Oral Bruton's tyrosine kinase (BTK) inhibitors are emerging as potential treatments for multiple sclerosis (MS), but recent clinical trial results from Roche and Sanofi highlight both the promise and the challenges of this drug class. These small molecule inhibitors are designed to cross the blood-brain barrier, offering a novel approach to managing MS.
Sanofi's Tolebrutinib Shows Mixed Results
Sanofi's tolebrutinib faced setbacks in two Phase III studies, failing to significantly reduce the annualized relapse rate (ARR) in patients with relapsing MS (RMS). However, a third late-stage trial demonstrated that tolebrutinib significantly delayed disability progression in patients with progressive MS. Despite the mixed outcomes, GlobalData predicts tolebrutinib could generate approximately $2.6 billion in sales by 2030 across major markets.
Jefferies analysts noted that despite the mixed news, tolebrutinib appears to be a de-risked opportunity with potential sales of $1-2 billion. Pooled data from secondary endpoints in the GEMINI 1 and 2 trials suggested a significant delay in the onset of confirmed disability worsening, aligning with positive findings from the HERCULES study.
Roche's Fenebrutinib Demonstrates Strong Efficacy
In contrast, Roche's fenebrutinib achieved a mid-stage win in RMS, demonstrating near-total elimination of disease activity. Data from an open-label extension of the Phase II FENopta study showed that 96% of patients treated with fenebrutinib were free of relapses after one year, with an annualized relapse rate of just 0.04. Furthermore, 99% of patients were free of T1 gadolinium-enhancing (T1-Gd+) lesions at 48 weeks, and there was a three-times greater reduction in the volume of T2 lesions compared to the end of the double-blind period.
Levi Garraway, MD, PhD, chief medical officer, head of global product development at Roche, stated that fenebrutinib was able to suppress nearly all disease activity and disability progression in people with multiple sclerosis after a year of treatment. He added that if these results are validated in the ongoing Phase III trials, fenebrutinib could further advance the treatment landscape for people living with multiple sclerosis.
Safety Concerns and Clinical Holds
Despite the promising efficacy results, safety remains a key concern for BTK inhibitors. Sanofi’s Phase III tolebrutinib studies were placed on partial clinical hold by the FDA in June 2022 after cases of drug-induced liver injury were reported. Similarly, Roche’s fenebrutinib was placed under a partial clinical hold in December 2023 after two patients experienced elevated hepatic transaminase and bilirubin levels indicative of liver injury.
Jefferies analysts noted that liver safety will be a key focus at upcoming presentations of Sanofi’s HERCULES and GEMINI 1 and 2 full results. Shiv Saidha, professor of neurology at Johns Hopkins University, emphasized the importance of benefit across secondary endpoints, noting the failure of Merck KGaA’s BTK inhibitor evobrutinib to show benefit on these measures before its development was terminated.
Market Potential and Future Outlook
Orally administered BTK inhibitors are already established in oncology, and U.S. neurologists are eagerly awaiting their arrival for MS treatment. However, safety setbacks have created an environment of uncertainty. GlobalData predicts worldwide sales of fenebrutinib will reach $810 million by 2030.
Roche has three ongoing Phase III trials for fenebrutinib, with data expected by the end of next year. The question remains whether orally administered BTK inhibitors can ultimately succeed in MS, overcoming the safety hurdles and demonstrating consistent efficacy across primary and secondary endpoints.
