Testing a Promising Remyelinating Agent for Relapsing-Remitting Multiple Sclerosis: The VISTA Trial

Relapsing-remitting multiple sclerosis (RRMS) is the most prevalent form of multiple sclerosis (MS). A defining feature of all MS types is the presence of demyelinating lesions in the brain and spinal cord. In healthy neurons, myelin, a specialized extension of the oligodendrocyte plasma membrane, acts as an insulator, enabling rapid and efficient conduction of electrical signals along the axon. In demyelinating conditions such as MS, the loss of myelin slows signal transmission and can ultimately result in permanent impairment of neuronal function.¹

PIPE-307 (Contineum Therapeutics), an oral, highly selective antagonist of the M1 muscarinic receptor, is currently being evaluated in the phase 2 VISTA trial (NCT06083753) of patients with relapsing-remitting MS. M1 acetylcholine receptor (mAChR) is primarily located in the cerebral cortex, hippocampus, and striatum, but is also found in the thalamus, brainstem, and cerebellum at lower levels. In oligodendrocyte progenitor cells (OPCs), M1, M3, and M4 mAChRs are most abundant, but expression of all M1-M5 subtypes decreases after differentiation, suggesting a role in maturation.

“What's unique is that it's targeting the pathway we identified, the M1 receptor pathway. By inhibiting that target, it's attempting to achieve clinical remyelination. If [the drug] showed an effect on low-contrast acuity, [the primary outcome] we'd be super encouraged. If an effect wasn't able to be seen, it's harder to know how to interpret that, because it might have something to do with the selection of that outcome - and challenges with low contrast letter acuity in a multi center trial," Ari Green, MD, chief of the Division of Neuroimmunology and Glial Biology in the Department of Neurology at the University of California at San Francisco, told NeurologyLive^® in a recent interview.

In this randomized, double-blind trial, 168 participants will be randomized into 1 of 3 separate dosing cohorts, given PIPE-307 dose A, PIPE-307 dose B, or placebo for approximately 30 weeks. The study will have a 28-day screening period followed by a 26-week treatment period where investigators will assess safety as well as change in binocular 2.5% low contrast letter acuity (LCLA). Other secondary end points include change in monocular 2.5% LCLA, changes in MRI measures of myelination and MS disease activity, neurofilament light chain, pharmacokinetics (PK), and other assessments such as Timed 25-Foot Walk Test, Nine-Hole Peg Test, and Symbol Digit Modalities Test.

READ MORE: International Committee Publishes 2024 Revisions to McDonald Diagnostic Criteria for Multiple Sclerosis

Eligible participants were adults aged 18 to 50 with a diagnosis of RRMS per the 2017 Revised McDonald Criteria. Participants were required to be fluent in English, in generally good health aside from MS-related conditions, and on stable treatment with no more than a single disease-modifying therapy (DMT) for at least 6 months. Additional requirements included meeting protocol-specified Expanded Disability Status Scale (EDSS) and retinal nerve fiber layer criteria, and agreeing to use effective contraception if of reproductive potential. For those in the visual evoked potential (VEP) sub-study, participants also needed a P100 latency above the upper limit of normal in at least one eye or a protocol-defined inter-eye difference.

Participants were excluded if they had recent optic neuritis, a long-standing multiple sclerosis diagnosis (over 10 years), severe eye conditions affecting visual assessments, or concurrent use of certain MS or anticholinergic medications. Additional exclusions included recent MS relapses or corticosteroid treatment, prior use of specific immunosuppressive therapies or bone marrow transplantation, active malignancy or high-risk cancer, significant cardiac conditions, use of drugs affecting CYP3A4, participation in other investigational interventions, presence of gadolinium-enhancing MRI lesions, or risk of suicide. For those enrolled in the VEP sub-study, any ophthalmologic or retinal disorder that could interfere with VEP measurements also led to exclusion.

Prior to this study, researchers tested multiple dose cohorts of PIPE-307 in a randomized, double-blind, placebo-controlled phase 1 trial (NCT04725175) of 70 healthy volunteers. with linear pharmacokinetic (PK) data consistent with preclinical modeling, and the drug was generally well tolerated across all dose cohorts. The phase 1 study included an analysis battery of neuropsychological measures, which covered tests of psychomotor function, attention, learning, and executive function. Researchers noted that analysis revealed no significant PK- or dose-related effects on cognitive function.^2,3

"We have lots of trials and studies that we've done that are supportive data. There are a bunch of papers on the drug known as clemastine, which helps support an approach on both how to measure remyelination and also this specific target," Green added. "Clemastine achieves its remyelinating effect via its targeting of the M1 receptor. I think that's all supportive data and approaches, and that really guided the selection of low-contrast letter acuity as well as the blood based biomarkers and the specific MRI outcome."

He continued, "Those are all derived from our work, which means we believe in that approach strongly. But the proof will come with what we see regarding appropriate implementation of these approaches in the trial and then being able to evaluate the data and the study execution after it's completed. Even if you have an excellent target and a great drug - it’s really a major endeavor to do these things right."

Editor’s Note: Green has disclosed that he was a former consultant at Contineum Therapeutics.

REFERENCES
1. Contineum Therapeutics Announces Publication of Encouraging Data in the Proceedings of the National Academy of Sciences on PIPE-307, Its M1 Receptor Selective Inhibitor, in Clinical Development for Relapse-Remitting Multiple Sclerosis. News Release. Contineum Therapeutics. Published July 31, 2024. Accessed September 19, 2025. https://ir.contineum-tx.com/news-releases/news-release-details/contineum-therapeutics-announces-publication-encouraging-data
2. Pipeline Therapeutics Reports Positive Phase 1 Clinical Results for PIPE-307, a Neuroregenerative Therapeutic for the Treatment of Multiple Sclerosis. News release. Pipeline Therapeutics. March 10, 2022. Accessed September 19, 2025. https://www.businesswire.com/news/home/20220310005312/en/Pipeline-Therapeutics-Reports-Positive-Phase-1-Clinical-Results-for-PIPE-307-a-Neuroregenerative-Therapeutic-for-the-Treatment-of-Multiple-Sclerosis
3. Poon MM, Lorrain KI, Stebbins KJ, et al. Targeting the muscarinic M1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis. Proc Natl Acad Sci U S A. 2024;121(32):e2407974121. doi:10.1073/pnas.2407974121