CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202992Orig1s000 MEDICAL REVIEW(S) MEMORANDUM DATE: August 25, 2012 FROM: Director Division of Neurology Products/HFD-120 TO: File, NDA 202,992 SUBJECT: Recommendation for Action on NDA 202,992, for the use of teriflunomide in the treatment of patients with relapsing forms of Multiple Sclerosis (MS) NDA 202,992, for the use of teriflunomide in the treatment of patients with relapsing forms of Multiple Sclerosis (MS), was submitted by Sanofi Aventis on 8/12/11. Teriflunomide is a selective and reversible inhibitor of mitochondrial dihydroorotate dehydrogenase (DHO-DH), which is necessary for pyrimidine synthesis. Presumably by inhibiting the enzyme, teriflunomide inhibits pyrimidine synthesis, which results in a cytostatic effect on peripheral T- and B-lymphocytes. This presumably decreases the number of activated lymphocytes that enter the Central Nervous System (CNS), thereby decreasing the inflammatory response known to be present in the CNS in patients with MS. Teriflunomide is the active metabolite of leflunomide, marketed as ARAVA for the treatment of rheumatoid arthritis (RA), since 1998. Indeed, leflunomide is essentially entirely metabolized to teriflunomide, and the plasma levels of teriflunomide that circulate at the sponsor’s proposed dose of teriflunomide of 14 mg/day are comparable to the circulating levels of teriflunomide when leflunomide is given at the recommended dose of 20 mg/day. The sponsor has submitted the results of a single adequate and well-controlled study, TEMSO, as the primary basis for the approval of the application. They have also submitted the results of a smaller controlled trial, 2001, and interim results of an on-going controlled trial (TOWER), of similar size to TEMSO, as supportive evidence of effectiveness. In addition, they have submitted reports of two additional placebo-controlled, relatively short-term, add-on trials, in which teriflunomide was added to interferon (Study 6045) or glatiramer acetate (Study 6046) as additional support. The NDA has been reviewed by Drs. Prafull Shiromani and Sarah Miksinski, Office of New Drug Quality and Assessment (ONDQA, CMC); Dr. Tien-Mien Chen, ONDQA, Biopharmaceutics; Dr. Richard Houghtling, pharmacology/toxicology reviewer; Dr. Lois Freed, pharmacology supervisor; Dr. Matthew Jackson, statistician (carcinogenicity); Drs. Vaneeta Tandon, Joo-Yeon Lee, and Jeffrey Kraft, Office of Clinical Pharmacology; Dr. Katherine Bonson, Controlled Substance Staff; Upasana Bhatnagar, Pediatric and Maternal Health Staff; Jung Lee, Division of Medication Error and Prevention and Analysis 1 Reference ID: 3185084 (DMEPA); Robin Duer and Reema Jain, Division of Risk Management (DRISK); Dr. Antoine El-Hage, Office of Scientific Investigations; the Interdisciplinary Review Team for QT Studies; Drs. Lourdes Villalba and Evelyn Mentari, safety reviewer; Dr. John Senior, Office of Pharmacovigilance and Epidemiology (OPE); Dr. Sally Yasuda, safety team leader; Dr. Sharon Yan, Office of Biostatistics; Dr. Jody Green, medical reviewer, and Dr. Billy Dunn, neurology team leader and Cross-Discipline Team Leader (CDTL). The review team recommends that the application be approved. I will briefly describe the relevant effectiveness and safety data, and offer the division’s recommendation for action on the NDA. Effectiveness TEMSO This was a multi-national study in which patients with relapsing forms of MS (Relapsing-Remitting, Secondary Progressive, and Progressive Relapsing) were randomized to receive either placebo, teriflunomide 7 mg, or teriflunomide 14 mg/day. The study was 108 weeks in duration. The outcomes assessed were: Primary outcome Reduction of confirmed relapses/year (annualized relapse rate, or ARR), defined as a documented 1 point increase in at least 2 FS functions (see below) or a 2 point increase in one FS function from the previous examination, or an increase of at least 0.5 points on the EDSS score (see below), or a 1 point increase if the EDSS=0, compared to the previous score. Key secondary outcome Time to confirmed disability progression as defined by change in Expanded Disability System Score-this standard measure of disability in patients with MS consists of assessment in 7 functional systems (FS); each FS is rated from 0-6. The scale is rated from 0 (Normal) to 10 (death due to MS). A score above 5.5 indicates that the patient is non-ambulatory. For this outcome, an increase of 1 point sustained over 12 weeks indicated progression of disability for patients with a baseline EDSS of 5.5 or less, and an increase of 0.5 points for patients with a baseline EDSS of 6 or above. Other clinical secondary outcomes Proportion of patients free of disability progression at 6, 12, and 24 months Fatigue Impact Scale (FIS)-a patient reported outcome