 23.5 35.5 25.2 4 3.1 P1522 4.45 4.22 4.55 4.44 4 5.21 4512?5531- 11219 ?11-9 19 2951 35555555155} 55.5 55.2 52.2 55.5 4 1.2 1215.55551? 5 1.15 5 1125.4 .552 . 551 5.53 4.45 5.15 4 5.21 15-. 5:55-55 35555555155} 21.2 23.1 22.2 25.2 4 5.5 P-gp Substrate Assessment Permeability and Recovery of VEC-162 Treatment Direction Parameters. 1 R2 R3 Aterage i SD gill445.2 55.1 15.15 32.45 5: 21 215?55431- 121? ??123 . 35555315135} 33.2 94.1 315.2 32.3 5: 352-355 5-- 5552' .- 32.5 23.5 31.3 29.3 5: 5.0 3545.45 35555315135} 39.9 99. 3 199 96.45 4 5.3 *5 *1 {51351212155} 49.3 15.3 -1.1 19.4 4 5 11M TEC- 35555315135} 39.9 31'. 3 192 99.1 4 11 43 1?52 P152 51.5 25.2 51.5 23.3 4 4.4 $454.45 1?1? 35555515135} 34.9 92.? 99.1 33.9 5: 4.5 141 Reference ID: 3403865 • • • • • • The efflux ratios of M9 were 0.868 and 0.698 at 1 and 5 μM of M9. At 0.5 μM and 1 μM with CsA groups, since the receiver concentrations of M9 in the AP-to- BL direction were below the lower limit of quantification, an accurate efflux ratio was not obtained at these two treatments. In the absence of CsA, the efflux ratios of M11 were 1.52, 1.47, and 1.31 at M11 dosing concentrations of 0.5, 1, and 5 μM. In the presence of 5 μM CsA, the efflux ratio of M11 was 1.05. In the absence of CsA, the efflux ratios of M12 were 1.39, 1.34, and 1.46 at M12 dosing concentrations of 0.5, 1, and 5 μM. In the presence of 5 μM CsA, the efflux ratio of M12 was 1.15. In the absence of CsA, the efflux ratios of M13 were 1.09, 1.23, and 1.35 at M13 dosing concentrations of 0.5, 1, and 5 μM (Table 26). In the presence of 5 μM CsA, the efflux ratio of M13 was 1.07. In the absence of CsA, the efflux ratios of M14 were 1.01, 1.28, and 1.22 at M14 dosing concentrations of 0.5, 1, and 5 μM (Table 27). In the presence of 5 μM CsA, the efflux ratio of M14 was 1.26. None of the test compounds showed efflux ratios of greater than 2 at the tested concentrations where the accurate efflux ratio was available. CONCLUSION Tasimelteon and its major metabolites M9, M11, M12, M13 or M14 are not P-gp substrates or inhibitors. 142 Reference ID: 3403865 4.3 OCP Filing/Review Form Office of Clinical Pharmacology and Biopharmaceutics New Drug Application Filing and Review Form General Information About the Submission Information Information NDA Number 205677 Brand Name Hetlioz OCPB Division (I, II, III) Medical Division OCPB Reviewer DCP-1 HFD-120 Jagan Mohan Parepally Generic Name Drug Class Indication(s) OCPB Team Leader Date of Submission Estimated Due Date of OCP Review PDUFA Due Date Angela Men 5/31/2013 10/30/2013 1/31/2014 Dosage Form Dosing Regimen Route of Administration Sponsor Tasimelteon, VEC-162 Circadian Regulator Treatment of Non-24 Hour Disorder in Totally Blind Capsules 20 mg QD Oral Vanda Division Due Date 11/8/2013 Priority Classification P Clin. Pharm. and Biopharm. Information Summary: This NDA is to support the marketing approval of tasimelteon, a circadian regulator, proposed to reset the master body clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The activity is believed to be mediated by the affinity of tasimelteon at the MT1 and MT2 receptors in the SCN. Plasma protein binding of tasimelteon is approximately 90%. Tasimelteon is extensively metabolized primarily by oxidation at multiple sites and oxidative dealkylation. Glucuronidation is the major phase II metabolic route. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. CYP1A1, CYP2C9/19, and CYP2D6 also minimally contribute to the metabolism of tasimelteon. Tasimelteon has many metabolites, 8 of which have been characterized - M1, M3, M8, M9, M11, M12, M13, and M14. All of these metabolites are present in plasma and M1, M3, M8, and M9 are also present in urine. M12 and M9 are present at higher plasma levels (180% and 130%, respectively) than the parent drug and M13 is present at about the same level. The pharmacokinetic profiles of the most abundant metabolites as well as other main metabolites (M3, M11, and M12) were studied in the clinical pharmacology program. Exposure to tasimelteon and its main metabolites are affected by drugs that inhibit CYP1A2 (fluvoxamine). The exposures to tasimelteon and its main metabolites are also affected by the induction of CYP1A2 (e.g. cigarette smoking) and/ or CYP3A4 (e.g. rifampin) and in subjects with mild and moderate renal impairment - approximately 2-fold for the parent, less for the metabolites. Mild and moderate hepatic impairment resulted in a corresponding increase in exposure, as measured by AUC(inf), of 144% and 189% respectively, less for the metabolites. The geometric mean ratios (GMR) of tasimelteon Cmax for subjects with mild or moderate hepatic impairment were 122.15% and 118.51%, respectively, as compared to healthy matched control subjects. Food effect was evaluated using 100 mg strength capsule. At one of the EOP2 meetings we pointed out that the study should be conducted using highest strength of to-be-marketed formulation or a justification should be provided based on proportionality in composition of the formulation. The sponsor provided argument based on compositions and in vitro dissolution. The clinical pharmacology evaluation included assessment of PK, tolerability, relative bioavailability, food effect, ADME, QTc prolongation, drug interaction and specific