CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 205003Orig1s000 MEDICAL REVIEW(S) DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS Divisional Memo NDA: 205003 Perindopril arginine-amlodipine (PRESTALIA) for hypertension. Sponsor: Symplmed Pharmaceuticals Review date: 12 January 2015 Reviewer: N. Stockbridge, M.D., Ph.D., HFD-110 Distribution: NDA 205003 This memo conveys the Division’s decision to approve this application. This application has been the subject of reviews of CMC (Jewel; 14 November 2014, 23 December 2014), biopharmaceutics (Suarez-Sharp; 20 November 2014), microbiology (Riley; 16 May 2014), pharmacology and toxicology (Yang; 4 August 2014), clinical pharmacology (Hinderling; 8 December 2014 and Hariharan; 8 December 2014), clinical effectiveness and safety (Hicks; 26 November 2014), and biometrics (Zhang; 6 November 2014 and 8 January 2015). There is also a CDTL memo (Thompson; 8 January 2014), with which I am in complete agreement. I comment here on a few aspects. All manufacturing site inspections are satisfactory. There is an 18-month expiration date for the 3.5/2.5-mg tablets, 24 months for 7/5- and 14/10-mg strengths. There are no outstanding CMC or biopharmaceutics issues. The sponsor conducted a 13-week toxicology study in rats, using both perindopril erbumine and perindopril arginine. There were no findings of concern. There is no direct comparison of bioavailability between the to-be-marketed combination and ACEON, and the cross-study comparison gives reason to think they may not be bioequivalent. The review team and I agree that there are adequate safety data in the sponsor’s studies to support approval, but not to cover special populations, so we will approve restricted labeling and a PMR to obtain data to support bridging. Two studies supported effectiveness. One compared doses1 of 3.5/2.5, 3.5/0, 5/0, 0/2.5, 0/5, and placebo. Not establishing an effect of the combination compared with high doses of the monotherapy, the sponsor conducted a second study comparing 14/10 with perindopril erbumine 16 mg and amlodipine besylate 10 mg—no placebo. The latter study demonstrated (systolic/diastolic; double differences from baseline and comparator) effects of -10.1/-6.3 mmHg compared with perindopril and -3.9/-2.5 mmHg compared with amlodipine, all difference highly statistically significant, but, of course, you cannot tell what the absolute effects were absent a placebo group. The sponsor proposes to market doses of 3.5/2.5 mg (which had placebo-subtracted effects of -7.2/-4.1 mmHg), 14/10 mg, and 7/5 mg, the latter of which has no empirical data, but all reviewers believe its effects will lie somewhere between effects of 3.5/2.5 and 14/10 (i.e., one is not on a plateau by 7/5 mg), for blood pressure and edema rates. Dr. Hinderling is concerned enough over the uncertainty and the likelihood that the blood pressure step may not be very big compared with a dose of 3.5/2,5 mg or the 1 Expressed as mg of perindopril arginine / mg of amlodipine base. C:\Users\STOCKBRIDGEN\Documents\NDA\N205003 Perindopril- amlodipine\PrestaliaDivMemo.doc Last saved 1 08:20 Monday, January 12, 2015 Reference ID: 3685440 Divisional memo NDA 205003 Prestalia (perindopril/amlodipine) Hypertension reduction in edema very big compared with a dose of 14/10 mg, so he proposes we not approve 7/5 mg, but the rest of the review team and I believe that we know enough to recommend 7/5 be available for patients whose edema is intolerable at the higher dose. I also wish to acknowledge concern raised about the process used to allocate subjects to treatment arms in the second study. While it was not random, the risk for unblinding was small, and all parties agree that the study was interpretable. The safety database revealed no concerns not predictable from known effects of the two monotherapies. Agreement on final labeling is the only barrier to approval. C:\Users\STOCKBRIDGEN\Documents\NDA\N205003 Perindopril- amlodipine\PrestaliaDivMemo.doc Last saved 2 08:20 Monday, January 12, 2015 Reference ID: 3685440 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- NORMAN L STOCKBRIDGE 01/12/2015 Reference ID: 3685440 CLINICAL REVIEW Application Type 505(b)(2) Application Number(s) NDA 205003 SDN 1, Sequence No. 0000 Priority or Standard Standard Submit Date(s) March 21, 2014 Received Date(s) March 21, 2014 PDUFA Goal Date January 21, 2015 Division / Office DCaRP / ODE 1 Reviewer Name(s) Karen A. Hicks, M.D. Review Completion Date November 26, 2014 Established Name Perindopril Arginine/ Amlodipine Besylate (Proposed) Trade Name PRESTALIA® Therapeutic Class Antihypertensive Applicant Symplmed® Formulation(s) Tablet Dosing Regimen 3.5/2.5 mg, 7/5 mg, 14/10 mg Indication(s) Treatment of Hypertension Intended Population(s) Adults Template Version: March 6, 2009 Reference ID: 3664988 Clinical Review Karen A. Hicks, M.D. NDA 205003 PRESTALIA® (perindopril arginine/amlodipine besylate) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 8 1.1 Recommendation on Regulatory Action ............................................................. 8 1.1.1. Approval of the 7 mg/5 mg Dose .................................................................. 8 1.2 Risk Benefit Assessment .................................................................................... 9 1.2.1. Pivotal Trial Results ...................................................................................... 9 1.2.2. Prescribing Information ............................................................................... 12 1.2.3. Safety Considerations ................................................................................. 13 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 13 1.4 Recommendations for Postmarket Requirements and Commitments .............. 13 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 14 2.1 Product Information .......................................................................................... 14 2.2 Tables of Currently Available Treatments for Proposed Indications ................. 15 2.3 Availability of Proposed Active Ingredient in the United States ........................ 18 2.4 Important Safety Issues With Consideration to Related Drugs ......................... 18 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 18 2.6 Other Relevant Background Information .......................................................... 19 3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 20 3.1 Submission Quality and Integrity ...................................................................... 20 3.2 Compliance with Good Clinical Practices ......................................................... 20 3.2.1 Study X985400 ............................................................................................. 20 3.2.1 Study CL2-05985-005 .................................................................................. 20 3.3 Financial Disclosures ........................................................................................ 21 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 23 4.1 Chemistry Manufacturing and Controls ............................................................ 23 4.2 Clinical Microbiology ......................................................................................... 24 4.3 Preclinical Pharmacology/Toxicology ............................................................... 24 4.4 Clinical Pharmacology ...................................................................................... 25 4.4.1 Mechanism of Action .................................................................................. 27 4.4.2 Pharmacodynamics.................................................................................... 28 4.4.3 Pharmacokinetics ....................................................................................... 29 5 SOURCES OF CLINICAL DATA............................................................................ 29 5.1 Tables of Studies/Clinical Trials ....................................................................... 32 5.2 Review Strategy ............................................................................................... 37 5.3 Discussion of Individual Studies/Clinical Trials ................................................. 37 5.3.1 Study X985400 (PATH) ................................................................................ 37 5.3.2 Study CL2-05985-005 and ABPM Substudy ................................................ 45 2 Reference ID: 3664988 Clinical Review Karen A. Hicks, M.D. NDA 205003 PRESTALIA® (perindopril arginine/amlodipine besylate) 6 REVIEW OF EFFICACY ......................................................................................... 53 Efficacy Summary ...................................................................................................... 53 6.1 Indication .........................................................................................................