Potential First-in-Class M1R Antagonist May Promote Remyelination and Restore Function in Patients with MS

Multiple sclerosis (MS) is an autoimmune disease in which aberrant inflammatory processes cause destruction of the protective myelin sheath in the brain and along the spinal cord. In addition to providing protective insulation for the central nervous system (CNS), myelin also conducts electrical signals along nerve cells.

Demyelination due to MS results in slowed signal transmission, leading to debilitating symptoms, such as vision and balance problems, issues with bladder control, and eventual loss of mobility.

Current MS treatments aim to reduce inflammation and prevent demyelination and nerve cell damage. So far, no treatments exist to remyelinate damaged neurons and reverse disease progression.

Researchers from biopharmaceutical company Contineum Therapeutics, based in San Diego, and the department of neurology at the University of California San Francisco are developing a novel, oral, CNS-penetrating small molecule targeting the M1 muscarinic acetylcholine receptor (M1R).

In healthy neurons, oligodendrocyte precursor cells (OPCs) can differentiate into oligodendrocytes which produce myelin. In patients with MS, OPCs are abundant but do not mature into oligodendrocytes. The researchers, led by Michael Poon, Ph.D., found that M1 receptors are highly expressed on OPCs and believe that blocking the M1 receptor can promote differentiation of OPCs and nerve cell remyelination.

The investigational drug, called PIPE-307, penetrates the blood-brain barrier and selectively inhibits M1R. In a study published last month in the journal Proceedings of the National Academy of Science (PNAS), PIPE-307 effectively induced OPC differentiation and remyelination in MS donor human brain tissue and an animal model and restored lost function in an MS mouse model.

Contineum Therapeutics is developing PIPE-307 in collaboration with Janssen Pharmaceutica NV, one of the Janssen Pharmaceutical Companies of Johnson & Johnson. The company completed two phase 1 trials of healthy volunteers assessing the molecule’s effect on cognitive function typically affected by other muscarinic receptor antagonists, such as scopolamine. No negative effects were noted.

PIPE-307 is currently in the VISTA phase 2 trial evaluating its safety and efficacy in adults ages 18 to 50 years with relapsing remitting MS. A total of 168 participants will be randomized to receive one of two doses of the study drug or placebo for 30 weeks. The primary outcomes include treatment-related adverse events and the change in binocular 2.5% low contrast letter acuity (LCLA) from baseline to week 26. LCLA is a common outcome measure to gauge visual disability in patients with MS.

If approved, PIPE-307 could become the first MS treatment to promote remyelination and potentially restore MS-associated loss of function.