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).

Dive Brief:An experimental Sanofi medicine failed two studies in multiple sclerosis but met its main objective in a third trial in a less common form of the disease, the company said Monday.In two Phase 3 studies of people with relapsing forms of MS, the drug tolebrutinib wasnt better than another Sanofi medicine, Aubagio, at reducing the rate of disease flare-ups. But tolebrutinib did meaningfully delay the onset of disability progression in people with non-relapsing secondary progressive MS in a separate late-stage trial, and showed a similar effect in the other two trials as well, Sanofi said.Sanofi only provided summary results. Specific data will be presented at a medical meeting later this month. But the company did say the findings will form the basis of discussions with drug regulators. A Phase 3 trial is also underway in primary progressive MS, for which success depends on tolebrutinibs ability to delay disability progression. Results are expected next year.Dive Insight:Analysts and investors have dialed back their expectations for tolebrutinib since Sanofi bought its developer, Principia Biopharma, four years ago.The drug is part of a newer generation of would-be MS medications called BTK inhibitors that, unlike their cancer-fighting predecessors, are designed to get into the brain and treat autoimmune conditions. However, study results so far have been underwhelming. Safety concerns slowed the progress of multiple programs, including tolebrutinib, while Merck KGaAs evobrutinib failed a pair of Phase 3 tests last December.Ahead of Sanofis readout, many investors anticipated negative tolebrutinib news, wrote Leerink Partners analyst David Risinger on Tuesday. Its studies in relapsing MS were designed similarly to Merck KGaAs trials and, even if the results had been positive, tolebrutinib would eventually have had to compete with several effective and convenient medicines, added Stifels Eric Le Berrigaud in a separate client note.Yet, by claiming success in non-relapsing secondary progressive MS, or nrSPMS, Sanofi may have a chance to make something of tolebrutinib. The condition is different from relapsing MS in that people accumulate disabilities over time, instead of experiencing periodic disease flares. There are also no therapies specifically approved to treat it, meaning tolebrutinib become a referenced drug for the disease, if not the standard of care, wrote Le Berrigaud. He estimates tolebrutinib still holds the potential to be a blockbuster medicine, with a market opportunity of about $3 billion to $3.5 billion in the U.S. alone.Even at that figure, tolebrutinibs sales potential would be lower than what Sanofi once envisioned. The company believes about 170,000 people are currently diagnosed with nrSPMS in the U.S. and Europe, far fewer than the 910,000 Sanofi has estimated to have relapsing MS.Additionally, Sanofi hasnt disclosed important information from the tolebrutinib trial, like how much the drug benefited patients or whether it caused liver-related side effects that have occurred in testing of BTK blockers for MS. A preliminary analysis of liver safety was consistent with previous tolebrutinib studies, Sanofi said in its statement.Leerinks Risinger also noted how, even if tolebrutinib is approved, insurers may limit access in nrSPMS and prioritize off-label use of other MS drugs since it couldnt outperform Aubagio.Further competition could be coming, too. Roche and Novartis have BTK inhibitors in advanced testing for MS, with results coming in the next couple of years, according to a federal database. '