Remyelination in Multiple Sclerosis: Progress and Pipeline Updates

Over the years, remyelination in multiple sclerosis (MS) has been an emerging and intriguing topic that several in the field are still trying to crack. While therapeutics for MS have been largely successful in reducing relapses, there are no approved medications that focus specifically on remyelination, a process where the body attempts to regenerate the myelin sheath, a fatty substance that insulates nerve fibers and speeds up nerve impulses.

Despite the lack of remyelinating medications on the market, there have been several notable advances in this research area. These include experimenting with mesenchymal stem cells and oligodendrocyte precursor cells (OPCs), gene therapy approaches such as CRISPR/Cas9 and molecular targets like brain-derived neurotrophic factor. In addition, there are other emerging neuroprotective and repair-promoting agents trying to make their way through the pipeline, as well as numerous preclinical studies evaluating potential targets and biomarkers.

There are still several challenges ahead for the field, including the timing and stage of disease, environmental factors that may impact remyelination, and the lack of validated biomarkers to show efficacy. In efforts to keep up with the latest drug development for small molecule remyelinating agents, NeurologyLive^® pieced together a feature highlighting the various drugs clinicians and patients alike should keep their eyes on in the coming years. In addition, we overview some of the previous therapies that were either unsuccessful or paved the way for future drug development.

Current Pipeline

Clinical

PIPE-307 (Contineum) – Phase 2

PIPE-307, an oral, highly selective antagonist of the M1 muscarinic receptor, is currently being evaluated in a phase 2 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.

The ongoing phase 2 study, a double-blind, randomized trial named VISTA, includes 168 patients with relapsing-remitting MS who are randomized to either 2 dose of PIPE-307 or placebo for a 26-week treatment period. In this proof-of-concept trial, patients will primarily be assessed on 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.

Prior to this study, PIPE-307 was tested in a phase 1 trial of healthy volunteers, with PK data consistent with preclinical modeling and a safety profile that was well tolerated across all dose cohorts. Importantly, analysis of a battery of neuropsychological measures, including tests involving psychomotor, attention, learning, and executive function, were administered in the Phase 1 study and showed no significant PK or dose related effects on cognitive function.¹

PTD802 (Pheno Therapeutics) – Phase 1

Earlier this year, the United Kingdom’s Medicines and Healthcare products Regulatory Agency gave clearance for a phase 1 trial assessing PTD802, a selective G protein-coupled receptor 17 (GPR17) antagonist, as a potentially remyelinating therapy for MS. GPR17 is a receptor expressed in OPCs, playing a pivotal role in regulating their maturation into myelin-producing oligodendrocytes.²

Under normal conditions, GPR17 acts as a “molecular timer,” promoting OPC proliferation while inhibiting premature differentiation; however, in MS, GPR17 expression becomes dysregulated, leading to a blockade in OPC maturation and impaired remyelination. Antagonizing GPR17 has emerged as a promising strategy to overcome this blockade. By inhibiting GPR17, the differentiation of OPCs into mature oligodendrocytes is facilitated, enhancing remyelination.

At the time of the announced phase 1 trial, Fraser Murray, PhD, chief executive officer at Pheno Therapeutics, said in a statement that “We are delighted to have received approval from the MHRA to progress our PTD802 program to a Phase 1 trial, a major milestone, marking our transition to a clinical stage organization. As the first company to carry out dosing of a selective GPR17 antagonist in healthy humans we are leading the way in the race to develop GPR17-targeting remyelination therapeutics.”³

FTX-101 (Find Therapeutics) – Phase 1

FTX-101 is a first-in-class therapeutic peptide that modulates the Plexin A1/Neuropilin 1 transmembrane receptor (NRP1) complex in the brain to promote remyelination. The NRP1 receptor complex plays a crucial role in regulating OPC behavior, particularly in the context of remyelination in MS. This receptor complex mediates the inhibitory effects of semaphorin 3A, a guidance cue that impedes OPC migration and differentiation.⁴

The agent is currently being tested in a phase 1 first-in-human study of healthy volunteers, split into 2 parts. Part 1 is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study comprised of 40 participants receiving FTX-101 or placebo while Part 2 is a randomized, double-blind, placebo-controlled, multiple ascending dose study that will enroll 24 participants receiving FTX-101 or placebo. Following the completion of the phase 1 study, the company plans to investigate the use of FTX-101 in individuals with chronic optic neuropathy, a long-term condition caused by demyelination in the visual tracts of the brain and optic nerve.⁵

Preclinical

CVL-1001 & CVL-2001 (Convelo) – IND enabling

Convelo Therapeutics is currently developing 2 remyelinating agents, CVL-1001 and CVL-2001, that act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP). Research has shown that inhibiting CYP51 or EBP leads to accumulatio of specific sterol intermediates that promote differentiation of OPCs into mature, myelinating oligodendrocytes, as well as enhance intrinsic remyelination capacity, especially in the aging or inflamed central nervous system where repair mechanisms are often impaired.

