CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-527 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA Application Number 22-527 Priority or Standard P Submit Date 12-21-2009 Received Date 12-21-2009 PDUFA Goal Date 9-21-2010 Division / Office FDA/ODE1 Reviewer Name Heather D. Fitter Review Completion Date August 26, 2010 Established Name Fingolimod (Proposed) Trade Name Gilenya Therapeutic Class S1P receptor modulator Applicant Novartis Formulation(s) Oral tablets Dosing Regimen 0.5 mg Indication(s) To reduce the frequency of relapses and delay the progression of disability in relapsing MS Intended Population(s) Relapsing Multiple Sclerosis Template Version: March 6, 2009 Clinical Review Heather D. Fitter, M.D. NDA 22-527 Fingolimod Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 7 1.1 Recommendation on Regulatory Action ............................................................. 7 1.2 Risk Benefit Assessment.................................................................................... 8 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 8 2.1 Product Information ............................................................................................ 9 2.2 Table of Currently Available Treatments for the Proposed Indication................. 9 2.3 Availability of Proposed Active Ingredient in the United States ........................ 12 2.4 Important Safety Issues with Consideration to Related Drugs.......................... 12 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 12 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 15 3.1 Submission Quality and Integrity ...................................................................... 15 3.2 Compliance with Good Clinical Practices ......................................................... 16 3.3 Financial Disclosures........................................................................................ 17 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 18 4.1 Chemistry Manufacturing and Controls ............................................................ 18 4.3 Preclinical Pharmacology/Toxicology ............................................................... 19 4.4 Clinical Pharmacology...................................................................................... 20 4.4.1 Mechanism of Action.................................................................................. 21 4.4.2 Pharmacodynamics.................................................................................... 21 4.4.3 Pharmacokinetics....................................................................................... 23 5 SOURCES OF CLINICAL DATA............................................................................ 24 5.1 Tables of Clinical Trials .................................................................................... 24 5.2 Review Strategy ............................................................................................... 25 5.3 Discussion of Clinical Trials.............................................................................. 25 5.3.1 Protocol CFTY720D2301 ............................................................................. 25 5.3.2 Protocol CFTY720D2302 ............................................................................. 39 5.3.3 Protocol CFY720D2201 ............................................................................... 49 5.3.4 Protocol FTY720D2201E1 ........................................................................... 50 5.3.5 Protocol FTY720D2309................................................................................ 51 6 REVIEW OF EFFICACY......................................................................................... 51 Efficacy Summary...................................................................................................... 51 6.1 Indication .......................................................................................................... 53 6.1.1 Method....................................................................................................... 53 6.1.2 Demographics............................................................................................ 53 6.1.3 Subject Disposition .................................................................................... 59 6.1.4 Analysis of Primary Endpoint ..................................................................... 60 2 Clinical Review Heather D. Fitter, M.D. NDA 22-527 Fingolimod 6.1.5 Analysis of Key Secondary Endpoints........................................................ 63 6.1.7 Subpopulations .......................................................................................... 80 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 82 6.1.9 Discussion of Persistence of Efficacy and/or Withdrawal/Rebound Effects87 8 POSTMARKET EXPERIENCE............................................................................... 88 9 APPENDICES ........................................................................................................ 88 9.1 Literature Review/References .......................................................................... 88 9.2 Labeling Recommendations............................................................................. 88 9.3 Advisory Committee Meeting............................................................................ 89 9.4 Pediatric Review Committee (PeRC) Meeting.................................................. 89 9.5 Reference Material for sponsor MSFC evaluation............................................ 90 3 Clinical Review Heather D. Fitter, M.D. NDA 22-527 Fingolimod Table of Tables Table 1: Table of Currently Available Treatment for Proposed Indications, ................... 10 Table 2: Summary of studies providing efficacy data .................................................... 24 Table 3: Assessment schedule: Protocol D2301........................................................... 28 Table 4: Abbreviated schedule of assessments for patients discontinuing study drug.. 31 Table 5: Assessment schedule: Protocol D2302........................................................... 42 Table 6: Abbreviated schedule of assessments for patients discontinuing study drug: D2302 ............................................................................................................ 43 Table 7: Demographic characteristics-trials D2301 and D2302 (randomized population) ....................................................................................................................... 54 Table 8: MS disease baseline characteristics: trials D2301 and D2302 (randomized population) ..................................................................................................... 55 Table 9: MS medication history of previous disease-modifying agents- trials D2301 and D2302 (randomized population)..................................................................... 56 Table 10: Multiple Sclerosis MRI baseline parameters- Trial D2301 and D2302 (randomized population) ................................................................................ 57 Table 11: Dr. Yan's Analysis of ARR by region- trial D2302.......................................... 58 Table 12: Study participation and discontinuation- studies D2301 and D2302 (randomized population) ................................................................................ 60 Table 13: Summary of clinical efficacy for the primary outcome measure, aggregate annualized relapse rate for protocol D2301 and D2302................................. 61 Table 14: Sensitivity analysis of the ARR up to 24 month- study D2301....................... 62 Table 15: Sensitivity analyses of the ARR up to month 12- trial D2302 ........................ 63 Table 16: Time to 3 month confirmed disability progression up to month 24- trial D2301 (ITT population).............................................................................................. 64 Table 17: Time to 3 month confirmed disability progression up to month 12-trial D2302 (ITT population).............................................................................................. 65 Table 18: Change from baseline in EDSS at month 12 and month 24- trials D2301 and D2302 ............................................................................................................ 66 Table 19: Change from baseline in MSFC z-score........................................................ 68 Table 20: Proportion of patients for categories based on percent change from baseline in MSFC (Trial D2301)................................................................................... 71 Table 21: Number of new or newly enlarged T2 lesions at month 12 in D2302: Original analysis sent in clinical study report............................................................... 73 Table 22: Number of new or newly enlarged T2 lesions at month 12- trial D2302 (ITT population) ..................................................................................................... 74 Table 23: Number of new or newly enlarged lesions at month 12 (ITT population)....... 75 Table 24: Number of new or newly enlarged T2 lesions at month 12 (study-drug