population studies, as summarized 143 Reference ID: 3403865 below: CN116-001 is a single ascending dose study evaluating safety, tolerability, PK and PD in Healthy Subjects. CN116-002 is a multiple ascending dose study evaluating safety, tolerability, PK and PD in Healthy Subjects. CN116-003 is a study comparing of the PK of single doses of tasimelteon in young and elderly subjects. VP-VEC-162-1101 is a human mass-balance study evaluating absorption, metabolism and excretion of tasimelteon in healthy males. VP-VEC-162-1102 is a study evaluating the effect of food on the absorption of 100 mg tasimelteon in healthy subjects. VP-VEC-162-1103 is a TQT study defining the ECG Effects of tasimelteon using a clinical and a supratherapeutic dose compared to placebo and moxifloxacin in healthy men and women. VP-VEC-162-1104 is a study conducted to evaluate potential PK interaction of co-administered tasimelteon at 100 mg with midazolam 10 mg in healthy subjects VP-VEC-162-1105 is a study conducted to compare the PK of tasimelteon in subjects with mild or moderate hepatic impairment with that in matched healthy control subjects. VP-VEC-162-1106 is a study conducted to compare the PK of tasimelteon in subjects with renal impairment and matched healthy control subjects. VP-VEC-162-1107 is a study conducted to evaluate effects of smoking status, age and body size on the pharmacokinetics, safety, and tolerability of tasimelteon in healthy volunteers VP-VEC-162-1108 is a study conducted to evaluate the pharmacodynamic and pharmacokinetic interactions of tasimelteon and ethanol VP-VEC-162-1110 is a study conducted to evaluate the effect of multiple doses of tasimelteon on the CYP 3A4 and 2C8 enzymes using midazolam and rosiglitazone as substrates in healthy subjects. VP-VEC-162-1111 is a study conducted to evaluate the drug-drug interaction between tasimelteon and a CYP1A2 inhibitor, fluvoxamine. VP-VEC-162-1112 is a study conducted to evaluate the drug-drug interaction between tasimelteon and a CYP3A4 inhibitor, Ketoconazole, or a CYP3A4 inducer, rifampin. Phase II VP-VEC-162-2101 is a study conducted to evaluate the effects of tasimelteon on circadian rhythm in healthy subjects. Characteristics of dose effectiveness relationship were evaluated in this dose finding study (10, 20, 50, and 100 mg). Phase III Clinical endpoints for the pivotal phase III studies, VP-VEC-162-3201 and VP-VEC-162-3203 included assessments of circadian period as measured by urinary 6-sulfatoxymelatonin (aMT6s) and urinary cortisol, nighttime sleep parameters, daytime sleep parameters, timing of sleep relative to desired bedtime and global functioning, Clinical Global Impression of Change (CGI-C). The to-be marketed formulation is the same as the one used in clinical studies. Dose Justification The selection of 20 mg as the dose used in the phase III clinical studies for the Non-24 indication is based on dose-finding clinical study and a non-clinical study of chronic phase shifting/ entrainment activity. 144 Reference ID: 3403865 if included Number of Number of Critical Comments If any at ?ling studies studies submitted reviewed present suf?cient to locate reports, tables, data, etc. ng uman HPK Summary Labeling Reference Bioanalytical and Analytical Methods I. Clinical Mass balance: VP-VEC-162-1101 characterization: ratio: Healthy Volunteers- CN116-002 Patients VP-VEC-162-1111 (Fluoxamine) VP- VEC-162-1107 (Smoking), VP-VEC- 162-1112 (Ketoconazole, Rifampin), VP-VEC-162-1108 (Ethanol), Study 1104and 1110 and ln?vivo effects of primary drug: Vitro: Study Study Study 552065016, Study (59063014, Study 92135015, Study and (W) 12700 CN116-003 VP-VEC-162-2101 Phase 1 and/or 2, proof of concept: Phase 2 dose-ranging study (VP-VEC- 162-2101 VEC-162-3203 and 1110 Reference ID: 3403865 Relative bioavailability solution as reference: alternate formulation as reference: Bioequivalence studies - - - - - traditional design; single / multi dose: Study VP-VEC-162-1101 - replicate design; single / multi dose: Food-drug interaction studies: 1 VP-VEC-162-1102 X Dissolution: (IVIVC): In vivo alcohol dose dumping BCS class III. Other CPB Studies Genotype/phenotype studies: Chronopharmacokinetics TQT Literature References - - - - - - X 1 - - VP-VEC-162-1103 X Total Number of Studies 16 + 10 in vitro + Bioanalytical Filability and QBR comments “X” if yes Comments Application filable? X Reasons if the application is not filable (or an attachment if applicable) For example, is clinical formulation the same as the to-be-marketed one? None Comments sent to firm? QBR questions (key issues to be considered) Is there a need for tasimelteon dose adjustment for subjects with hepatic or renal impairment? Is the Clinical Pharmacology of tasimelteon adequately characterized? Is dose selection for Non-24 indication in totally blind adequately supported? Other comments or information not included above Primary reviewer Signature and Date Secondary reviewer Signature and Date On initial review of the NDA/BLA application for filing: Content Parameter Criteria for Refusal to File (RTF) 1 Has the applicant submitted bioequivalence data comparing to-bemarketed product(s) and those used in the pivotal clinical trials? 2 Has the applicant provided metabolism and drug-drug interaction information? 