Remyelinating Agent PIPE-307 Falls Short in Phase 2 Trial of Relapsing Multiple Sclerosis

In recent news, Continuem’s PIPE-307, an M1 receptor antagonist developed for patients with relapsing-remitting multiple sclerosis (RRMS), failed to meet its primary end point in the phase 2 VISTA trial (NCT06083753), a placebo-controlled trial testing the drug’s effect on remyelination.¹

Although the study failed to achieve its prespecified end points, the company is still planning to take a more detailed look at the exploratory end points, as well as present and publish the findings at a later time in a peer-reviewed journal. VISTA, a double-blind, proof-of-concept trial, comprised 168 patients with RRMS testing 2 doses of PIPE-307 against placebo for a 30-week treatment period. The trial’s primary end point, change in binocular 2.5% low contrast letter acuity (LCLA), was ultimately not successful for the investigational agent.

"We’re disappointed by these results, but are grateful to the VISTA trial investigators, and especially to the patients and their families,” Timothy Watkins, MD, MSc, chief medical officer and head of Development at Continuem, said in a statement.¹ "We intend to learn from these data and remain committed to pursuing novel therapies for patients with inflammatory and fibrotic diseases."

For years, the field has been in search of therapies that can encompass remyelinating properties to ultimately counteract the loss of myelin seen in a condition like RRMS. PIPE-307 was among one of the more highly anticipated therapies, with VISTA being the latest stage trial for a remyelinating agent.

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PIPE-307, an oral, highly selective antagonist of the M1 muscarinic receptor (mAChR), was shown to be safe and well tolerated in VISTA, despite not meeting the primary end point. For context, M1 acetylcholine receptor is primarily located in the cerebral cortex, hippocampus, and striatum, but is also found in the thalamus, brainstem, and cerebellum at lower levels. Over the years, M1 mAChR has emerged as a potential remyelination target in MS because of how it regulates oligodendrocyte lineage progression and the balance between differentiation and maturation in the central nervous system.

VISTA, a phase 2 study, included patients with RRMS aged 18 to 50 who were on stable disease-modifying treatment for no more than 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.

Before VISTA, PIPE-307 was studied in a phase 1, placebo-controlled trial (NCT04725175) of healthy volunteers, where the therapy was shown to be well tolerated across all dose cohorts. In this multi-dose, randomized study, investigators studied the safety of PIPE-307, as well as a battery of neuropsychological measures, which covered tests of psychomotor function, attention, learning, and executive function. In the phase 1 analysis, there was no significant pharmacokinetic or dose-related effects on cognitive function.²

A 2024 study published in PNAS: Neuroscience supported M1 muscarinic receptor antagonism as a viable remyelination strategy and provided a rationale for continued clinical development of PIPE-307. Using a combination of in vitro and in vivo models, investigators demonstrated high potency and selectivity for M1 receptors over M2–M5 and showed that M1 blockade alone was sufficient to drive oligodendrocyte differentiation and remyelination. In the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis, PIPE-307 produced meaningful efficacy, with improvements observed across disability measures, histopathology, electron microscopy, and visual evoked potentials.³

REFERENCES
1. Contineum Therapeutics Reports Topline Data From Its Phase 2 PIPE-307 VISTA Trial for the Treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). News release. November 20, 2025. Accessed December 22, 2025. https://ir.contineum-tx.com/news-releases/news-release-details/contineum-therapeutics-reports-topline-data-its-phase-2-pipe-307
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 December 22, 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. PNAS: Neuroscience. 2024;121(32):e2407974121. doi:10.1073/pnas.2407974121