DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 208030 ACCELERATED APPROVAL ApoPharma Inc. c/o Cato Research Ltd. Attention: Lynda Sutton Chief Regulatory Officer 4364 South Alston Avenue Durham, NC 27713-2220 Dear Ms. Sutton: Please refer to your New Drug Application (NDA) dated November 17, 2014, received November 17, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Ferriprox® (deferiprone) oral solution, 100mg/mL. We acknowledge receipt of your amendments dated December 5 and 18, 2014; January 15 and 30; February 6; April 30; May 1, 5, 6, 7, and 22; June 10 and 24; and July 9, 15, and 31; August 19 and 20, 2015. This new drug application provides for the use of Ferriprox® (deferiprone) oral solution for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. APPROVAL & LABELING We have completed our review of this application, as amended. It is approved under the provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug product and related activities must adhere to the substance and procedures of the referenced accelerated approval regulations. An expiration dating period of 18 months is granted for Ferriprox (deferiprone) oral solution, when stored at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF), protected from light. CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content Reference ID: 3816623 NDA 208030 Page 2 of labeling must be identical to the enclosed labeling (text for the package insert and Medication Guide). Information on submitting SPL files using eLIST may be found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. The SPL will be accessible via publicly available labeling repositories. CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and container labels that are identical to the enclosed carton and immediate container labels, as soon as they are available, but no more than 30 days after they are printed. Please submit these labels electronically according to the guidance for industry titled “Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar material. For administrative purposes, designate this submission “Final Printed Carton and Container Labels for approved NDA 208030.” Approval of this submission by FDA is not required before the labeling is used. Marketing the product(s) with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug. ACCELERATED APPROVAL REQUIREMENTS Products approved under the accelerated approval regulations, 21 CFR 314.510, require further adequate and well-controlled clinical trials to verify and describe clinical benefit. You are required to conduct such clinical trials with due diligence. If postmarketing clinical trials fail to verify clinical benefit or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 314.530, withdraw this approval. We remind you of your postmarketing requirement specified in your submission dated August 20, 2015. This requirement, along with required completion dates, is listed below. 2944-1 Conduct a trial to determine the efficacy and safety of the use of deferiprone to treat iron overload in patients with sickle cell disease and transfusional hemosiderosis who have not been adequately treated with available chelating agents. Submit the protocol for review and concurrence prior to commencing. The trial will enroll a sufficient number of patients with sickle cell disease as described above, to provide sufficient evidence to assess the efficacy and safety in the sickle cell disease population described. The trial may enroll patients with other conditions who have developed transfusional iron overload. The trial will stratify for hematologic diagnosis for the randomization. The primary and secondary endpoints will measure changes in cardiac iron concentration and liver iron concentration. Final Protocol Submission: Reference ID: 3816623 Completed NDA 208030 Page 3 Trial Completion: Final Report Submission: 02/2017 07/2017 Submit clinical protocols to your IND 045724 for this product. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each requirement in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. Submit final reports to this NDA as a supplemental application. For administrative purposes, all submissions relating to this postmarketing requirement must be clearly designated “Subpart H Postmarketing Requirement(s).” REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement. POSTMARKETING REQUIREMENTS UNDER 505(o) Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute. We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a known serious risk for agranulocytosis. Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk. Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following: 2944-2 Reference ID: 3816623 Establish a registry in order to perform an enhanced pharmacovigilance study of agranulocytosis. Procedures should include: Creation of marketing materials to inform and encourage clinicians to report agranulocytosis events to the sponsor; monitoring of all reported cases and active follow-up to characterize the demographics, recent prior blood counts, concomitant medications, co-existing conditions, duration of drug exposure prior to onset, outcomes of the event, and NDA 208030 Page 4 other factors that may help to characterize the agranulocytosis event. Sponsor also will institute procedures to obtain blood samples from patients with reported cases of agranulocytosis to store for later analysis of possible genetic underlying factors that may predict the risk of agranulocytosis. Submit interim reports annually describing the above results. The timetable you submitted on August 20, 2015, states that you will conduct this study according to the following schedule: Annual Interim Report #1: Annual Interim Report #2: Annual Interim Report #3: Study Completion: Final Report Submission: 04/2016 04/2017 04/2018 10/2018 04/2019 Submit the protocol(s) to your IND 045724, with a cross-reference letter to this NDA. Submit all interim and final reports to your NDA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate: “Required Postmarketing Protocol Under 505(o),” “Required Postmarketing Final Report Under 505(o),” “Required Postmarketing Correspondence Under 505(o).” Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials. FDA will consider the submission of your annual report under section 506B and 21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action. PROMOTIONAL MATERIALS Under 21 CFR 314.550, you are required to submit, during the application pre-approval review period, all promotional materials, including promotional labeling and advertisements, that you intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If you have not already met this requirement, you must immediately contact the Office of Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory project manager or the appropriate reviewer to discuss this issue. Reference ID: 3816623 NDA 208030 Page 5 As further required by 21 CFR 314.550, submit all promotional materials that you intend to use after the 120 days following marketing approval (i.e., your post-launch materials) at least 30 days before the intended time of initial dissemination of labeling or initial publication of the advertisement. We ask that each submission include a detailed cover letter together with three copies each of the promotional materials, annotated references, and approved package insert (PI)/Medication Guide/patient PI (as applicable). Send each submission directly to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotions (OPDP) 5901-B Ammendale Road Beltsville, MD 20705-1266 Alternatively, you may submit promotional materials for accelerated approval products electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Guidance for Industry (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM443702.pdf). REPORTING REQUIREMENTS We remind you that you must comply with the reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, call Kris Kolibab, Regulatory Project Manager, at (240) 402-0277. Sincerely, {See appended electronic signature page} Edvardas Kaminskas, MD Deputy Director Division of Hematology Products Office of Hematology Oncology Products Center for Drug Evaluation and Research ENCLOSURES: Content of Labeling Carton and Container Labeling Reference ID: 3816623 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------EDVARDAS KAMINSKAS 09/09/2015 Reference ID: 3816623