Remyelination therapies are achievable in clinical practice—Yes

The advent of high-efficacy disease-modifying therapies (DMTs) has transformed multiple sclerosis (MS), dramatically reducing relapses and lesion formation and improving quality of life for many patients. Yet, important challenges remain. Many people with multiple sclerosis (pwMS) continue to live with disability, driven by incomplete recovery from inflammatory injury and insidious functional decline across all phases of disease. Both forms of disability remain inadequately addressed by current therapies. In fact, none are able to promote recovery from either new or remote demyelinating injury.

Chronic demyelination contributes to disability by impairing efficient signal transduction and leaving axons metabolically vulnerable to injury and neurodegeneration. ¹ Thus, therapies that promote remyelination are among the most promising approaches for neuroprotection in pwMS.

We strongly believe that remyelination is possible. However, for remyelination to be impactful, we must ask: (1) Is remyelination neuroprotective? (2) Is it feasible and measurable in pwMS? and (3) Is it clinically meaningful? We argue the answer to all three is likely yes—provided we identify the right patients, biology, and outcomes.

Is remyelination neuroprotective?

Animal models strongly suggest that remyelination is neuron- and axon-protective. In multiple inflammatory and genetic models of demyelination, impaired remyelination leads to more pronounced axonal injury and functional decline, ² while accelerating remyelination significantly improves both measures.^3,4

Human data from pwMS corroborate this relationship. In MS autopsy tissue, acutely or chronically demyelinated lesions exhibit high degrees of axonal injury, while “shadow plaques” (remyelinated or incompletely demyelinated lesions) contain levels of axonal injury comparable to control white matter. ⁵

Meanwhile, in vivo, serum neurofilament light chain (NfL) can be used to measure axonal damage. In two independent trials of remyelinating candidates, clemastine and bexarotene, treatment was associated with reduced serum NfL levels, suggesting that therapeutic remyelination provides measurable neuroprotection.^6,7 In addition, following optic neuritis, visual evoked potential (VEP) latency—a measure of myelin integrity within the visual pathway ⁸ —was inversely associated with the extent of retinal nerve fiber layer degeneration.^9,10

Is promoting remyelination feasible and measurable in pwMS?

Endogenous remyelination likely occurs in pwMS, albeit variably and incompletely. Potential reasons for remyelination failure include impaired oligodendrocyte precursor cell (OPC) recruitment, differentiation, and survival. Drug development has mainly targeted OPC differentiation, though other mechanisms may hold promise.

The phase II ReBUILD trial established proof of concept that remyelination is achievable. In this randomized, placebo-controlled, cross-over trial of 50 pwMS with chronic demyelinating optic neuropathy, clemastine fumarate (M1 muscarinic receptor antagonist) significantly improved VEP latency versus placebo by 1.7 msec/eye. ¹¹ Delayed-treatment analyses showed improved low contrast letter acuity, and exploratory analyses demonstrated increased myelin water fraction (a quantitative magnetic resonance imaging [MRI] measure of myelin) in the corpus callosum. ¹² The CCMR-Two trial, which studied the combination of clemastine fumarate and metformin, was also recently reported to have met its primary endpoint of improved VEP latency in MS patients with demyelinating optic neuropathy. ¹³ The peer-reviewed results are highly anticipated. Together, the positive treatment effects seen across sites and complementary outcomes bolster the conclusion that remyelination was achieved.

While other early remyelination programs did not meet their primary endpoints, several showed promising signals on secondary and exploratory measures. For example, treatment with the RXRγ agonist bexarotene increased the magnetization transfer ratio in gray matter lesions and decreased VEP latency in chronically demyelinated eyes. ¹⁴ Poor drug tolerability, rather than efficacy concerns, was ultimately what stalled further development. Other programs, such as opicinumab (LINGO-1 antibody)^15,16 and GSK239512 (H3 receptor inverse agonist), ¹⁷ did not meet their primary endpoints, but similarly showed trends for treatment effects across electrophysiologic and MRI outcomes. Trial failure may be related to drug mechanism or trial design decisions, which in smaller phase II trials, can significantly impact the ability to detect treatment effects. For example, cross-over studies risk carryover because remyelination may be durable; delayed-start designs reduce effective exposure but enable within-group comparisons; and small parallel-arm trials are variance-limited and often underpowered. The optimal design depends on study size, outcome choice, population variance, and anticipated effect size. If unaccounted for, these limitations can lead to premature discontinuation of programs with genuine therapeutic potential.

Collectively, these data indicate that remyelination can be enhanced pharmacologically in pwMS, and early-stage trials must be designed strategically to optimize success.

Is remyelination clinically meaningful?

We do not yet have sufficient phase III trial data to definitively answer this question, and for the aforementioned reasons, small phase II trials of short duration should not be used to judge clinical benefit. In our view, the issue is not whether remyelination can matter for patients, but under what conditions its biological effects translate into meaningful outcomes.

We believe the major bottleneck here is also trial design. Several considerations are crucial. First is population selection. Benefit should be greatest when a substantial portion of viable axons remain or when demyelination is the dominant constraint on function. It is unlikely that remyelination will be beneficial when neurodegeneration is prominent. Thus, we should develop methods to refine patient selection to enhance the potential response. In addition, the duration of treatment and observation must be extended to see functional improvement. Myelin repair and downstream neuroaxonal damage evolve over months. It is unrealistic to expect large changes in global disability measures over short windows, especially in pwMS on background immunotherapy. Finally, we need pathway-specific endpoints that are both sensitive and specific for remyelination. More reliable biomarkers can help with optimal patient selection and serve as surrogate endpoints in shorter trials. This will hopefully increase the number of successful therapeutics proceeding to pivotal phase III studies.

Critics may point to past trial failures and current design contstraints as evidence that remyelination is unattainable in clinical practice. Yet, the trajectory of anti-amyloid therapies in Alzheimer’s disease offers a useful precedent and counterpoint. After years of negative and inconclusive trials, two monoclonal antibodies have now been Food and Drug Administration (FDA)-approved. As a neurodegenerative disease that evolves over decades, drug development was met with similar challenges that we now face in MS. Success only followed refinements in trial population (early symptomatic disease guided by biomarker confirmation), treatment duration, and both clinical and surrogate endpoints.

Translating these lessons to remyelination in MS, early programs should enrich for the ideal “window of opportunity” (demyelination with preserved axons) and utilize biomarkers that demonstrate target engagement. Realistic clinical endpoints must also be employed, demonstrating pathway-specific performance first and global disability second.

Additional failures should not dissuade the field. They should be taken as an opportunity to iterate toward a better solution. With this approach, the field will be poised to bring the first robust repair agents to individuals living with MS.