Fenebrutinib

iStock, PaperFox Sanofi’s multiple sclerosis hopeful tolebrutinib faced dual setbacks on Monday, with a late-stage failure in one form of the disease and yet another regulatory setback in another. Sanofi reported a double whammy of bad news for multiple sclerosis drug tolebrutinib on Monday. The investigational therapy failed to slow disability progression in a Phase III trial, while on the regulatory side, it faces yet another delay for an approval application in progressive disease. Starting with the trial , the BTK inhibitor was being studied in patients with primary progressive multiple sclerosis (PPMS) in the Phase III PERSEUS trial. This indication applies to about 10% of patients with MS. The study failed to meet its primary endpoint, a measure of disability progression when compared with placebo. Sanofi did not provide specific numbers but said it would not pursue regulatory applications in PPMS. Leerink Partners, in a series of notes leading up to the readout, had been anticipating the study to be a success. Specifically, the firm believed Sanofi’s offering would beat Roche’s approved MS drug Ocrevus on delaying disease progression compared to placebo at week 24. The French pharma was also mum on the potential for liver injury with tolebrutinib in the Monday press release. While Sanofi acknowledged the risk of drug-induced liver injury associated with tolebrutinib, it did not provide detailed safety results from the PERSEUS trial, simply noting that results were consistent with previous studies. Leerink had been keenly awaiting these stats to weigh the potential for success of tolebrutinib’s existing FDA application for secondary progressive multiple sclerosis (SPMS). On the regulatory front, the FDA has once again delayed a decision on tolebrutinib’s application for non-relapsing secondary progressive multiple sclerosis (nrSPMS). In September, the agency pushed back the decision timeline to December 28. Sanofi now says the decision has been delayed again and no firm date has been provided. The FDA requested additional information on an expanded access protocol in nrSPMS. The FDA will provide an updated decision date by the end of the first quarter of 2026, Sanofi said. Leerink called today’s updates “disappointing” in a brief note on Monday morning. The firm had been projecting sales of about $1.1 billion for the drug. Rival Roche also has a BTK inhibitor in development called fenebrutinib, which Leerink said has already demonstrated similar efficacy to Ocrevus in PPMS. Sanofi’s tolebrutinib has had a tough path through the clinic, with several failures as well as cases of liver injury that spurred clinical holds from the FDA. In September 2024, Sanofi finally reported Phase III success in the HERCULES trial, with the drug delaying disease progression by 31% in patients with nrSPMS. These results teed up the regulatory filing that is now once again being pushed back. The HERCULES trial also showed an increase in adverse events, including a rate of liver enzyme elevations in 4.1% of patients who took the study drug. Most resolved without issue, but a patient who underwent a liver transplant after treatment died. Sanofi implemented changes to the study protocol to boost liver monitoring. Designed to be administered orally, tolebrutinib is a small molecule inhibitor of the BTK protein, which under healthy circumstances is important for the development and activity of antibody-producing B cells. Tolebrutinib’s mechanism of action allows it to suppress B cells and the disease-driving microglia. Sanofi came to own tolebrutinib in the $3.7 billion acquisition of Principia Biopharma in August 2020.

Sanofi is scrapping plans to get one of its more advanced experimental medicines approved for a certain kind of multiple sclerosis, following negative results from a clinical trial disclosed Monday.The French pharmaceutical giant didnt release any specific data, only that its drug, tolebrutinib, failed to meet the main goal of a late-stage trial titled PERSEUS. The study enrolled 767 participants with a rarer form of MS known as primary progressive, and looked at whether tolebrutinib was any better at delaying the disabilities that typically worsen over the course of the disease.Based on these results, Sanofi will not attempt to get the drug approved in this setting. The company is also evaluating if it needs to take an impairment charge related to tolebrutinibs intangible value, given that the drug was the centerpiece of a $3.7 billion buyout. Sanofi intends to provide an update on this evaluation in January though it noted that, either way, the outcome wont impact net income or earnings per share. Its 2025 financial guidance remains unchanged.We are disappointed by todays results; however, we do believe [they] will improve our understanding of the underlying disease biology of multiple sclerosis, said Houman Ashrafian, head of Sanofis research and development, in a statement.Separately, Sanofi on Monday revealed that an approval verdict for tolebrutinib as a treatment for non-relapsing secondary progressive MS will likely come later than expected.The Food and Drug Administration had previously aimed to make a decision by Sept. 28, but pushed that deadline back by three months after Sanofi made a major amendment to its application. Now, the company suspects recent discussions with the FDA indicate a ruling wont come by the revised date of Dec. 28. Sanofi anticipates more guidance from the agency sometime in the first three months of next year.The company said it strongly believes in tolebrutinibs risk-benefit profile. In response to an FDA request, it has submitted an expanded access protocol so eligible patients with non-relapsing secondary progressive MS can get ahold of the drug.The fact that the FDA has requested an extended access program suggests the agency is comfortable with the risk/benefit for now, wrote analysts at the investment bank Jefferies, in a note to clients.The market may well write the asset off, but that seems a bit premature, the analysts added. We wonder if more share price pressure will mean more pressure on management.Tolebrutinib comes as a tablet, and is part of a class of drugs designed to inhibit Brutons tyrosine kinase, an immune system-regulating enzyme that plays a key role in the development of B cells.Those cells make antibodies that alert the body to potential threats. Research suggests a root cause of MS is antibodies mistakenly attacking the protective myelin sheaths that cloak nerve fibers.Sanofi already has one BTK-blocking drug, Wayrilz, on the market for a different autoimmune condition. So does Novartis. BTK inhibitors like Imbruvica, Calquence and Brukinsa are used to treat certain blood cancers as well. The class as a whole carries safety concerns, namely the potential for liver injury, which in recent years led the FDA to issue partial clinical holds on tolebrutinib and similar drugs from Roche, Merck KGaA and InnoCare Pharma.This fall, that Roche drug, fenebrutinib,succeeded in two large MS trials. One recruited primary progressive patients, while the other focused on the far more common relapsing form of the disease. Jefferies analysts described those readouts as a positive surprise, though they also questioned whether Roche had collected enough supportive evidence to file for approval. '