CENTER FOR DRUG EVALUATION AND RESEARCH APPLI CA I 0N NUMBER: 2056410rig13000 SUMMARY REVIEW Summary Review of Regulatory Action Date April 25, 2014 From Lydia I. Gilbert-McClain, MD Subject Summary Review of regulatory action NDA NDA 205-641 Applicant Merck, Sharpe, and Dohme Date of Submission June 27, 2013 PDUFA Goal Date April 25, 2014 Proprietary Name/Established (USAN) names Dosage forms/Strength Recommended Action Asmanex HFA/mometasone furoate inhalation aerosol Inhalation aerosol(metered dose inhaler)/100 and 200 mcg mometasone furoate/actuation “maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older Approval MATERIALS REVIEWED Reviewers Clinical Review Kimberly Witzmann, MD CDTL Memo Anthony Durmowicz, MD Biometrics Review Robert Abugov, PhD Division of Medical Policy Programs (DMPP) – OPDP review Twanda Scales, RN, MSN/Ed Proposed Indication (s) 1. Introduction Merck, Sharp, and Dohme (the Applicant) submitted a 505(b) (1) NDA on June 27th 2013, to support approval of Asmanex HFA (mometasone furoate) inhalation aerosol for the maintenance treatment of asthma in patients 12 years of age and older. This product is the corticosteroid component of the already approved fixed dose combination product Dulera comprised of a inhaled corticosteroid (ICS) mometasone furoate (MF) and a long-acting beta agonist (LABA) (b) (4) formoterol (FF). Dulera was approved on June 22, 2010, for the treatment of asthma in patients 12 years of age and older. The Division encouraged the Applicant to develop the corticosteroid component of the Dulera combination product as a monotherapy for asthma. Conceptually, patients on a fixed dose combination of LABA/ICS would have a smoother transition when stepping down from an ICS/LABA fixed dose combination product if they can step down to the ICS of the same formulation as in the combination product and vice versa. The Applicant moved forward with the Division’s recommendation and completed development of the ICS (mometasone furoate) HFA for marketing. There is already a single ingredient mometasone furoate inhalation product approved and marketed for asthma, however, this product (Asmanex Twisthaler) is a different formulation (dry powder). The clinical data to support the single ingredient mometasone furoate HFA is principally derived from the studies 1 Reference ID: 3495705 conducted to support the approval of the fixed dose combination LABA/ICS product. This summary review highlights the key elements of the application and basis for the regulatory decision. 2. Background Asthma is a chronic inflammatory respiratory disease characterized by periods of acute symptoms of wheezing, and shortness of breath, and inhaled corticosteroids play a principal therapeutic role in the management of patients with persistent asthma. Patients with persistent asthma whose disease remains uncontrolled in spite of treatment with controller therapy such as inhaled corticosteroids are candidates for treatment with LABA/ICS fixed dose combination products. Patients can be stepped down from LABA/ICS treatment to a monotherapy steroid when stable as deemed appropriate by their healthcare provider and having a monotherapy ICS in the same formulation as the combination product, makes for a smoother transition. Therefore, during the review of the Dulera NDA the Applicant was encouraged to pursue marketing approval for the ICS component and this NDA was submitted to support the efficacy and safety of MF in the same HFA formulation as the Dulera fixed dose combination product. 3. CMC/Facilities/Inspections The active ingredient (API) is mometasone furoate which is a well known corticosteroid approved in another single ingredient product for oral inhalation (Asmanex Twisthaler), and as the ICS in the Dulera fixed dose combination product. Asmanex HFA is an inhalation aerosol in a pressurized mini dose inhaler propelled by the hydrofluroalkane (HFA) 227. The product is formulated in 2 strengths of MF 100 and 200 mcg/actuation [ex-actuator]. The product also (b) (4) (b) (4) (b) (4) contains ethanol and oleic acid. The product has a dose counter attached to the pressurized canister. There are no outstanding CMC issues. 4. Nonclinical Pharmacology/Toxicology No new non-clinical pharmacology/toxicology studies were required or performed for this application. Pharmacology/toxicology information was previously submitted and reviewed under NDA 22-518 [Dulera]. 5. Clinical Pharmacology/Biopharmaceutics No new clinical pharmacology/biopharmaceutics were conducted to support this application. Supporting clinical pharmacology information is referenced from NDA 22-518 [Dulera]. 6. Clinical Microbiology Not applicable 7. Clinical/Statistical Efficacy The determination of efficacy for Asmanex HFA was based on the data generated from the clinical studies conducted with the Dulera program. Table 1(copied from Dr. Anthony Durmowicz’s CDTL review) outlines the relevant studies used to support the efficacy of Asmanex HFA. 2 Reference ID: 3495705 Table 1: Clinical Studies Used to Support the Ef?cacy of Mometasone HFA Study/ Study Study Age Baseline Treatments Primary Endpoint Year Design Duration Initiated Primary Efficac and Safety P04334 R. DB. 26 week 12-76 60-90% 781 200/10 BID Post-dose FEVI U5, Catlada, PC predicted MP 200 BID EU, Asra, F10 BID South America Safety Placebo 2008 Ef?cacy P04431 R. DB 12 week 12-84 50-85% 728 200/10 BID Post-dose FEVI US, predicted 400/10 BID Safety MP 400 BID America 2008 Ef?cacy Dose Selection PC. AC. 12 week 12-81 60-90% 435 MP-MDI 50 BID 1-4 hr post-dose PEVI US predicted MP-MDI 200 BID Dose- MP-MDI 400 BID 1998 range MF-MDI 600 BID BDP 168 BID Placebo PC 12 week 12-72 60-90% 