Receptor interacting protein kinase (RIPK) family

The K2 trial tested oditrasertib’s safety and ability to reduce the blood levels of neurofilament light chain, a biomarker of neuronal damage in multiple sclerosis. However, the trial failed to meet its primary and undisclosed key secondary endpoints, according to a filing ​. Multiple sclerosis is a degenerative and progressive disorder where the immune system attacks the insulation around nerve cells, leading to the death of the cells and to increasing disability in people with the condition, which number around 2.8 million ​. Oditrasertib is designed to block a protein called receptor-interacting protein kinase 1 (RIPK1), which is involved in cell death. Blocking RIPK1 could make nerve cells more resistant to the pathology and slow down the disease. Denali obtained oditrasertib in 2016 when it took over the previous developer Incro Pharmaceuticals. Sanofi then got in on the action when it inked a $1 billion strategic collaboration with Denali in 2018 to develop candidates for the treatment of immunological and neurological conditions. Numerous setbacks The partnership has faced numerous obstacles in the last few years. Another of the RIPK1 inhibitors in the deal flopped in a phase 1b trial for the treatment of Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) in 2020, leading the partners to focus on oditrasertib. In February this year, however, oditrasertib failed in a phase 2 trial for the treatment of ALS and Sanofi discontinued the trial. Another RIPK1 inhibitor in the sights of the partners is eclitasertib, which cannot penetrate the central nervous system and is in phase 2 development for the treatment of ulcerative colitis. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Denali Therapeutics raised $500 million in a private placement in February this year and its main candidate, an enzyme replacement therapy to treat the rare disease mucopolysaccharidosis type II, is in a phase 2/3 trial set to complete enrollment this year. The growing prevalence of multiple sclerosis is set to drive the global market ​ for treatments, which was worth $21.3 billion in 2023 and is projected to grow by 7.9% to $38.9 billion by 2032. Getting a RIPK1 blocker ​ to the market is proving difficult for many players, with a candidate developed by GlaxoSmithKline showing no efficacy signs in clinical results in patients with ulcerative colitis published ​ in 2021. Some of the most advanced RIPK1 contenders include phase 1-stage programs by China’s GenFleet Therapeutics, Roche’s U.S. company Genentech, and a compound developed by Eli Lilly and Rigel Pharmaceuticals.

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).

Sanofi is ending a Phase 2 clinical trial that’s testing a drug from Denali for multiple sclerosis, putting a stop to the development plan. Denali said in an SEC filing Thursday that Sanofi notified the company that the drug, oditrasertib, did not meet primary or key secondary endpoints in the study. The drug looked to block RIPK1, a signaling protein that when overstimulated can drive neuroinflammation and cell death, root causes of diseases like multiple sclerosis. A Sanofi spokesperson said the company has no other planned studies. The new data are the latest in a string of disappointing readouts since the collaboration got off the ground. Sanofi paid Denali $125 million upfront back in 2018 with more than $1 billion in potential milestone payments, a huge bet on the RIPK1 target that oditrasertib was aimed at. In February, oditrasertib failed a Phase 2 ALS study , after failing to improve patient symptoms as measured by the ALS Functional Rating Scale. Another drug that headlined the 2018 deal, DNL747, was fully halted in 2020 after the companies got a peek at Phase 1b data in patients with Alzheimer’s and ALS. A third asset, DNL758, is still in the middle of a Sanofi-run Phase 2 study for patients with ulcerative colitis. But the company discontinued an earlier study in October 2023 after the drug was found to not be effective in patients with cutaneous lupus erythematosus. Despite the pared-back collaboration, Denali entered the third quarter with $1.35 billion in cash, equivalents and marketable securities as of the end of June. That funding will help pay for advancing the company’s mid- to late-stage pipeline, including a potential treatment for Hunter syndrome that Denali is teeing up for an accelerated approval application. The company said last month that it had a successful meeting with the FDA about a surrogate endpoint and plans to submit the application in early 2025.