measure 2 Reference ID: 3185084 Multiple Sclerosis Functional Composite (MSFC)-consisting of Timed 25 Foot Walk; 9 Hole Peg Test; and Paced Auditory Serial Addition Test (PASAT-3), each component assessing a different function Medical Outcome Study SF-36-a self-administered quality of life scaleEuroQoL EQ-5D-another patient-rated quality of life scale Other secondary imaging measures MRI variables: Burden of Disease (BOD), defined as the total volume of abnormal brain tissue, further defined as the sum of the T2 lesion load and the T1 hypointense lesion component. Volume of post-gadolinium T 1 hypointense black holes Total number of gadolinium enhanced T1 lesions Total volume of enhanced T1 lesions/scan Volume of T2 component Average number of unique active lesions/scan Atrophy Volume of white matter Volume of gray matter Analyses were to be performed on the 14 mg dose-placebo contrast for the ARR first, then for the 7 mg-placebo contrast for ARR, then for the 14 mg-placebo contrast for disability progression, then for the 7 mg-placebo contrast for disability progression. The protocol also stated that the following endpoints would be tested in the following order, each at alpha 0.025, only if the proceeding contrast was significant at 0.025 (presumably independent of dose): 1) Change from baseline in total FIS at week 108 2) Total number of gadolinium enhancing T1 lesions/scan over the treatment period 3) Change from baseline in MRI BOD at Week 108 3 Reference ID: 3185084 Results The trial was conducted at 126 sites in 21 countries. For some analyses, countries were grouped into regions; Americas (23%), Eastern Europe (31%), and Western Europe (46%). The greatest percentage of study subjects from one country was Canada, which supplied about 17% of the study sample. There were only 8 patients from the US. A total of 1088 patients were randomized; 1086 were included in the intent-to- treat population. The following chart displays the progression of patients through the study: Placebo Ter 7 Ter 14 Randomized 363 366 359 Completed 108 weeks 259 (71%) 274 (75%) 263 (73%) Reason for Discontinuation Adverse event 29 37 38 Lack of efficacy 24 14 17 Progressive disease 11 4 2 Patient request 33 32 26 Protocol violation 3 2 5 Lost to follow-up 4 0 2 Other 0 2 5 Important baseline characteristics were acceptably well distributed (see, for example, Dr. Yan’s Tables 3, 4, pages 10 and 11 of her review). The following charts display the results of the primary (ARR) and key secondary (time to disability progression) outcomes: Placebo Ter 7 Ter 14 Adjusted ARR 0.54 0.37 0.37 Relative Risk 0.69 0.69 P-value 0.0002 0.0005 Relapse Free 49% 58% 61% 4 Reference ID: 3185084 Although there were numerical trends in favor of both doses of teriflunomide in the Americas and Eastern Europe, statistical significance was achieved only in Western Europe, as displayed below: ARR Placebo Ter 7 Ter 14 Americas 0.31 0.21 0.27 (N=82) (N=83) (N=80) Eastern Europe 0.52 0.42 0.42 (N=114) (N=116) (N=108) Western Europe 0.71 0.45 0.4 (N=167) (N=166) (N=170) P-value 0.001 <0.0001 Time to Disability Progression Placebo Ter 7 Ter 14 Number of patients With progression 86 (24%) 68 (19%) 62 (17%) Hazard ratio 0.76 0.70 P-value 0.08 0.03 The estimate of the percentage of patients with disability progression at Week 108 was 27%, 22%, and 20% for the placebo, 7 mg, and 14 mg groups, respectively. For this outcome, statistical significance was seen only in Eastern Europe, with numerical superiority of the 7 mg group compared to the 14 mg group. 5 Reference ID: 3185084 Secondary outcomes Fatigue Impact Scale There were no significant differences between either treatment group and placebo (P=0.4 and 0.09 for the 7 and 14 mg groups, respectively). MSFC There were no statistically significant differences between either group and placebo, except on the PASAT-3 component (p=0.04 for each dose contrast). MRI Outcomes The following chart displays the results of the key MRI outcomes: Outcome Pla Ter 7 Ter 14 BOD Mean Change from baseline Cubic volume 0.13 0.08 0.04 P-value 0.03 0.0003 Cumulative Gd-enhancing lesions/scan 1.3 0.57 0.26 P-value <0.0001 <0.0001 Mean Change Volume of T1 hypointense Lesions 0.1 0.08 0.07 P-value 0.2 0.02 Mean Change Volume of T2 lesions 0.12 0.065 0.03 P-value 0.04 0.0004 TOWER As described above, the sponsor has submitted the results of an interim analysis of the TOWER study. This trial has several key similarities to TEMSO, including comparing the same treatments (placebo and teriflunomide 7 and 14 mg/day) and the same primary outcomes (ARR and time to disability progression). A key difference was that each patient did not have a fixed duration in study. 6 Reference ID: 3185084 Specifically, the study was to be terminated when the last patient enrolled completed 48 weeks of treatment.