Sanofi halts phase 2 trial of Denali's multiple sclerosis drug

Denali Therapeutics has been testing its drug, oditrasertib, in various clinical trials to evaluate its effectiveness and safety in treating multiple sclerosis (MS). MS is a chronic disease where the immune system attacks and damages the protective covering of nerve cells, which leads to neuronal death and increasing disability in sufferers. Approximately 2.8 million people worldwide are affected by this condition.

Oditrasertib was specifically designed to inhibit receptor-interacting protein kinase 1 (RIPK1), a protein that plays a crucial role in cell death. The idea behind this drug is that by blocking RIPK1, nerve cells could become more resilient against the disease's effects, potentially slowing its progression. Denali acquired oditrasertib in 2016 from Incro Pharmaceuticals. Subsequently, in 2018, Sanofi entered into a strategic collaboration with Denali, investing $1 billion to help develop treatments for various immunological and neurological conditions using Denali’s drug candidates.

Despite the promising mechanism of action, the development of RIPK1 inhibitors, including oditrasertib, has faced significant challenges. The K2 trial aimed to assess the drug's safety and its ability to reduce neurofilament light chain levels in the blood, a marker of neuronal damage in MS patients. Unfortunately, the trial did not meet its primary and key secondary endpoints, leading to doubts about its efficacy.

The partnership between Denali and Sanofi has encountered various setbacks over the years. In 2020, another RIPK1 inhibitor from their collaboration failed in a phase 1b trial for Alzheimer's disease and amyotrophic lateral sclerosis (ALS), prompting the focus to shift to oditrasertib. However, earlier this year, oditrasertib also failed in a phase 2 trial for ALS, leading Sanofi to terminate the trial.

Amid these challenges, Denali and Sanofi have looked at other RIPK1 inhibitors, including eclitasertib, which is currently in phase 2 trials for ulcerative colitis. Unlike oditrasertib, eclitasertib cannot cross the blood-brain barrier, limiting its use to conditions outside the central nervous system.

In February 2023, Denali Therapeutics managed to raise $500 million through a private placement. Its primary drug candidate, an enzyme replacement therapy for the rare condition mucopolysaccharidosis type II, is currently in a phase 2/3 trial, expected to complete enrollment later this year.

The increasing prevalence of multiple sclerosis is driving the global market for treatments. Valued at $21.3 billion in 2023, this market is anticipated to grow at a rate of 7.9% annually, potentially reaching $38.9 billion by 2032. However, bringing a successful RIPK1 inhibitor to market remains a formidable challenge. For instance, GlaxoSmithKline's RIPK1 inhibitor showed no efficacy in a clinical trial for ulcerative colitis in 2021. Other advanced RIPK1 inhibitors are in the early stages of development, including programs from GenFleet Therapeutics in China, Roche’s U.S. company Genentech, and a joint effort by Eli Lilly and Rigel Pharmaceuticals.

Denali’s journey with RIPK1 inhibitors highlights the complexities and obstacles inherent in drug development, particularly for conditions involving the central nervous system. While the setbacks have been noteworthy, both Denali and other pharmaceutical companies continue to explore and invest in RIPK1 inhibitors, hoping to eventually bring effective treatments to market.