Enrollment Complete for Phase 2 Trial of Novel M1 Receptor Antagonist in Relapsing MS

Stephen Huhn, MD

In recent news, a phase 2 trial (NCT06083753) exploring the therapeutic potential of PIPE-307 (Contineum Therapeutics), an M1 receptor antagonist in development for relapsing-remitting multiple sclerosis (RRMS), has completed enrollment, according to the company. The randomized, double-blind study will include 168 patients who will be randomized to either 2 doses of PIPE-307 or placebo for a 26-week treatment period.¹

In this proof-of-concept trial, patients will primarily be assessed on safety, through treatment-emergent adverse events (TEAEs), 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, and other assessments such as Timed 25-Foot Walk Test, Nine-Hole Peg Test, Symbol Digit Modalities Test.

"We are pleased to reach this significant milestone for the PIPE-307 VISTA trial ahead of schedule," Stephen Huhn, MD, chief medical officer at Contineum Therapeutics, said in a statement. "The trial is designed to show evidence of remyelination as a potentially first-in-class and differentiated therapy for RRMS patients. We believe that PIPE-307 could represent the next evolution in the treatment paradigm for RRMS. We are grateful for the VISTA trial investigators, patients and their families, and we look forward to sharing topline data from this trial."

This study includes English-speaking individuals aged 18 to 50 with RRMS diagnosed per the 2017 Revised McDonald Criteria. Participants must have an Expanded Disability Status Scale (EDSS) score and retinal nerve fiber layer measurements within protocol limits and have been on stable immunomodulatory therapy with no more than one disease-modifying therapy (DMT) for at least 6 months. Notably, reproductive-age participants must use effective contraception through one month after the last study drug dose. For the visual evoked potential (VEP) sub-study, additional criteria include prolonged P100 latency or a latency difference between eyes.²

Exclusion criteria include optic neuritis within 9 months, MS diagnosed over 10 years ago, or eye conditions affecting vision tests. Participants using medications like dalfampridine, corticosteroids within six months, or drugs affecting Cytochrome P450 3A4 are excluded. Other disqualifications include gadolinium-enhancing lesions, prior treatments like bone marrow transplantation, investigational drug use within 30 days, active malignancy, significant heart disorders, or a history of suicidal behavior.

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The study’s pending success could have ramifications for future drug development in MS. M1 receptors, the main target for PIPE-307, hold significance in the central nervous system, modulating neurotransmission, learning, and memory. While muscarinic receptors have been explored in various neurological conditions, their specific role in MS pathology, which involves autoimmune-driven neuroinflammation and demyelination, has not been a primary focus of treatment strategies thus far.

A 2024 paper published in PNAS: Neuroscience provided support for targeting M1 receptors for remyelination and encouraged further development of PIPE-307 for clinical studies. Through a series of in vitro and in vivo studies of the agent, the investigators characterized potency and selectivity for M1 receptors over M2-5R and confirmed the sufficiency of blocking this receptor to promote differentiation and remyelination. According to the study authors, PIPE-307 displayed significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and VEPs.³

REFERENCES
1. Contineum Therapeutics Completes Enrollment in Phase 2 PIPE-307 VISTA Trial for the Treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). News release. Contineum Therapeutics. January 9, 2025. Accessed February 4, 2025. https://www.biospace.com/press-releases/contineum-therapeutics-completes-enrollment-in-phase-2-pipe-307-vista-trial-for-the-treatment-of-relapsing-remitting-multiple-sclerosis-rrms
2. Study to Evaluate the Safety and Efficacy of PIPE-307 in Subjects with Relapsing-Remitting Multiple Sclerosis (VISTA). Clinicaltrials.gov. Updated January 7, 2025. Accessed February 4, 2025. https://clinicaltrials.gov/study/NCT06083753
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