Genzyme Corporation: tolebrutinib

Please refer to your new drug application (NDA) om for © (tolebrutinib) tablets.

However, we have determined that a serious risk of severe drug-induced liver injury (DILI), which was identified during the conduct of your clinical trials, cannot be adequately mitigated by the proposed risk evaluation and mitigation strategy (REMS).

Given the gravity of this serious and potentially fatal risk, the review of your application focused on attempting to identify a population in whom the benefit-risk assessment is favorable to support approval, such as a population of patients with multiple sclerosis (MS) that has the greatest unmet need because there are no approved therapies.

The risk of severe DILI (i.e., requiring transplant or fatal) with tolebrutinib is substantial and unusually high for drug development programs in general, and specifically for MS therapies.

Liver Injury: Premarketing Clinical Evaluation (July 2009), the presence of even a single case meeting Hy's Law criteria in the premarket development program of a drug is a signal of a high level of hepatotoxicity.

Most of the drugs withdrawn rom the market for hepatotoxicity have caused death or transplantation at rates so low (i.e., $1 per 10,000) that severe hepatotoxicity is not typically identified in he premarket development program.

In the irst 6 months of double-blind treatment of Study EFC16645, 3.6% of tolebrutinibreated subjects versus 1.9% of placebo-treated subjects experienced aminotransferases greater than 3 times the upper limit of normal.

Additionally, we acknowledge that DILI is a class effect of BTK inhibitors discussed in current approved labeling, but the risk of fatal DIL] associated with olebrutinib appears to be among the highest in the class.

There is therefore a significant and unusually high risk of severe DILI associated with tolebrutinib.

Therefore, even with the implementation of weekly monitoring, the predicted postmarket rate of severe DILI associated with tolebrutinib remains substantial.

The benefit-risk assessment must assume that there will be severe and potentially fatal cases of DILI in the postmarketing setting, even with a REMS requiring weekly laboratory monitoring.

Subgroup analyses of Study EFC16645 indicate that the observed treatment effect was greater in subjects who had T1 gadolinium-enhancing (GdE) lesions at baseline (i.e., active SPMS), which comprised 13% of the enrolled population.

For subjects with GdE lesions at baseline, the hazard ratio (HR) (95% confidence interval [Cl]) for the primary endpoint was 0.346 (0.183, 0.656), and without GdE lesions at baseline was 0.777 (0.601, 1.006).

This subgroup analysis suggests that the treatment effect is largely driven by the small group of subjects with active SPMS based on their baseline MRI scan, a population for which there are approved therapies.

Phase 3 studies in the RMS population (Studies EFC16033 and EFC16034) that did not meet their primary endpoint.

The Division considered the issues cited above in the benefit-risk assessment for he proposed indication of nrSPMS.

We acknowledge that this subpopulation was not predefined in the enrolled population; however, the Division was willing to show flexibility to consider narrowing the indication to a population for which there are no FDA-approved therapies, and for which there is a significant unmet medical need.

Biological Products (December 2019),° therapies with greater risks may require a greater magnitude and certainty of benefit to support approval.

Overall, substantial evidence of effectiveness has not been established in a clinically identifiable population for whom the benefits potentially outweigh the risks.

Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) OR FDCA authorizes FDA to require the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks [section 505-1 (a)].