Multiple Sclerosis Research Repository

FDA Summary Review (202992Orig1s000): Aubagio/Teriflunomide

-FDA agreed in principle to an NDA supported by one apparently robust primary

study with additional supportive evidence.

-the sponsor presents the results from one controlled Phase 3 efficacy study (EFC6049 or TEMSO).

-The primary efficacy endpoint was the annualized relapse rate (ARR) over a 2 year treatment

period. This is widely used in multiple sclerosis studies.

-The “key” secondary efficacy endpoint was time to disability progression (defined as the time

to an increase from baseline of at least 1 point on EDSS if the baseline EDSS score was < 5.5,

or the time to an increase from baseline of at least 0.5 points on EDSS if the baseline EDSS

score was > 5.5, with the respective increase in EDSS score sustained for at least 12 weeks).

-The results for the secondary outcome concerning disability progression in the standard ITT

population, presented by the sponsor and confirmed by the review team, are below:

progression probability at year 2 p-value hazard ratio p-value

-7mg: 1) progression probability at year 2 (21.7%); p-value: 0.0835; hazard ratio: 0.762; p-value: 0.0962

-14 mg: 1) progression probability at year 2 (20.2%); p-value: 0.0279; hazard ratio: 0.702; p-value: 0.0337

-placebo: progression probability at year 27.3%

-An analysis of progression sustained for 24 weeks (rather than 12) revealed no significant treatment effect in either teriflunomide group.

-Dr. Yan conducted an analysis of the change in EDSS score from baseline at 1 year and 2

years and found little change between groups (Dr. Yan’s review, Table 8). She argues that this

diminishes the significance of the 14 mg group’s improvement in the probability of

progression.

-Dr. Yan performed an additional subgroup analysis on the Americas population in TEMSO in

order to further evaluate disability progression. She found that in this population of about 80

patients per treatment group, both teriflunomide groups progressed notably more than the

placebo group, with the placebo group experiencing virtually no progression. There was no

baseline imbalance in the EDSS scores to potentially explain this subgroup finding.

-An analysis of another clinical secondary endpoint, the FIS, was not significant for either dose

of teriflunomide, though it did trend in favor of 14 mg.

-Dr. Yan points out that the above two analyses may not be viewed as statistically valid due to

the failure of the 7 mg dose to significantly differ from placebo in disability progression.

-A descriptive analysis of progression on EDSS in Study 2001 is below:

  -7mg: 29% with progression

  -14mg: 7% with progression

  -placebo: 21%

  -*placebo outperformed 7mg Aubagio

-Dr. Green also briefly discusses the efficacy results of two open-label extension trials (LTS 6048 and LTS 6050)…Although the results are not discouraging, the nature of these trials precludes the drawing of any meaningful conclusions regarding efficacy

-…Dr. Yan…feels that the disability findings in TEMSO, while promising, require further confirmation…