An investigational new drug application is expected to be submitted later this year, sending these two therapies into their first in-human clinical trials. At the 2024 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, Convelo presented an update on the two agents during a poster session. Using mass spectrometry-based sterol-omics, the study authors characterized the selectivity and potency of each screening hit.

Presented in the talk, results showed that these inhibitors promote the dose-dependent formation of mouse and human oligodendrocyte in vitro at low nano-molar concentrations. Through extensive experimentation, the investigators defined the pharmacodynamic pharmacokinetic relationship and target-inhibition profile that leads to an increase in remyelination in the rodent central nervous system. Lastly, the study established a mechanistic biomarker to access target engagement in the CNS and periphery to guide preclinical and clinical development.⁶

TASIN-1 (Barricade) – Discovery

TASIN-1 is a small molecule developed by Barricade Therapeutics that promotes oligodendrocyte formation by inhibiting specific enzymes in the cholesterol biosynthesis pathway. The agent has not been tested in preclinical MS models, but has advanced to early-stage trials for colorectal cancer. TASINs inhibition of EBP leads to accumulation of certain sterol intermediates in the cholesterol biosynthetic pathway, which then promotes oligodendrocyte formation.

An experiment with OPCs treated with 72 hours with DMSO only (no drug), indicated the lack of oligodendrocyte myelin basic protein. In contrast, the same experiment performed with TASIN-1 showed the presence oligodendrocyte MBP+ via the abundance of immunostaining. Barricade plans to advance the second-generation TASIN molecule for neurology applications, with potential for rapid human proof-of-concept.

Previous Failures and Lingering Agents

Opicinumab (Biogen)

Opicinumab, also known as anti-LINGO-1, was a monoclonal antibody that targeted and inhibited the protein LINGO-1 (leucine-rich repeat and Ig domain-containing Nogo receptor-interacting protein). LINGO-1 is a key inhibitor of nerve regeneration and myelination in the central nervous system. While the biological rationale behind targeting LINGO-1 for remyelination was compelling, the clinical results were ultimately unsuccessful, leading to the drug’s discontinuation in 2020.

The phase 2 program for opicinumab included RENEW (NCT01721161) and SYNGERY (NCT01864148), two double-blind, placebo-controlled trials. Conducted between 2012 and 2014, RENEW showed that remyelination did not differ significantly between the opicinumab and placebo groups in the intent-to-treat population after 24 weeks. Despite this, results in the prespecified per-protocol population suggested that enhancing remyelination in the human central nervous system with opicinumab may be possible, ultimately prompting further evaluation in the SYNERGY study.⁷

SYNERGY, a study of 419 adults with relapsing-remitting MS and secondary progressive MS, tested opicinumab in combination with Biogen’s interferon beta-1a. In June 2016, Biogen announced that opicinumab was not superior to placebo at improving patients’ functional capacity and/or at slowing disease progression, ensuing SYNERGY had failed both its main and secondary efficacy goals. The official discontinuation of opicinumab came years later, when data from another follow-up study, the phase 2 AFFINITY trial, failed to meet both its main and secondary goals.^8,9

Clemastine fumarate

Clemastine fumarate is an over-the-counter first-generation antihistamine primarily used to treat allergic symptoms such as rhinitis and urticaria. It works by blocking the effects of histamine, a substance released by the body during allergic reactions. The medication showed some potential in the phase 2 ReBUILD study (NCT02040298); however, it has not advanced since then. Clemastine fumarate was also tested in the TRAP-MS trial (NCT03109288), although investigators discontinued the treatment arm after observing increased disability accumulation in patients with non-lesional MS.

ReBUILD was a single-center, 150-day, double-blind, placebo-controlled trial of patients with relapsing MS with chronic demyelinating optic neuropathy who were on stable immunomodulatory therapy. Patients received either clemastine fumarate for 90 days followed by placebo for 60 days (group 1; n = 25), or placebo for 90 days followed by clemastine fumarate for 60 days (group 2; n = 25). Overall, the primary end point was met, with the therapy showing reduced P100 latency delay by 1.7 ms/eye (95% CI, 0.5-2.9; P = .0048).¹⁰

Pepinemab (Vaccinex)

Pepinemab, formerly VX15, is a monoclonal antibody designed to target and inhibit semaphoring 4D (SEMA4D), a signaling molecule involved in immune cell regulation and nervous system development. SEMA4D plays a critical role in axon guidance and neuronal growth, and it is also implicated in inhibiting remyelination. For its clinical path, the drug showed an ability to slow the progression of disability in primary progressive MS, but the results were not robust enough to move forward to large-scale trials. Ultimately, Vaccinex decided to stop development for MS, pivoting to other neurodegenerative disorders like Alzheimer disease and Huntington disease.