3 Has the sponsor submitted bioavailability data satisfying the CFR 146 Reference ID: 3403865 Yes No N/A Comment X X X 4 5 6 7 8 requirements? Did the sponsor submit data to allow the evaluation of the validity of the analytical assay? Has a rationale for dose selection been submitted? Is the clinical pharmacology and biopharmaceutics section of the NDA organized, indexed and paginated in a manner to allow substantive review to begin? Is the clinical pharmacology and biopharmaceutics section of the NDA legible so that a substantive review can begin? Is the electronic submission searchable, does it have appropriate hyperlinks and do the hyperlinks work? X X X X X Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality) Data 9 Are the data sets, as requested during pre-submission discussions, X submitted in the appropriate format (e.g., CDISC)? 10 If applicable, are the pharmacogenomic data sets submitted in the appropriate format? Studies and Analyses 11 Is the appropriate pharmacokinetic information submitted? X 12 Has the applicant made an appropriate attempt to determine reasonable dose individualization strategies for this product (i.e., appropriately designed and analyzed dose-ranging or pivotal studies)? X 13 Are the appropriate exposure-response (for desired and undesired effects) analyses conducted and submitted as described in the Exposure-Response guidance? X 14 Is there an adequate attempt by the applicant to use exposure-response relationships in order to assess the need for dose adjustments for intrinsic/extrinsic factors that might affect the pharmacokinetic or pharmacodynamics? 15 Are the pediatric exclusivity studies adequately designed to demonstrate effectiveness, if the drug is indeed effective? 16 Did the applicant submit all the pediatric exclusivity data, as described in the WR? 17 Is there adequate information on the pharmacokinetics and exposureresponse in the clinical pharmacology section of the label? General 18 Are the clinical pharmacology and biopharmaceutics studies of X appropriate design and breadth of investigation to meet basic requirements for approvability of this product? 19 Was the translation (of study reports or other study information) from another language needed and provided in this submission? X X X X X X IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE? ___Yes_ If the NDA/BLA is not filleable from the clinical pharmacology perspective, state the reasons and provide comments to be sent to the Applicant. Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter. CC: NDA 205677 HFD-850 (Electronic Entry), HFD-120, HFD-860 (Jagan Parepally, Angela Men, Ramana Uppoor, Mehul Mehta) 147 Reference ID: 3403865 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JAGAN MOHAN R PAREPALLY 11/07/2013 YUXIN MEN 11/07/2013 Reference ID: 3403865 BIOPHARMACEUTICS REVIEW Office of New Drug Quality Assessment Application No.: NDA 205-677 Submission Dates: 5/31/13; 8/20/13; 10/10/13; 10/25/13 Division: DNP Applicant: Vanda Pharmaceuticals Trade Name: Hetlioz Generic Name: tasimelteon Indication: Treatment of Non-24-Hour Disorder in the totally blind Formulation/strengths: Route of Administration: Reviewer: Kareen Riviere, Ph.D. Acting Biopharmaceutics Team Leader: Sandra Suarez, Ph.D. Biopharmaceutics Supervisor: Richard Lostritto, Ph.D. Date 6/4/13 Assigned: Date of 10/30/13 Review: Type of Submission: 505(b)(1) Original NDA IR Capsule/ 20 mg Oral SUMMARY: Submission: This submission is a 505(b)(1) New Drug Application for 20 mg tasimelteon immediate release capsules. The proposed indication is for the treatment of Non-24-Hour Disorder in the totally blind. Review: The Biopharmaceutics review for this NDA is focused on the evaluation and acceptability of 1) the proposed dissolution methodology, 2) the proposed dissolution acceptance criterion. A. Dissolution Method The proposed dissolution method is shown below. USP Apparatus Rotation Speed Media Volume Temp Medium II 50 rpm 500 mL 37 °C 0.1 N HCl The proposed dissolution method is deemed acceptable. B. Dissolution Acceptance Criterion The proposed acceptance criterion is shown below. Acceptance Criterion Q= (b) (4) The proposed dissolution acceptance criterion is not supported by the data and is not acceptable. Therefore, in an IR letter to the Applicant dated September 20, 2013, the ONDQA Biopharmaceutics Team recommended a dissolution acceptance criterion of Q = (b) (4) at 15 minutes based on the mean in-vitro dissolution profiles of the pivotal clinical and primary stability batches at release and 12 month stability. In a submission dated October 25, 2013, the Applicant 1 Reference ID: 3399131 submitted a revised specifications sheet reflecting the recommended dissolution accetpance criterion. C. Evalaution of Data to Support BCS Class ) Designation (b ( The solubility and dissolution data demonstrate that the drug substance is (b) (4) soluble and the proposed product is (b) (4) However, the Clinical Pharmacology reviewer, Dr. Jagan Parepally, has not yet determined as of October 30, 2013 whether the drug substance can be classified as (b) (4) permable. Thus, the determination of BCS Class b( Designation for this proposed product is still pending. RECOMMENDATION: 1. Hetlioz (tasimelteon) capsules, 20 mg is recommended for approval from a Biopharmaceutics standpoint.  