Phase 2 trial of oditrasertib in MS patients stopped after goals not met
Therapy to lower NfL levels tested in people with relapsing, progressive disease
Sanofi has ended a Phase 2 clinical trial into oditrasertib, an investigational RIPK1 inhibitor therapy, in people with relapsing and progressive multiple sclerosis (MS) after it failed to meet its goals.
The study, which had started dosing early last year, failed to show that oditrasertib significantly lowered levels of neurofilament light chain (NfL), a biomarker of neurodegeneration. Treatment also did not meet any key secondary endpoints, according to an SEC filing by Sanofi’s development partner Denali Therapeutics.
Sponsored by Sanofi, the Phase 2 K2 clinical trial (NCT05630547) was evaluating the effect of oditrasertib on blood NfL levels in adults, ages 18-60, with relapsing-remitting, secondary progressive, or primary progressive MS.
Denali acquired a portfolio of RIPK1 inhibitors through its 2016 acquisition of Incro Pharmaceuticals. The company then teamed up with Sanofi in 2018 to further develop these molecules for treating various diseases.
Oditrasertib aimed to ease inflammation, protect against neurodegeneration
Oditrasertib, also known as SAR443820 or DNL788, is an orally available inhibitor of RIPK1, a protein that’s involved in inflammation and cell death pathways. It is also brain-penetrant, meaning it’s able to cross the selective blood-brain barrier to reach brain tissue.
RIPK1 and related proteins are found to be overactive in neurodegenerative diseases, including MS, where it is thought to contribute to inflammation and nerve cell death.
By blocking the protein, oditrasertib aimed to ease inflammation and protect against neurodegeneration in MS, as well as other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
The Phase 2 trial enrolled a total of 174 patients, mostly across Europe, who were randomly assigned to treatment with oditrasertib tablets or to a placebo for 48 weeks (nearly a year). This was to be followed by a 48-week open-label extension period, where all would receive oditrasertib.
A breakdown of participants by disease type was not mentioned in the SEC filing.
The study’s main goal was to evaluate changes in blood NfL levels after 48 weeks and again at the end of the open-label period (96 weeks). Secondary outcomes included measures of brain lesions, disability, MS relapses, brain volume, motor function, and safety.
Treatment did not differ from placebo significantly with NfL levels
NfL is a structural component of nerve fibers that gets released into nearby fluids and the bloodstream when nerve cells are damaged. As a result, NfL levels are usually high in people with neurodegenerative conditions, and a reduction in those levels after treatment generally indicates that the therapy is able to ease neurodegeneration. As such, NfL is commonly used as an indicator of treatment responses in neurodegenerative disease clinical trials.
Per Denali’s SEC document, the primary goal was not met, meaning oditrasertib failed to lower NfL levels relative to the placebo. Other key secondary goals also were not met, although the filing did not detail which specific secondary outcomes were missed.
Earlier this year, a Phase 2 clinical trial testing oditrasertib in people with ALS also failed to meet its main goal of slowing disease progression, prompting the developers to discontinue its development for that disease.
The companies previously were working toward another brain-penetrant RIPK1 inhibitor called DNL747, but its development was paused in 2020 in favor of oditrasertib, which was showing a better therapeutic profile.
Currently, no active clinical trials are evaluating oditrasertib for any indication. Sanofi and Denali have another other RIPK1 inhibitor in development called eclitasertib (SAR443122), which does not enter the brain. That molecule failed a clinical trial for a type of lupus last year, but it is still being tested in people with ulcerative colitis.
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