Merck and Sanofi’s Bruton tyrosine kinase inhibitors were dealt setbacks when the FDA put partial clinical holds on their development because of liver toxicity issues.
Drugmakers have been racing to develop the first Bruton tyrosine kinase (BTK) inhibitor to treat multiple sclerosis (MS). BTK is an enzyme that plays a critical role in regulating B-cell development and activating B cells and myeloid lineage cells, both of which are heavily involved in MS pathology.
A year ago, three pharmaceutical giants were in the lead pack with potential candidates in late-stage trials. Merck has been developing evobrutinib; Sanofi, tolebrutinib; and Roche and its subsidiary Genentech, fenebrutinib. Novartis was a bit behind, launching phase 3 trials for the BTK inhibitor remibrutinib in December 2021.
Since then, both Merck and Sanofi have been slammed with FDA partial clinical holds related to liver toxicity issues. Roche and Novartis, so far, have been spared clinical trial holds by the FDA, but it remains unclear whether this type of toxicity is a class effect with BTK inhibitors.
Last month, it seemed that Roche was winning the competition when it announced positive top line results from the phase 2 FENopta study evaluating the use of fenebrutinib in adults with relapsing forms of MS (RMS). Study results showed that the oral investigational drug met its primary endpoint, significantly reduced the number of new T1 brain lesions, a measure of active inflammation in MS. A secondary endpoint of significant reduction in the number of new or enlarging T2 brain lesions was also met. T2 lesions are an indicator of disease burden.
Roche reported no new safety concerns in this study and cited a safety profile consistent with that of previous and ongoing trials. The company says the results will be presented at an upcoming medical meeting.
Roche asserts that fenebrutinib is more than 100 times more selective for BTK than other BTK inhibitors. It is also the only non-covalent (reversible) molecule currently in late-stage development. The company says these attributes may help curtail off-target effects and support a favorable safety profile for fenebrutinib.
The company is currently running twin phase 3 trials (FENhance and FENhance 2) evaluating the use of fenebrutinib compared with Aubagio (teriflunomide) in adults with RMS and the phase 3 FENtrepid trial evaluating fenebrutinib against Ocrevus (ocrelizumab) in adults with primary progressive MS (PPMS). Ocrevus is an antibody manufactured by Roche and Genentech and approved to treat RMS and PPMS. Aubagio is Sanofi’s oral pyrimidine synthesis inhibitor approved to treat RMS.
Completion of the FENhance studies is expected in 2025, and results for the FENtrepid study are expected in 2026.