The following dissolution method and acceptance criterion are recommended and have been agreed upon with the Applicant (submission dated October 25, 2013): i. Dissolution method: Apparatus II, 50 rpm agitation rate, 500 mL media volume, 37 °C, 0.1 N HCl. ii. Acceptance criterion: Q = (b) (4) at 15 minutes. Kareen Riviere, Ph.D. Biopharmaceutics Reviewer Office of New Drug Quality Assessment Sandra Suarez, Ph.D. Acting Biopharmaceutics Team Leader Office of New Drug Quality Assessment cc: Dr. Richard Lostritto 2 Reference ID: 3399131 ASSESSMENT OF BIOPHARMACEUTICS INFORMATION 1. Background Drug Substance The structure of tasimelteon is shown in Figure l. The applicant reports that tasimelteon is BCS Class 6 comp01md. Figure 1. Chemical structure of tasimelteon The solubility of tasimeltion at pH 1. 4.6. and 7.6 is shown in Table 1. Table 1. Solubility of Tasimelteon at 1.0 0.1 HCI 1.5 0.1 Sodium Acetate 4.6 Buffer 1.5 0.1N Sodium Phosphate 7'6 Buffer 1'2 Reviewer ?5 Assessment: From these data, it can be concluded that the solubility of tasimelteon is not pH dependent in the physiological pH range. For sink conditions to be achieved, the solubility of tasimelteon needs to be at least in the proposed medium. Hence, sink conditions are achieved in the physiological pH range. Less than 00(4) of aqueous buffer with pH 1- 7.6 is required to dissolve 20 mg of tasimelteon. Drug Product The composition of the proposed drug product is shown below. Table 2. Composition of 20 mg Tasimelteon IR Capsule Component Function Quantitative composition weight per capsule (mg) Tasimelteon drug substance Active 20.001 ingredient Lactose (1) cellulose (0 ollo:dal dxomde Croscarmellose sodium Magnesium stearate (4) (4) Size 1. dark blue opaque. hard gelatin capsules printed with 20 mg" in white? Total capsule weight for size 1 NA 376.00 2. Dissolution Method 3 Reference ID: 3399131 The proposed dissolution method is shown below. USP Rotation Media Apparatus Speed Volume Temperature Medium 2 50 500 mL 37 0.1 Effect of Dissolution Medium Reviewer ?s Assessment: The data in Table I con?rm that the solubili tasimelteon is The 20 mg tasimelteon capsules all the media tested. Thus, the Applicant?s selection for the proposed dissolution medium 0.1 is acceptable. Effect of Dissolution Medium Volume The Applicant generated dissolution pro?les using - 500 and. mL of 0.1N These data are presented in Figure 3. Figure 3. Dissolution Pro?les of 20 Tasimelteon 1R 105 sules in 250, 500 and 900 mL of 0.Reference ID: 33991 31 Reviewer ?s Assessment: Figure 3 shows that 20 mg tasimelteon capsules in all the volumes tested. Therefore, the Applicant?s selection of 500 mL for the dissolution medium volume is acceptable. Effect of Rotation Speed and Apparatus The effect of the ddle rotation speed on the dissolution pro?le was evaluated. The Applicant tested rotational speeds 0.1N (refer to Figure 4). Figure 4. E?ect of Paddle Rotational on Dissolution Pro?les of 20 Tasimelteon lR Capsules %Dmolved saausasa Time (min) The Applicant also evaluated the basket apparatus at agitation speeds. Testing was performed using 500 mL of 0. IN using basket rotation speeds 0 Figure 5.E?ectofB. 105 an . IR Capsules %Release 883d8888 Reviewer ?s Assessment: Figure 4 and 5 show that the dissolution pro?le of 20 mg tasimelteon capsules is similar using either the basket or paddle at the speeds tested. Hence, the Applicant?s selection of 50 paddle speed is acceptable. Discriminating Ability The Applicant evaluated the e?ect of substance particle size on dissolution. Note that the proposed particle size acceptancecriterionist=NMT Aco 'nofthe dissolution pro?les in of 0.1N for the capsules containing di?'erent particle size is presented in Figure 6. 5 Reference ID: 33991 31 Figure 6. Dissolution Pro?les for 20 mg Tasimelteon IR Capsules Containing Di??erent Particle Size Drug Substance- in 500 mL of 0.Tim (mil) Reviewer ?5 Assessment: Figure 6 demonstrates that the proposed dissolution method can discriminate changes in drug substance particle size. Overall, the proposed dissolution method is deemed acceptable. 3. Dissolution Acceptance Criterion The proposed dissolution acceptance criterion is shown below. Acceptance Criterion Dissolution pro?le data for the pivotal phase 3 clinical batches are shown in Reviewer?s Figure 1. Reviewer?s Figure 1. Dissolution Pro?le Data for the Pivotal Clinical Batches 110 - 100 Nate (min) 96 Dissolved MAW: The proposed disolution acceptance criterions is not supported by the data and therefore is not acceptable. The following at comment was conveyed to the Applicant in a letter dated September 20, 2013. FDA Comment Your proposed dissolution criterion of is not supported by the provided data and is not acceptable. Your dissolution ta cal and primary stability batches at Reference ID: 33991 31 release and under long term stability (12 months) support an acceptance criterion of at 15 minutes. Implement this change and provide a revised drug product speci?cation table incorporating the updated dissolution acceptance criterion. The following at comment was conveyed to the Applicant in a letter dated October 1 7, 2013 in response to their proposal of FDA Comment We do not agree with your proposal of Your product is and the dissolution data ?'om the clinical and primary sta ty atches at release an un er ong term stability (12 months) support an acceptance criterion of at 15 minutes. Nevertheless, it must be recognized that some batches may require Stage 2 an occasionally, Stage 3 testing. Accordingly, please impluent the dissolution acceptance criterion of at 15 minutes and provide the revised speci?cation table for your drug product. In a submission dated October 25, 2013, the Applicant accepted the recommendation to revise the dissolution acceptance criterion. 