The most notable MS trial for pepinemab was the phase 1 SIGNAL-MS study, published in 2017. Overall, 50 adults with relapsing MS were included, with 40 receiving doses ranging from 1 to 20 mg/kg and 10 receiving a placebo. Overall, pepinemab was well-tolerated across all dose groups, with no maximum tolerated dose identified. Importantly, the trial did not include efficacy end points, so no data on the drug’s potential to promote remyelination or affect disease progression were collected.¹¹

Ibudilast (MediciNova)

Ibudilast is a small-molecule neuroimmune modulator that exerts its effects through multiple mechanisms, including phosphodiesterase inhibition, macrophage migration inhibitory factor inhibition, and toll-like receptor 4 inhibition. MediciNova, the company developing ibudilast, has strategically focused on progressive MS due to the limited treatment options available for this patient population. In addition, the drug is also being studied in other conditions, such as amyotrophic lateral sclerosis, Long COVID, alcohol use disorder, and degenerative cervical myelopathy.

The promise behind ibudilast in progressive MS stemmed from previously published data of the phase 2 SPRINT-MS trial (NCT01982942). This double-blind, placebo-controlled trial comprised 255 patients with primary or secondary progressive MS who received either ibudilast 100 mg daily or placebo for 96 weeks. On the primary end point of whole brain atrophy change, measured by brain parenchymal function, ibudilast-treated patients showed a 48% reduction relative to placebo. Additional MRI measures, such as gray matter atrophy and cortical thickness, also showed improvement with ibudilast.¹²

In a subsequent analysis of SPRINT-MS, results suggested ibudilast may have a more pronounced effect in patients with primary progressive MS compared with those with secondary progressive MS. The SPRINT-MS Follow-On study, conducted by those at Cleveland Clinic, is an ongoing study testing the long-term clinical outcomes of the participants, assessing disability progression and correlating these with the imaging biomarkers collected during the original trial.

REFERENCES
1. 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 May 27, 2025. https://www.contineum-tx.com/pipeline-therapeutics-reports-positive-phase-1-clinical-results-for-pipe-307-a-neuroregenerative-therapeutic-for-the-treatment-of-multiple-sclerosis/
2. Dziedzic A, Miller E, Saluk-Bijak J, Bijak M, The GPR17 Receptor-A Promising Goal for Therapy and a Potential Marker of the Neurodegenerative Process in Multiple Sclerosis. Int J Mol Sci. 2020;21(5):1852. doi:10.3390/ijms21051852
3. Pheno Therapeutics Granted Clinical Trial Authorisation for Lead Multiple Sclerosis Therapeutic Candidate PTD802. News release. Pheno Therapeutics. January 14, 2025. Accessed May 27, 2025. https://www.businesswire.com/news/home/20250114556677/en/Pheno-Therapeutics-Granted-Clinical-Trial-Authorisation-for-Lead-Multiple-Sclerosis-Therapeutic-Candidate-PTD802
4. Blame F, Pham-Van L, Splenle C, et al. Disruption of Sema3A/Plexin‐A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination. EMBO Molecular Medicine. Published online September 2019. doi:10.15252/emmm.201910378
5. First Subject Dosed in Phase 1 Clinical Study of FTX-101. Find Therapeutics. October 20, 2024. Accessed May 27, 2025. https://www.findtherapeutics.com/ftx-101-phase-1-clinical-trial-launched/
6. Factor D, Savage J, Gottipatti M, et al. Identification of CVL-1001 and CVL-2001 as Selective Brain Penetrant Therapeutics for Enhanced Remyelination. Presented at: 2024 ACTRIMS Forum. LB1
7. Cadavid D, Balcer L, Galetta S, et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(3):189-199. doi:10.1016/S1474-4422(16)30377-5
8. Biogen Reports Top-Line Results from Phase 2 Study of Opicinumab (Anti-LINGO-1) in Multiple Sclerosis. News release. Biogen. June 7, 2016. Accessed May 27, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-reports-top-line-results-phase-2-study-opicinumab-anti
9. BIOGEN REPORTS Q3 2020 RESULTS. News release. Biogen. October 21, 2020. Accessed May 27, 2025. https://investors.biogen.com/static-files/9d0b52a8-22b5-4742-af9d-8138469ac89f
10. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489. doi:10.1016/S0140-6736(17)32346-2
11. LaGanke C, Samkoff L, Edwards K, et al. Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial. Neural Neuroimmnol Neuroinflamm. 2017;4(4):e367. doi:10.1212/NXI.0000000000000367
12. Fox RJ, Coffey CS, Conway R, et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018;379(9):846-855. doi:10.1056/NEJMoa1803583