Oditrasertib

iStock, JHVEPhoto Oditrasertib, which blocks the inflammatory RIPK1 protein, earlier this year also failed a Phase II trial in amyotrophic lateral sclerosis, forcing the company to discontinue its development a few months later. Sanofi is discontinuing a Phase II multiple sclerosis study of its investigational RIPK1 blocker oditrasertib after the candidate failed to meet its primary and key secondary endpoints, according to an SEC filing on Thursday by partner Denali Therapeutics. Denali and Sanofi were evaluating oditrasertib in the mid-stage K2 study , a randomized, double-blinded and placebo-controlled trial that enrolled more than 170 patients with relapsing-remitting multiple sclerosis (MS), secondary progressive MS or primary progressive MS. The primary efficacy endpoint was oditrasertib’s effect on serum neurofilament light chain levels. No specific details were provided in Denali’s SEC document, nor did the company identify which particular secondary outcomes oditrasertib missed. The California biotech also did not address oditrasertib’s safety profile. Designed to be orally available, oditrasertib is an investigational inhibitor of the RIPK1 protein, which is a crucial signaling player in inflammatory and cell death pathways. In neurodegenerative diseases, RIPK1—along with other proteins from the same family— tends to be overactivated , leading to widespread inflammation and large-scale cell death in the brain. By targeting RIPK1, oditrasertib disrupts this pathological process, in turn preserving the integrity and function of the brain. Despite a promising mechanism of action, however, oditrasertib has had a challenging clinical showing recently. In April 2024, Sanofi announced plans to terminate a Phase II trial of oditrasertib in amyotrophic lateral sclerosis (ALS) after a disappointing mid-stage readout. A few months earlier, in February 2024, Sanofi and Denali announced that oditrasertib failed the Phase II HIMALAYA study in ALS , unable to significantly improve disease severity, as measured by the ALS Functional Rating Scale-Revised. Developing effective therapies for MS has proven difficult. In September 2024, another Sanofi asset, the BTK inhibitor tolebrutinib, failed to significantly improve relapse rates in two Phase III studies. Tolebrutinib redeemed itself a few weeks later by significantly delaying disability onset in patients with non-relapsing secondary progressive MS in a third Phase III trial. That same month, a study published in the peer-reviewed journal Neurology raised questions about the use of anti-CD20 antibodies in multiple sclerosis. According to its findings, there appear to be no significant difference in relapse or the progression of disability between patients who were given these therapies versus those who were untreated. The study focused on primary progressive multiple sclerosis, for which the only approved anti-CD20 therapy is Roche’s Ocrevus (ocrelizumab). Other agents in the same drug class are also approved for relapsing forms of MS, including Novartis’ Kesimpta (ofatumumab) and TG Therapeutics’ Briumvi (ublituximab).

iStock, JHVEPhoto The positive readout in patients with non-relapsing secondary progressive multiple sclerosis comes on the heels of back-to-back failures in which tolebrutinib was unable to improve relapse rates in patients with relapsing MS. Sanofi on Friday announced that its investigational BTK inhibitor tolebrutinib delayed the onset of disability progression by 31% in patients with non-relapsing secondary progressive multiple sclerosis. The results come from the Phase III HERCULES study, a double-blinded randomized trial that compared daily oral tolebrutinib against placebo in terms of confirmed disease progression at six months, defined using scores in the expanded disability status scale. Friday’s readout from HERCULES also showed that 10% of patients on tolebrutinib experienced confirmed disability improvement, versus around 5% in the placebo arm. This corresponded to an 88% increase in the likelihood of improvement, with a nominal p-value of 0.021, according to Sanofi. In terms of safety, preliminary data from HERCULES pointed to a “slight increase” in adverse events among patients treated with tolebrutinib. Of the patients treated with the BTK inhibitor, 4.1% saw liver enzyme elevations greater than thrice the upper limit of normal, as compared with only 1.6% among placebo comparators. “All but one” case of liver enzyme elevation resolved without medical intervention. One patient in the tolebrutinib arm underwent liver transplantation and died due to complications related to the surgery. This fatality occurred after Sanofi revised its protocol to have more stringent and frequent monitoring, which has since “mitigated such serious liver sequelae.” Tolebrutinib “has demonstrated its ability to delay disability by targeting underlying drivers” of non-relapsing secondary progressive multiple sclerosis (nrSPMS), Houman Ashrafian, Sanofi’s head of R&D, said in a statement. The company will bring these finding to global regulatory authorities, with submissions set to start in the second half of 2024. Jefferies analyst Peter Welford called HERCULES’ readout “promising” in a note to investors. “We view data as positive to enable global filings and approvals given current unmet need for nrSPMS with no effective drugs available.” Importantly, Friday’s findings from HERCULES now makes tolebrutinib a “de-risked $2-3bn opportunity,” Welford wrote. 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 secured the rights to tolebrutinib in August 2020, when it acquired Principia Biopharma for almost $3.7 billion. The drug candidate has since become a pillar of Sanofi’s multiple sclerosis program , alongside the late-stage antibody frexalimab and the Phase II RIPK1 inhibitor oditrasertib. However, tolebrutinib’s clinical development has not been without its challenges. In June 2022, the FDA slapped a partial clinical hold on the drug and suspended enrollment in its Phase III trials due to drug-induced liver injuries. Earlier this month, Sanofi reported back-to-back Phase III failures for tolebrutinib, which was unable to significantly improve relapse rates in the patients with relapsing forms of MS.