4. Dissolution Data to Bridge 20 mg and 100 mg Formulation used in Study 1102 The Applicant conducted Study 1102, a food e?ect study, with a 100 mg capsule, not the 20 mg strength commercial formulation. Table 3 compares the composition of tasimelteon capsules used in clinial studies. Table 3. Composition of Tasimelteon Capsules used in Clinial Studies Component Qnandtatlve for-Ila weight per capsule (lg) Reference to quality Tasimebon drug Vanda substance (Section 3.2.5.4. l) Lactose NF Colloidal silicon dioxide Croscarmellose sodium Magnesium stealate Total?llweight The Applicant performed a dissolution pro?le comparison study in four di?emnt dissolution media. The comparative dissolution pro?le data at 15 minutes are presented in Table 4. Table 4. Comparative Dissolution Data for 20 mg and 100 mg Tasimelteon Capsules Percent of Label Claim Dissolved at 15 Minutes. Dissolution Medium Reference ID: 33991 31 Reviewer ?s Assessment: The dissolution data show that the 20 mg and 100 mg formulation in the physiological pH range. Iherefore, the 20 ans 100 ormulation have similar dissolution rates. Howeverare Thus, from the Biopharmaceutics perspective, in vitro dissolution data can not be used to bridge the 20 mg and 100 mg formulation. 17w Clinical Pharmacology reviewer, Dr. Jagan Parepally, will determine whether the food e?'ect data generated with the 100 mg capsule formulation will be extrapolated to the 20 mg strength commercial product. 5. Dissolution Pro?le Comparison of Size. and Size 1 Capsules The Applicant changed the capsule size form size to size 1 and performed a dissolution pro?le comparison study in four different dissolution media: 0.1 -. The comparative dissolution pro?le data are own Figure 7 a, c, . Figure 7 a, b, c, d. Dissolution Pro?les for Tasimelteon 20mg Size' and Size 1 Capsules in 500 mL Medium 0.1NHCI 1.0 96 Disolved saausasa??5 96 Dinlvel ssaasass? 88:3318388 'l'iu Tim! (Ilia) Reviewer ?s Assessment: Figure 7 shows that for both capsule sizes, the dissolution rate was - dissolved prior to the 15-minute sample regardless of the dissolution medium. Thus, the dissolution of the proposed drug product is considered similar in Sizel and Size 1 capsules. 6. Evalaution of Data to Support BCS Class! Designation The solubili and dissohition data demonstrate that the proposed drug substance is and the drug product is However, the Clinical Pharmacolo reviewer, Dr. Jagan y, has not yet determined er substance has at the time of this review. Thus, the determination of BCS Classl Designation for propos is pending. Reference ID: 33991 31 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KAREEN RIVIERE 10/30/2013 SANDRA SUAREZ 10/30/2013 Reference ID: 3399131 Office of Clinical Pharmacology and Biopharmaceutics New Drug Application Filing and Review Form General Information About the Submission Information Information NDA Number 205677 Brand Name Hetlioz OCPB Division (I, II, III) DCP-1 Generic Name Tasimelteon Medical Division HFD-120 Drug Class Circadian Regulator OCPB Reviewer Jagan Mohan Parepally Indication(s) Treatment of Non-24 Hour Disorder in Totally Blind OCPB Team Leader Angela Men Dosage Form Capsules Date of Submission 5/31/2013 Dosing Regimen 20 mg QD Estimated Due Date of OCP Review 10/30/2013 Route of Administration Oral PDUFA Due Date 1/31/2014 Sponsor Vanda Division Due Date 11/8/2013 Priority Classification P Clin. Pharm. and Biopharm. Information Summary: This NDA is to support the marketing approval of tasimelteon, a circadian regulator, proposed to reset the master body clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The activity is believed to be mediated by the affinity of tasimelteon at the MT1 and MT2 receptors in the SCN. Plasma protein binding of tasimelteon is approximately 90%. Tasimelteon is rapidly and extensively metabolized primarily by oxidation at multiple sites and oxidative dealkylation. Glucuronidation is the major phase II metabolic route. