PIPE-307 shows potential to repair myelin in MS mouse model
Phase 2 trial for oral therapy is recruiting adults with RRMS in US
PIPE-307, an experimental oral therapy that’s currently in Phase 2 testing for relapsing-remitting multiple sclerosis (RRMS), was shown to promote myelin repair in a mouse model of multiple sclerosis (MS).
The preclinical findings were published in PNAS, in the study “Targeting the muscarinic M1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis.”
The work was conducted by scientists at Contineum Therapeutics, the company developing PIPE-307, in collaboration with researchers at the University of California, San Francisco.
“We believe that PIPE-307 represents a differentiated and clinically validated approach for the treatment of RRMS, and we are pleased to have our innovative science validated by a high-quality journal like PNAS,” Carmine Stengone, president and CEO of Contineum, said in a company press release.
Multiple sclerosis is driven by inflammation in the brain and spinal cord, which causes damage to the myelin sheath, a fatty covering around nerve fibers that helps nerves to send electrical signals. Damage to myelin disrupts normal nerve signaling, ultimately driving the symptoms of MS.
To date, no treatment has been proven to promote repair of damaged myelin
RRMS is the most common form of MS, marked by relapses where symptoms suddenly worsen and periods of remission where symptoms ease or disappear entirely. Many approved treatments for RRMS are available, but all of them work by dampening inflammation. To date, no treatment has been proven to promote the repair of damaged myelin (a process called remyelination).
In the brain and spinal cord, myelin is produced by specialized cells called oligodendrocytes, but their maturation from oligodendrocyte precursor cells (OPCs) is often impaired in people with MS due to the ongoing inflammation.
PIPE-307 is designed to promote this differentiation from OPCs to mature oligodendrocytes that can repair myelin. It works by blocking M1 muscarinic receptors (M1R), which is found particularly in OPCs close to MS lesions with ongoing inflammation.
“As observed in our preclinical studies, we believe that the immune-mediated effects of RRMS drive M1 signaling … which in turn, limits OPC maturation and remyelination,” said Stephen Huhn, MD, Contineum’s chief medical officer and senior vice president of clinical development. “The M1 receptor is highly expressed on OPCs and, by blocking M1 and lifting this inhibitory brake on maturation, we believe that PIPE-307 can lead to OPC maturation and [nerve fiber] remyelination.”
In the new paper, researchers first presented data validating that PIPE-307 can block M1R to promote the maturation of OPCs into oligodendrocytes as intended.
The researchers then tested the therapy in mice with experimental autoimmune encephalomyelitis (EAE), a lab-made disease used to model MS.
Analyses suggest PIPE-307 increased myelin repair in mouse model
PIPE-307-treated EAE mice showed significantly less physical disability than their untreated counterparts, and analyses of the mice’s nervous systems suggested the therapy increased myelin repair as designed.
“Oral delivery of PIPE-307 to mice resulted in increased remyelination in the [EAE] model of inflammatory demyelination and functional recovery,” the researchers concluded.
PIPE-307 also was shown to promote remyelination in samples of human brain tissue, implying these findings may extend to people. Collectively, the data “lend support for M1R as a target for remyelination and underscore the potential use of PIPE-307 for treating MS and other demyelinating diseases,” the researchers wrote.
Having completed Phase 1 testing in healthy volunteers, Contineum is currently running a Phase 2 clinical trial dubbed VISTA (NCT06083753) to test PIPE-307 in people with RRMS. Recruitment is ongoing at more than 20 locations across the U.S.
The study is seeking 168 patients, ages 18 to 50, who are on stable treatment with an available MS disease-modifying therapy. They will be randomly assigned to receive one of two doses of oral PIPE-307 or a placebo, daily for 26 weeks.
The main goals are to test PIPE-307’s safety in people with RRMS, as well as changes in visual acuity, indicative of better myelination in the nerve that sends messages from the eyes to the brain, in a subgroup of patients. Other vision measures, as well as changes in walking function, dexterity, cognition, and disease biomarkers will also be assessed.
“We are pleased to have published these data in PNAS and to have advanced into a multi-center Phase 2 study investigating PIPE-307’s efficacy and safety in patients,” Huhn said.
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