Evobrutinib

iStock, WhataWin Roche’s fenebrutinib this week scored a mid-stage win in relapsing multiple sclerosis, while Sanofi’s tolebrutinib met the primary endpoint in a Phase III trial for progressive MS but flopped in two late-stage relapsing MS studies. It was a big news week for multiple sclerosis clinical trial readouts involving oral BTK inhibitors, which leverage their small molecular structure to cross the blood-brain barrier. Roche was the outright winner while Sanofi announced mixed results. Sanofi’s tolebrutinib on Monday missed the primary efficacy endpoints in two Phase III studies, failing to significantly reduce annualized relapse rate (ARR) in patients with relapsing MS (RMS), while succeeding in a third late-stage trial showing that the BTK inhibitor significantly delayed disability progression in patients with a less common form of progressive MS. Still, according to GlobalData, tolebrutinib “stands out as being particularly promising” and is expected to generate sales of approximately $2.6 billion in 2030 across seven major markets—the U.S., France, Germany, Italy, Spain, U.K. and Japan. The data analytics firm predicted worldwide sales of fenebrutinib will only reach $810 million that same year. Jefferies analysts described positivity around tolebrutinib, saying in a note to investors that despite the “mixed news,” Sanofi’s drug “now appears a largely de-risked perhaps $1–2 billion opportunity.” Meanwhile, just two days after Sanofi’s announcement, Roche’s fenebrutinib scored a mid-stage win in RMS, demonstrating near-total elimination of disease activity. GlobalData said the BTK inhibitor “shines” with 96% of patients treated free of relapses at one year, with data from three ongoing Phase III trials expected by the end of next year. According to Spherix Global Insights, orally administered BTK inhibitors are “already established in oncology” with U.S. neurologists “eagerly” awaiting the drug class for MS. However, the market research firm contends that setbacks involving safety have created an environment of uncertainty. Liver Safety and Secondary Endpoints in Focus While the overall sentiment for BTK inhibitors for MS is positive, the safety pro these treatments remains a point of concern. Sanofi’s Phase III tolebrutinib studies were placed on partial clinical hold by the FDA in June 2022 after researchers found cases of drug-induced liver injury in some patients, while the regulator put Roche’s fenebrutinib under a partial clinical hold in December 2023 after two patients experienced elevated hepatic transaminase and bilirubin levels indicative of liver injury. According to Jefferies analysts, liver safety “will be a key focus” at the Sept. 20 presentations of Sanofi’s HERCULES and GEMINI 1 and 2 full results at the 40th Congress of European Committee for Treatment and Research in Multiple Sclerosis in Copenhagen, Denmark. Shiv Saidha, professor of neurology at Johns Hopkins University, said on a Jefferies call Thursday that another important aspect of these data will be the benefit across secondary endpoints, noting the failure last year of Merck KGaA’s BTK inhibitor evobrutinib to show benefit on these measures in MS before the German pharma decided in March 2024 to terminate its development. Although Sanofi’s Phase III GEMINI 1 and 2 trials did not demonstrate a reduction in ARR, GlobalData observed that pooled data from secondary endpoints suggested a significant delay in the onset of confirmed disability worsening, aligning with the positive confirmed disability progression findings from the late-stage HERCULES study, and “providing a measure of support for tolebrutinib’s potential efficacy.” Nevertheless, there appears to be a bit of a confidence problem in the wider drug class, Jefferies analysts noted. “Investor expectations have likely been notably lower after competitor Merck KGaA’s evobrutinib RMS failure.” So the question remains: Can orally administered BTK inhibitors ultimately succeed in MS like they have in oncology?

Roche announced on September 4 the latest results from the Phase II FENopta Open Label Extension (OLE) study of the BTK inhibitor fenebrutinib. The results of the study showed that patients with relapsing multiple sclerosis (RMS) who received fenebrutinib for up to one year maintained extremely low levels of disease activity and did not experience disability progression. Roche plans to present the latest data from the FENopta-OLE study at the 40th session of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   Fenebrutinib is an oral, reversible, non-covalently bound BTK inhibitor that can effectively block the function of BTK. Preclinical studies have shown that fenebrutinib has significant activity and is highly selective, being 130 times more selective to BTK than other kinases. Currently, fenebrutinib is the only reversible BTK inhibitor in Phase III trials for the treatment of multiple sclerosis.   The FENopta study is a 12-week global, randomized, double-blind, placebo-controlled Phase II clinical trial designed to evaluate the efficacy, safety, and pharmacokinetics of fenebrutinib in 109 RMS patients aged 18 to 55 years. The primary endpoint was the number of new T1 lesions (T1-GD +) detected by brain magnetic resonance imaging (MRI) at weeks 4, 8, and 12, while secondary endpoints included the number of new/expanded T2 lesions detected by brain MRI at weeks 4, 8, and 12. And the proportion of patients with new T1-Gd+ lesions and new/enlarged T2 lesions at week 4, 8 and 12. T1 lesions are markers of active inflammation, while T2 lesions represent disease burden or lesion load.   Data from the 12-week study showed that fenebrutinib significantly reduced the number of new T1 lesions and new/enlarged T2 lesions compared to the placebo group. Of the patients who completed the FENopta study, 99 chose to continue participating in the Open Label Extension (OLE) study to receive fenebrutinib for up to 192 weeks. During OLE, 96% of patients treated with fenebrutinib were disease free at one year, with an annualized recurrence rate (ARR) of 0.04, and disability remained stable at 48 weeks. MRI scans showed that fenebrutinib treatment effectively suppressed disease activity in the brain. At 48 weeks, 99% of patients had no T1-Gd+ lesions. Within 48 weeks of continued treatment with fenebrutinib, T2 lesion volume decreased by a factor of 3 compared to the end of the double-blind period (-0.33 cm3 vs -0.11 cm3).   The safety profile of Fenebrutinib in OLE is consistent with previously reported data. The most common adverse events (aes) in more than 5% of patients included urinary tract infections (8%), COVID-19 (7%), and pharyngitis (5%). One patient (1%) had a serious adverse event. Another patient (1%) had an asymptomatic elevation of alanine aminotransferase (ALT), which returned to normal after discontinuation.   There are currently three ongoing Phase III clinical trials of fenebrutinib, including the FENhance 1 and FENhance 2 studies in patients with RMS, and the FENtrepid study in patients with primary progressive multiple sclerosis (PPMS). Data from these studies are expected to be available by the end of 2025.   Levi Garraway, MD, Roche's chief medical officer and head of global product development, said: "After one year of treatment, our BTK inhibitor fenebrutinib was able to effectively inhibit virtually all disease activity and disability progression in patients with multiple sclerosis. If these results are confirmed in the ongoing Phase III study, fenebrutinib is expected to further improve the treatment landscape for patients with multiple sclerosis."   According to the information of the Medical Rubik's Cube database, a total of 4 BTK inhibitors are currently undergoing phase III clinical studies for multiple sclerosis in the world, and fenebrutinib is the only third-generation BTK inhibitor. The other three are evobrutinib (Merck), remibrutinib (Novartis) and tolebrutinib (Sanofi). In addition, there are three BTK inhibitors in Phase II clinical studies in multiple sclerosis, including obutinib (Norzenogenat), pitobutinib (Eli Lilly), and BIIB091 (Bogen).