This blog post is the second in our series about the Complete Response Letters (CRLs) that the U.S. Food and Drug Administration (FDA) issued to Sanofi for tolebrutinib to treat non-relapsing secondary progressive multiple sclerosis (nrSP-MS) on December 23, 2025, and to Corcept Therapeutics for relacorilant to treat Cushing syndrome on December 30, 2025. Both drugs are included in the Clarivate “Drugs to Watch 2026” report, and these decisions came after the report was finalized.
The CRL for tolebrutinib, a Bruton tyrosine kinase (BTK) inhibitor, centered on four key issues: (1) serious risk of severe (including fatal) drug-induced liver injury (DILI), (2) uncertainties regarding benefit in disease subpopulations, (3) insufficient evidence of effects on slowing disability accumulation independent of relapse activity, and (4) no study population was identified with a favorable benefit-risk profile.
The FDA characterized the hepatotoxicity risk as “substantial and unusually high for drug development programs in general, and specifically for MS therapies.” Of approximately 2,700 participants, six cases met Hy’s Law criteria, including one death after requiring a liver transplant. The agency raised concerns over sufficiency of the monitoring program in Sanofi’s proposed REMS and noted that “the risk of fatal DILI associated with tolebrutinib appears to be among the highest in the class” of BTK inhibitors.
The clinical context
The CRL’s impact is striking given tolebrutinib’s clinical performance. In the phase 3 HERCULES trial, tolebrutinib met its primary endpoint by delaying the time to onset of six-month confirmed disability progression by 31% compared with placebo, making it the first drug to successfully demonstrate significant slowing of disability progression in nrSP-MS, an important clinical achievement.
However, the drug’s broader development program revealed complexities. In September 2024, results from two of three phase 3 trials of tolebrutinib in relapsing MS did not meet their primary endpoints. More recently, the PERSEUS trial in primary progressive MS did not achieve its primary endpoint, leading Sanofi to discontinue development in that indication. These mixed results, combined with earlier liver safety concerns that triggered partial clinical holds in 2022, created a challenging regulatory environment.
The market impact
Clarivate analysts had projected peak sales of $1.4bn in the G7 markets by 2031 if approved, with some estimates suggesting a market opportunity of $3bn to $3.5bn in the U.S. alone. The drug was positioned to become “a referenced drug” or potentially “the standard of care” in nrSP-MS, an indication with virtually no approved therapies.
Sanofi’s stock fell 6% following the dual announcement of the FDA delay and PERSEUS trial failure. The company is now assessing a potential impairment related to its $3.7bn acquisition of Principia Biopharma, through which it acquired tolebrutinib in 2021.
Patient and clinical implications
Unlike relapsing MS, where numerous effective therapies exist, limited treatment options exist for nrSP-MS. The disease is characterized by progressive disability accumulation without the episodic relapses that define other MS forms, making it notoriously difficult to treat.
The FDA’s request for an expanded access protocol suggests the agency recognizes this unmet need. As Jefferies analysts noted, “The fact that the FDA has requested an extended access program suggests the agency is comfortable with the risk/benefit for now,” indicating potential pathways forward. If approved, it would be the first drug with a label specifically for nrSP-MS.
How Clarivate can help address regulatory setbacks
Leveraging AI-powered intelligence in the Clarivate solutions enables pharma companies to respond to regulatory setbacks, including CRLs, with greater speed, precision and regulatory alignment.
Cortellis Regulatory Intelligence + AI-powered Regulatory Assistant
Cortellis Regulatory Intelligence delivers critical regulatory intelligence combining broad and deep insights with subject matter expertise, now enhanced by AI-powered capabilities through the Regulatory Assistant.
- Precedent analysis: The platform comprises FDA AdComm transcripts since 2000 and expert analysis from over 285k documents and 7k reports, helping to understand exactly how other companies have successfully addressed similar safety concerns. Queries to the AI Assistant could include “Show me hepatotoxic drugs approved after CRL for liver safety concerns” or “Compare REMS strategies that successfully managed severe DILI risk.”
- Regulatory strategy synthesis: The AI Assistant can retrieve relevant documentation, synthesize regulatory requirements across jurisdictions and generate actionable insights. This can help rapidly synthesize regulatory expectations for managing hepatotoxicity risk across the FDA, EMA, PMDA and more.
- Transparent and auditable: The Clarivate approach to AI ensures transparency, by always providing links to source documents. This addresses concerns about AI reliability and maintains full auditability.
- Comparative jurisdictional analysis: Tolebrutinib’s development continues in other markets. The real-time monitoring of regulatory developments, precedent analysis for approval pathways and comparative assessments of regulatory strategies across jurisdictions can identify differences in regulatory approaches (e.g., if EMA or PMDA views the benefit-risk differently) to inform the FDA resubmission strategy.
DRG Fusion
DRG Fusion is powered by uniquely connected real-world data and an AI-driven experience that empower disease analysis from any angle.
Generate additional real-world safety evidence and identify lower-risk subpopulations
- Class-wide safety analysis: Analysis of real-world hepatotoxicity patterns across the BTK inhibitor class (ibrutinib, acalabrutinib, zanubrutinib) in medical and pharmacy claims data as well as other real-world data sources helps contextualize tolebrutinib’s safety profile.
- Patient subpopulation identification:The patient segmentation capabilities can help identify nrSP-MS patient subgroups with lower baseline liver risk — e.g., patients without metabolic comorbidities, alcohol use or concomitant hepatotoxic medications.
- Comparative effectiveness in context:Analysis of real-world effectiveness outcomes in MS populations can help build the case that tolebrutinib’s efficacy benefits justify careful risk management in appropriately selected patients.
- Monitoring strategy validation:The platform can evaluate real-world liver monitoring practices to support development of enhanced REMS strategies. Real-world data can help validate the effectiveness of the intensive monitoring protocols adopted by Sanofi.
Cortellis clinical development intelligence solutions: protocol optimization
Cortellis Clinical Trials Intelligence and OFF-X offer insights into clinical trial progression, competitor strategies and protocol design optimization.
Design enhanced safety monitoring protocols and potential subpopulation trials
- Benchmarking of safety monitoring: Successful liver monitoring protocols can be analyzed across more than 600k clinical trials to identify optimal biomarkers, monitoring frequency and early stopping rules that maximize safety without compromising trial feasibility.
- Protocol design for subpopulations: If Sanofi pursues a targeted approval in a lower-risk subpopulation, they could gain insights into clinical trial progression, competitor strategies and protocol design optimization specific to MS patient subgroups.
In our next post in this series, Relacorilant: when evidence meets the established evidence bar, we’ll look at the impacts of the end-of-year CRL for Corcept Therapeutics’ relacorilant, another of 2026’s Drugs to Watch, and how Clarivate intelligence could be used to move forward.
Learn more about our 2026 Drugs to Watch , and you can read about how Clarivate is using AI tools to empower its clients to make better decisions faster.
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