Evobrutinib

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).

iStock, JHVEPhoto The BTK inhibitor showed promise in non-relapsing secondary progressive multiple sclerosis but not relapsing MS. The company said it plans to apply for approval for the former “as soon as possible.” Sanofi ’s investigational BTK inhibitor tolebrutinib missed the primary efficacy endpoints in the Phase III GEMINI 1 and GEMINI 2 studies, failing to significantly improve relapse rates in patients with relapsing multiple sclerosis, according to a company announcement of three late-stage readouts on Monday. A third trial, however, succeeded. Results from the Phase III HERCULES study showed that tolebrutinib significantly delayed disability progression in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). Early analysis of toxicities also showed that tolebrutinib’s liver safety pro consistent with what had been established in prior studies, according to Sanofi. The pharma did not provide specific data from any of the studies in its news release, instead promising to reveal more detailed findings and analyses from the trials at the upcoming European Committee for Treatment and Research in Multiple Sclerosis, happening later this month in Copenhagen. “Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation,” Houman Ashrafian, Sanofi’s head of R&D, said in a statement. The accumulation of disabilities in patients as their disease progresses “remains the greatest unmet medical need” in nrSPMS patients. In an interview with Fierce Biotech , Ashrafian added that Monday’s triple readouts “bring into sharp focus which patient population we should be treating.” The pharma plans to tolebrutinib’s approval in nrSPMS “as soon as possible,” he said. MS is a chronic, neurodegenerative disorder that arises when the body’s immune system attacks the protective covering of its own nerve cells. It typically manifests as numbness or weakness in the limbs, lack of coordination and unsteady gait and partial or complete blindness. According to Sanofi’s news release, the accumulation of disabilities is a central and largely under-addressed problem in MS. For instance, in relapsing MS, patients experience episodes of worsening symptoms, also called relapses, alternating with periods of recovery. While nrSPMS does not include relapses, patients continue to accumulate disabilities such as fatigue, impaired cognition and sexual dysfunction. Tolebrutinib is an orally available and brain-penetrant inhibitor of the BTK protein, which is a central player in the development of the antibody-producing B cells. Through this mechanism of action, tolebrutinib can help temper the activity of B lymphocytes and disease-driving microglia. In addition to tolebrutinib, Sanofi is also addressing MS with its anti-CD40L antibody frexalimab. In February 2024, the company reported Phase II data for frexalimab, demonstrating a significant reduction in disease activity and active inflammation in patients with relapsing MS. Tolebrutinib’s road to Monday’s readouts has been rough. In June 2022, the FDA put a partial clinical hold on Phase III trials of the drug, suspending enrollment into these studies. The regulatory pause was triggered by multiple cases of drug-induced liver injuries. Aside from the HERCULES and the GEMINI studies, Sanofi continues to evaluate tolebrutinib in the Phase III PERSEUS trial, for primary progressive MS. PERSEUS is expected to read out next year. Monday’s back-to-back Phase III failures for tolebrutinib illustrate the difficulty of advancing BTK inhibitors in MS. In December 2023, for instance, Merck KGaA’s evobrutinib also failed its Phase III evolutinRMS 1 and evolutionRMS 2 studies, unable to significantly curb relapse rates in patients. A few months later, in March 2024, the German pharma announced it had discontinued the development of evobrutinib in MS. Fellow pharma powerhouse Roche has also struggled with MS, announcing in December 2023 that its investigational BTK inhibitor fenebrutinib was put under partial clinical hold after the FDA detected multiple cases of liver injury.