Less than two weeks after rejecting Sanofi’s investigational multiple sclerosis drug, the FDA has publicly shared the complete response letter, citing both efficacy and safety concerns—including a case of serious liver injury that led to death.
Dec. 24, the FDA refused to approve tolebrutinib, a BTK inhibitor designed to treat non-relapsing secondary progressive MS (nrSPMS). The French pharma did not share the reasoning behind the rejection, although R&D head Houman Ashrafian, Ph.D., said at the time that the decision was “a significant and meaningful change in direction from the feedback the agency previously provided to Sanofi.”
Now, the regulatory agency is unexpectedly sharing the recently delivered CRL, writing that “a favorable benefit-risk profile could not be established for any patient subpopulation.”
The agency said the risk of severe drug-induced liver injury (DILI) recorded in tolebrutinib trials can’t be adequately managed by Sanofi’s proposed risk evaluation and mitigation strategy (REMS).
Sanofi believed the benefit-risk profile was favorable for patients with nrSPMS because there currently aren’t any approved treatments for the subpopulation.
But the FDA disagreed, writing that it couldn’t “identify a population for which the benefit could be clearly established and for which that benefit would be anticipated to outweigh the serious risk of severe DILI to support approval.”
The agency outlined four reasons for its determination: severe DILI risk; uncertainties about benefit in subpopulations; insufficient evidence of effects on slowing disability accumulation independent of relapse activity; and no subpopulation had a favorable benefit-risk profile.
The first component of the letter highlights the fact that severe DILI can require transplant or even be fatal. The agency wrote that the DILI risk “with tolebrutinib is substantial and unusually high for drug development programs in general, and specifically for MS therapies.”
The agency identified six cases in Sanofi’s phase 3 program that met Hy’s Law—a rule of thumb for assessing the risk of DILI—out of 2,700 total patients, including one patient who died after requiring a liver transplant. This indicates a high level of hepatotoxic risk with tolebrutinib, according to the FDA.
The FDA branded the DILI risk tied to the investigational drug as “idiosyncratic.” While DILI is a known class effect for BTK inhibitors, the risk of fatal DILI associated with tolebrutinib “appears to be among the highest in the class,” the regulator added.
According to the CRL, Sanofi changed its monitoring strategy to weekly liver monitoring after identifying Hy’s Law cases, including the patient death. Since the monitoring switch-up, no additional cases of DILI resulting in death or transplant occurred, the FDA said.
That being said, additional DILI cases—including one Hy’s Law case—did still occur after the weekly monitoring launched, leading the regulator to believe that severe liver injury will occur in a larger population of patients if approved, even with Sanofi’s proposed REMS.
Moving on to its next point about uncertain benefit in patient subpopulations, the FDA said a lack of historical MRI data collection hindered the agency from retrospectively determining whether subjects had active or non-active SPMS.
Sanofi “attempted to retrospectively obtain historical MRI data to characterize enrolled subjects” in a response to an information request, but the FDA said these were of “limited interpretability” because the data reflected less than 40% of the enrolled population.
Furthermore, a subgroup analysis using baseline MRI scans indicated that therapeutic effect was mainly driven by patients with active SPMS—a population that already has access to approved therapies. The findings raise questions about the consistency of any potential benefit across patients with nrSPMS, the FDA wrote.
Thirdly, the regulator said Sanofi failed to provide sufficient evidence of effects on slowing disability accumulation that weren’t related to relapse activity—a measure the FDA said is still an emerging construct. The agency underscored the fact that Sanofi’s data from two phase 3 trials in relapsing MS did not meet their primary endpoints.
Given all the above information, the agency determined that no study subpopulation had a favorable benefit-risk profile.
“Overall, substantial evidence of effectiveness has not been established in a clinically identifiable population for whom the benefits potentially outweigh the risks,” the FDA said.
Looking forward, the federal agency said it was open to continued discussion with the French pharma in attempts to identify a population for whom the potential benefits of tolebrutinib outweigh the risk of severe DILI. Sanofi would need to support its argument with additional safety analyses from the recently completed phase 3 Perseus trial for primary progressive MS and an ongoing extension study.
As of publication, Sanofi has not responded to Fierce Biotech’s request for comment.
It’s been a rocky road for tolebrutinib. In mid-December, Sanofi announced that the FDA approval decision was expected to be delayed again.
The Big Pharma had previously picked up priority review status for the filing and anticipated a decision by Sept. 28. But, as that date neared in the fall, the drugmaker disclosed a three-month delay due to its submission of “additional analyses” during the review, which constituted a “major” amendment to the application by the FDA’s standards.
At the same time, Sanofi also shared that the Perseus study failed to delay time to six-month composite confirmed disability progression versus placebo.
Sanofi picked up the drug via its $3.7 billion buyout of Principia Biopharma back in 2021. The following year, the FDA placed a group of late-stage studies under a partial clinical hold so it could review reports of DILI—including data from a phase 3 trial called Hercules that were part of the recent approval package submitted to the FDA.