232 MP-MDI 50 BID 1-4 hr post-dose U5 predicted MP-MDI 200 BID Ef?cacy. BDP 168 BED 1998 Safety Placebo I97-200 AC 12 week 12-76 55-90% 715 MP-MDI 100 BID 1-4 hr. post-dose PEVI EU, South predicted MP-MDI 200 BID Amen?, Ef?cacy. MP-MDI 400 BID South A??rca 1998 Safety PP MDI 250 BID- CFC Long Term Safety R. AC. 52 week 12-70 60-90% 308 MP MDI 200 BID Safety U5 0L predicted MP MDI 600 BID BDP 168 BID 1999 P04139 R. OL. 52 weeks 12-75 60-90% 404 200/10 BID Safety AC predicted 400/ 10 BID HPA axis 250/50 BID 500/50 BID =mornetasone furoate: P=fomroterol frunarate: MP formoterol: beclomethasone diproprionate: ?uticasone salmeterol: ?uticasone propionate: R=randomized: DB=double blind: OL=open label: AC =active control Studies that provided support for the doses selected for the phase 3 trials (C 97-208, 97-225, and 197-200) were conducted with a closely related but older MP MDI formulation and the studies showed that after 12 weeks of treatment there is not much of a dose response (based on PEV1 assessment) from doses 200 mg and higher (11p to 800 mg). The doses in this range are all on the ?at part of the dose response cruve. This range of doses is within the approved recommended dose ranges for Asmanex Twisthaler, and this range of doses was studied in the Dulera program. The data to support ef?cacy of the MP monotherapy are from the two factorial designed studies in the Dulera program. Both of these studies provide adequate support for MP as monotherapy for asthma. In one study (P043 34 supports 200 twice daily dosing) the change in mean trough FEV1 from baseline to week 12 compared to placebo showed signi?cantly greater improvement in patients on MP monotherapy compared to placebo with a treatment difference from placebo of 120 mL, 95% CI (0.05, 0.20) and patients on NIP monotherapy had less deteriorations in asthma compared to placebo patients. In the other study Reference ID: 3495705 (P04431 – supports the 400 mcg twice daily dosing) conducted to demonstrate the added benefit of the higher dose of mometasone (400 mcg twice daily) compared to 200 mcg twice daily in the fixed dose combination product, there was numerical separation between the two product products MF/FF 200 mcg/10 mcg, and 400 mcg/10 mcg for trough FEV1. This finding indicates that the MF 400 mcg component had an additional efficacy benefit above the efficacy shown with MF/FF 200 mcg/10 mcg. As this study was conducted in a more severe asthma population a placebo arm was (appropriately) not included in the study. There is however, placebo-controlled data (from the dose ranging studies) comparing the 400 mcg MF to placebo. Given that efficacy of MF 200 mcg twice daily has been demonstrated, the efficacy of MF 400 mcg is not in question. More appropriately, the MF 400 mcg product should be recommended for patients with more severe asthma on higher doses of ICS or oral corticosteroids. 8. Safety There are no new safety signals with this HFA formulation of mometasone furoate. Like all ICS, the product will be labeled with the standard class labeling safety warnings and precautions that are in other ICS labels. No new safety signals emerged from the program to suggest that the HFA formulation of MF has a different or worse safety profile than other ICS for the treatment of asthma. 9. Advisory Committee Meeting An advisory committee meeting was not necessary for this application. The active ingredient in the product is a well know corticosteroid. 10. Pediatrics This application triggered PREA because it is a new dosage form. The Applicant has asked for a waiver of pediatric studies in children less than 5 years of age and a deferral of pediatric studies in children 5 to 11 years of age. These are reasonable requests and the PeRC agrees with granting the partial waiver and deferral of pediatric studies. 11. Other Relevant Regulatory Issues  Data Quality, Integrity, and Financial Disclosure There was no need for a DSI audit for this application. The financial disclosure information for this application is contained in the Dulera NDA22-518 (already approved) the three investigators who had disclosable financial interests did not affect the outcome of the studies. 12. Labeling There are no outstanding labeling issues. The name Asmanex HFA is acceptable. Patient Labeling and Medication Guide A medication guide for this product is not warranted. 13. Action and Risk Benefit Assessment Regulatory action The regulatory action for the application is approval. The submitted data support approval of Asmanex HFA for the maintenance treatment of asthma in patients 12 years of age and older. (b) (4) The recommended dose for patients on medium inhaled corticosteroids is 200 mcg twice daily (from the Asmanex HFA 100 mcg product) and for patients with more severe asthma 4 Reference ID: 3495705 on oral corticosteroids, the recommended dose is 400 mcg twice daily (from the Asmanex HFA 200 mcg product). Risk Benefit Assessment Inhaled corticosteroids for the maintenance treatment of asthma have a well established risk benefit profile. The safety profile of this product appears to be similar to other approved ICS and the benefit of ICS in the management of asthma is well established. Postmarketing Risk Management Activities None Postmarketing Study Commitments/Requirements No additional postmarketing studies are required for this application. The PREA requirements are being conducted under the Dulera pediatric development program Comments to the Applicant There are no deficiency comments to be conveyed to the Applicant. 5 Reference ID: 3495705 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------LYDIA I GILBERT MCCLAIN 04/25/2014 Reference ID: 3495705