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. CYP1A1, CYP2C9/19, and CYP2D6 also minimally contribute to the metabolism of tasimelteon. Tasimelteon has many metabolites, 8 of which have been characterized - M1, M3, M8, M9, M11, M12, M13, and M14. All of these metabolites are present in plasma and M1, M3, M8, and M9 are also present in urine. M12 and M9 are present at higher plasma levels (160% and 95%, respectively) than the parent drug and M13 is present at about 92%. The pharmacokinetic profiles of the most abundant metabolites as well as other main metabolites (M3, M11, and M12) were studied in the clinical pharmacology program. Exposure to tasimelteon and its main metabolites are affected by drugs that inhibit CYP1A2 (fluvoxamine). The exposures to tasimelteon and its main metabolites are also affected by the induction of CYP1A2 (e.g. cigarette smoking) and/ or CYP3A4 (e.g. rifampin) and in subjects with mild and moderate renal impairment - approximately 2-fold for the parent, less for the metabolites. Mild and moderate hepatic impairment resulted in a corresponding increase in exposure, as measured by AUC(inf), of 144% and 189% respectively, less for the metabolites. The geometric mean ratios (GMR) of tasimelteon Cmax for subjects with mild or moderate hepatic impairment were 122.15% and 118.51%, respectively, as compared to healthy matched control subjects. Food effect was evaluated using 100 mg strength capsule. At one of the EOP2 meetings we pointed out that the study should be conducted using highest strength of to-be-marketed formulation or a justification should be provided based on proportionality in composition of the formulation. The sponsor provided argument based on compositions and in vitro dissolution. The clinical pharmacology evaluation included assessment of PK, tolerability, relative bioavailability, food effect, ADME, QTc prolongation, drug interaction and specific population studies, as summarized below: CN116-001 is a single ascending dose study evaluating safety, tolerability, PK and PD in Healthy Reference ID: 3382219 Subjects. CN116-002 is a multiple ascending dose study evaluating safety, tolerability, PK and PD in Healthy Subjects. CN116-003 is a study comparing of the PK of single doses of tasimelteon in young and elderly subjects. VP-VEC-162-1101 is a human mass-balance study evaluating absorption, metabolism and excretion of tasimelteon in healthy males. VP-VEC-162-1102 is a study evaluating the effect of food on the absorption of 100 mg tasimelteon in healthy subjects. VP-VEC-162-1103 is a TQT study defining the ECG Effects of tasimelteon using a clinical and a supratherapeutic dose compared to placebo and moxifloxacin in healthy men and women. VP-VEC-162-1104 is a study conducted to evaluate potential PK interaction of co-administered tasimelteon at 100 mg with midazolam 10 mg in healthy subjects VP-VEC-162-1105 is a study conducted to compare the PK of tasimelteon in subjects with mild or moderate hepatic impairment with that in matched healthy control subjects. VP-VEC-162-1106 is a study conducted to compare the PK of tasimelteon in subjects with renal impairment and matched healthy control subjects. VP-VEC-162-1107 is a study conducted to evaluate effects of smoking status, age and body size on the pharmacokinetics, safety, and tolerability of tasimelteon in healthy volunteers VP-VEC-162-1108 is a study conducted to evaluate the pharmacodynamic and pharmacokinetic interactions of tasimelteon and ethanol VP-VEC-162-1110 is a study conducted to evaluate the effect of multiple doses of tasimelteon on the CYP 3A4 and 2C8 enzymes using midazolam and rosiglitazone as substrates in healthy subjects. VP-VEC-162-1111 is a study conducted to evaluate the drug-drug interaction between tasimelteon and a CYP1A2 inhibitor, fluvoxamine. VP-VEC-162-1112 is a study conducted to evaluate the drug-drug interaction between tasimelteon and a CYP3A4 inhibitor, Ketoconazole, or a CYP3A4 inducer, rifampin. Phase II VP-VEC-162-2101 is a study conducted to evaluate the effects of tasimelteon on circadian rhythm in healthy subjects. Characteristics of dose effectiveness relationship were evaluated in this dose finding study (10, 20, 50, and 100 mg). Phase III Clinical endpoints for the pivotal phase III studies, VP-VEC-162-3201 and VP-VEC-162-3203 included assessments of circadian period as measured by urinary 6-sulfatoxymelatonin (aMT6s) and urinary cortisol, nighttime sleep parameters, daytime sleep parameters, timing of sleep relative to desired bedtime and global functioning, Clinical Global Impression of Change (CGI-C). The to-be marketed formulation is the same as the one used in clinical studies. Dose Justification The selection of 20 mg as the dose used in the phase III clinical studies for the Non-24 indication is based on dose-finding clinical study and a non-clinical study of chronic phase shifting/ entrainment activity. “X” if included at filing STUDY TYPE Reference ID: 3382219 Number of studies submitted Number of studies reviewed Critical Comments If any Table of Contents present and sufficient to locate reports, tables, data, etc. Tabular Listing of All Human Studies HPK Summary Labeling Reference Bioanalytical and Analytical 6 Methods I. Clinical Pharmacology Mass balance: 1 - VP-VEC-162-1101 Isozyme characterization: Blood/plasma ratio: - - Plasma protein binding: 1 - Study 910073823 Pharmacokinetics Phase I) - Healthy Volunteers- single dose: 1 - Study CN116-001 multiple dose: 1 Study CN116-002 Patients- single dose: - - multiple dose: - - Dose proportionality - fasting non-fasting single dose: - - Assessed in SD and MD studies fasting non?fasting multiple dose: - - - Drug-drug interaction studies - ln-vivo effects on primary drug: 6 - VP-VEC-162-1111 (Fluoxamine) VP- VEC-162-1107 (Smoking), VP-VEC- 162-1112 (Ketoconazole, Rifampin), VP-VEC-162-1108 (Ethanol), Study 1104 and Study 1110 (3A4 and 208) ln-vivo effects of primary drug: - - - ln-vitro: 9 - Study 1101, Study Study Study ?b>12A024, Study W065016, Study ??osao14, Study $921350?, Study 18VNDAP1R1, and (W) 12700 Subpopulation studies - ethnicity: - - - gender: 1 - Study CN116-003 pediatrics: - - - geriatrics: renal impairment: 1 - VP-VEC-162-1106 hepatic impairment: 1 - VP-VEC-162-1105 PD: Phase 1: - - - Phase 2: 1 - VP-VEC-162-2101 PKIPD: Phase 1 and/or 2, proof of concept: - - Phase 2 dose-ranging study (VP-VEC- 162-2101) Phase 3 clinical trial: - - Studies VP-VEC-162-3201 and VP- VEC-162-3203 Population Analyses - Data rich: - - Study 1105, Study 1106, Study 1107, and Study 1110 Data sparse: - - - ll. Biopharmaceutics Absolute bioavailability: - - - Relative bioavailability - - - Reference ID: 3382219 solution as reference: alternate formulation as reference: - - Study VP-VEC-162-1101 - - Food-drug interaction studies: X 1 Dissolution: - - - - - - Genotype/phenotype studies: - - - Chronopharmacokinetics - - - TQT X 1 - Literature References X - - Bioequivalence studies traditional design; single / multi dose: replicate design; single / multi dose: VP-VEC-162-1102 (IVIVC): In vivo alcohol dose dumping BCS class III. Other CPB Studies Total Number of Studies VP-VEC-162-1103 16 + 10 in vitro + Bioanalytical Filability and QBR comments “X” if yes Application filable? X Comments Reasons if the application is not filable (or an attachment if applicable) For example, is clinical formulation the same as the to-be-marketed one? None Comments sent to firm? Is there a need for tasimelteon dose adjustment for subjects with hepatic or renal impairment? QBR questions (key issues to be considered) Is the Clinical Pharmacology of tasimelteon adequately characterized? Is dose selection for Non-24 indication in totally blind adequately supported? Other comments or information not included above Primary reviewer Signature and Date Secondary reviewer Signature and Date On initial review of the NDA/BLA application for filing: Content Parameter Criteria for Refusal to File (RTF) 1 Has the applicant submitted bioequivalence data comparing to-be-marketed product(s) and those used in the pivotal clinical trials? 2 Has the applicant provided metabolism and drug-drug interaction information? 3 Has the sponsor submitted bioavailability data satisfying the CFR requirements? 4 Did the sponsor submit data to allow the evaluation of the validity of the analytical assay? 5 Has a rationale for dose selection been submitted? Reference ID: 3382219 Yes No N/A Comment X X X X X 6 7 8 Is the clinical pharmacology and biopharmaceutics section of the NDA organized, indexed and paginated in a manner to allow substantive review to begin? Is the clinical pharmacology and biopharmaceutics section of the NDA legible so that a substantive review can begin? Is the electronic submission searchable, does it have appropriate hyperlinks and do the hyperlinks work? X X X Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality) Data 9 Are the data sets, as requested during pre-submission discussions, submitted X in the appropriate format (e.g., CDISC)? 10 If applicable, are the pharmacogenomic data sets submitted in the appropriate format? Studies and Analyses 11 Is the appropriate pharmacokinetic information submitted? 12 Has the applicant made an appropriate attempt to determine reasonable dose individualization strategies for this product (i.e., appropriately designed and analyzed dose-ranging or pivotal studies)? 13 Are the appropriate exposure-response (for desired and undesired effects) analyses conducted and submitted as described in the Exposure-Response guidance? 14 Is there an adequate attempt by the applicant to use exposure-response relationships in order to assess the need for dose adjustments for intrinsic/extrinsic factors that might affect the pharmacokinetic or pharmacodynamics? 15 Are the pediatric exclusivity studies adequately designed to demonstrate effectiveness, if the drug is indeed effective? 16 Did the applicant submit all the pediatric exclusivity data, as described in the WR? 17 Is there adequate information on the pharmacokinetics and exposureresponse in the clinical pharmacology section of the label? General 18 Are the clinical pharmacology and biopharmaceutics studies of appropriate design and breadth of investigation to meet basic requirements for approvability of this product? 19 Was the translation (of study reports or other study information) from another language needed and provided in this submission? X X X X X X X X X X IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE? ___Yes_ If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and provide comments to be sent to the Applicant. Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter. CC: NDA 205677 HFD-850 (Electronic Entry), HFD-120, HFD-860 (Jagan Parepally, Angela Men, Ramana Uppoor, Mehul Mehta) Reference ID: 3382219 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JAGAN MOHAN R PAREPALLY 10/01/2013 YUXIN MEN 10/01/2013 Reference ID: 3382219 PRODUCT QUALITY - BIOPHARMACEUTICS FILING REVIEW NDA Number Submission Date Product name, generic name of the active Dosage form and strength Applicant Clinical Division Indication Type of Submission Biopharmaceutics Reviewer Biopharmaceutics Team Leader Acting Biopharmaceutics Supervisor 205-667 5/31/2013 Hetlioz (tasimelteon) IR Capsule/ 20 mg Vanda Pharmaceuticals DNP Treatment of Non-24-Hour Disorder in the totally blind 505(b)(1) Original NDA Kareen Riviere, Ph.D. Angelica Dorantes, Ph.D. Richard Lostritto, Ph.D. The following parameters for the ONDQA’s Product Quality-Biopharmaceutics filing checklist are necessary in order to initiate a full biopharmaceutics review (i.e., complete enough to review but may have deficiencies). ONDQA-BIOPHARMACEUTICS A. INITIAL OVERVIEW OF THE NDA APPLICATION FOR FILING 1. 2. 3. 4. 5. 6. 7. Parameter Does the application contain dissolution data? Is the dissolution test part of the DP specifications? Does the application contain the dissolution method development report? Is there a validation package for the analytical method and dissolution methodology? Does the application include a biowaiver request? Is there information provided to support the biowaiver request? Does the application include an IVIVC model? 8. Is information such as BCS classification mentioned, and supportive data provided? 9. Is information on mixing the product with foods or liquids included? 10. Is there any in vivo BA or BE information in the submission? Yes No Comment x x Refer to the Initial Assessment. x x x Not Applicable. x Not Applicable. x Not Applicable. The Applicant reports that tasimelteon is a BCS Class (b) compound. A comment will be conveyed to( the Applicant to clarify whether they are requesting BCS Class (b) designation. x x x Not Applicable. There are several PK studies that will be reviewed by the Clinical Pharmacology reviewer. NDA 205-677 Product Quality - Biopharmaceutics Filing Review Reference ID: 3339916 Page 1 PRODUCT QUALITY - BIOPHARMACEUTICS FILING REVIEW B. FILING CONCLUSION 11. 12. 13. Parameter IS THE BIOPHARMACEUTICS SECTIONS OF THE APPLICATION FILEABLE? If the NDA is not fileable from the biopharmaceutics perspective, state the reasons and provide filing comments to be sent to the Applicant. Are there any potential review issues to be forwarded to the Applicant? Yes No Comment x - x IR comments will be sent to the Applicant prior to the 74 day letter. The comments are outlined in the Initial Assessment. {See appended electronic signature page} Kareen Riviere, Ph.D. Biopharmaceutics Reviewer Office of New Drug Quality Assessment 7/11/13 Date {See appended electronic signature page} Angelica Dorantes, Ph.D. Biopharmaceutics Team Leader Office of New Drug Quality Assessment 7/11/13 Date NDA 205-677 Product Quality - Biopharmaceutics Filing Review Reference ID: 3339916 Page 2 PRODUCT QUALITY - BIOPHARMACEUTICS FILING REVIEW INITIAL ASSESSMENT OF BIOPHARMACEUTICS INFORMATION This submission includes a drug product development section with the proposed dissolution method, the proposed dissolution acceptance criterion, and dissolution data bridging the 20 mg commercial product with the 100 mg formulation used in Study 1102 (a food effect study). Note that the 20 mg and 100 mg strengths are (b) (4) There are PK, efficacy, and safety data/information on the to-be marketed 20 mg strength commercial product. The proposed dissolution method is: USP Rotation Apparatus Speed 2 50 rpm Media Volume Temp Medium 500 mL 37 °C 0.1 N HCl The proposed acceptance criterion is: Acceptance Criterion Q= (b) (4) The Biopharmaceutics review for this NDA will be focused on the evaluation and acceptability of 1) the proposed dissolution methodology, 2) the proposed dissolution acceptance criterion, and 3) dissolution data to bridge the 20 mg commercial product with the 100 mg formulation used in Study 1102 (a food effect study). Although the Applicant claims that tasimelteon is a BCS Class (b) compound, it is unclear whether the Applicant is requesting BCS Class (b) designation for the drug product. If the Applicant is requesting BCS Class (b) designation for the drug product, the Biopharmaceutics review will also focus on the evaluation and acceptability of the data/information to support this designation. RECOMMENDATION: The ONDQA Biopharmaceutics team has reviewed NDA 205677 for filing purposes. We found this NDA fileable from a Biopharmaceutics perspective. The Applicant has submitted a reviewable submission. To aid the review of the NDA submission, the following comments will be conveyed to the Applicant: 1. Provide complete dissolution profile data (raw data and mean values) from the pivotal clinical and primary stability batches supporting the selection of the proposed dissolution acceptance criteria (i.e., specification-sampling time points and values) for your proposed product. 2. Clarify whether you are requesting FDA to designate your proposed product as a BCS Class b( drug product. Note that solubility, permeability, gastric stability, and dissolution data will be needed to support the BCS-Class (b) designation for your product. For the specific information/data that are needed to classify your (proposed product, please refer to the attached BCS document and the BCS guidance (link is below). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC M070246.pdf NDA 205-677 Product Quality - Biopharmaceutics Filing Review Reference ID: 3339916 Page 3 7 page(s) have been withheld for BCS Guidance. Refer to http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM070246.pdf --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KAREEN RIVIERE 07/11/2013 ANGELICA DORANTES 07/11/2013 Reference ID: 3339916