Clinical Trials in Progressive MS: An Assessment of Advances and Remaining Challenges

The past decade has seen “a step change” in the treatment of progressive multiple sclerosis (MS), particularly with the approval of immunomodulatory therapies, but much progress remains before the gains begin to approach those seen in the treatment of relapsing MS. So concludes a new review of clinical trials for progressive MS published in Lancet Neurology (2024;23[3]:277-301) by a small group of international MS experts including Robert Fox, MD, and Daniel Ontaneda, MD, PhD, of Cleveland Clinic’s Mellen Center for Multiple Sclerosis Research and Treatment.

Update of a prior comprehensive review

The review follows an earlier review published by this author team on 25 years of clinical trials in progressive MS up to April 2014 (Lancet Neurol. 2015;14[2]:208-223). That effort, which covered approximately 50 phase 2b and phase 3 studies, reported scant therapeutic success. The new review takes up where the prior paper left off, assessing an additional 22 phase 2b trials and eight phase 3 trials published from April 2014 to the beginning of 2024, which included a total of 8,924 study participants.

The authors offer a critical appraisal of the collective evidence from that 10-year period. They begin by considering the trial evidence for each of three mechanistic approaches: immunomodulation, neuroprotection, and remyelination and repair. Trials are detailed via an abundance of comprehensive tables for comparative assessment. The paper then turns to discussion of several issues central to clinical trials for progressive MS, including target patient population, outcome measures, trial design and ensuring that trials address patient priorities. This article recaps select takeaways from key sections.

Immunomodulators show benefit for active progressive MS

Most of the phase 3 trials reported since 2014 involved immunomodulatory treatments. Two such studies yielded practice-changing results, showing that the anti-CD20 therapy ocrelizumab (ORATORIO trial) and the sphingosine-1-receptor modulator siponimod (EXPAND trial) can slow disability progression by 20% to 25% relative to placebo in primary progressive MS (PPMS) and secondary progressive MS (SPMS), respectively. These effects appear to be driven by suppression of peripherally mediated inflammatory disease activity, as evidenced by reduced gadolinium-enhancing lesions and relapse rates. As a result, some licensing agencies have restricted use of these therapies to patients with recent inflammatory activity.

Other immunomodulatory agents have shown mixed results, reinforcing the pattern that benefits depend on sufficient baseline inflammation. Fingolimod failed to impact confirmed disability progression in a PPMS cohort with lower enhancing lesion rates. Although natalizumab reduced relapse rates and lesion activity in SPMS, effects on a multicomponent disability measure did not reach statistical significance.

Small-molecule immunomodulatory compounds with potential to cross the blood-brain barrier, like Bruton tyrosine kinase (BTK) inhibitors, are now entering late-phase testing. By targeting innate immune cells and B-cell lineages, both in the periphery and possibly within the nervous system, some of them may also address the compartmentalized neuroinflammation driving disease progression.

The authors note that as patients age, focal active inflammation becomes less dominant in MS pathology while neurodegeneration and CNS-specific inflammation loom larger. As a result, some patients might not need to continue their disease-modifying immunomodulatory therapies past a certain age, although guidance around when and how to stop therapy is uncertain.

Neuroprotection: phase 3 evidence still awaited

In contrast to the landscape for immunomodulation, no phase 3 trials of neuroprotection have yielded positive results. Phase 2b trials of several forms of neuroprotective therapy — spanning antioxidants, anti-inflammatories, mitochondrial modulators and more — have failed to impact whole brain atrophy or disability measures. However, the small-molecule compound ibudilast demonstrated slowing of brain atrophy by nearly half compared with placebo in a study among patients with PPMS and SPMS, although confirmation in a phase 3 trial is awaited.

The authors note that because neuroprotective approaches to progressive MS often involve multiple mechanisms and thus may require multiple treatments, clinical trial design presents particular challenges due to regulatory requirements that each component of a combination therapy be shown to contribute to the therapeutic effect.

Remyelination research: making the most of visual markers

The need for therapies that can remyelinate, promote repair and restore function is substantial among patients with cumulative neurologic disability due to MS. No such therapies are approved for commercial use, but potential remyelinating compounds have been identified. Trials of these compounds have found visual measures, such as visual evoked potential (VEP) conduction latency, useful both as inclusion criteria and as outcome measures.

In a phase 2b trial in individuals with relapsing MS and chronic optic neuropathy, the muscarinic receptor antagonist clemastine was linked to improvement in VEP P100 latency. Another phase 2b trial assessed the retinoid receptor agonist bexarotene in patients with relapsing-remitting MS. It found that while bexarotene did not impact the primary outcome of lesion magnetization transfer ratio, secondary MRI endpoints and a prespecified analysis of VEPs hinted at a potential remyelinating effect that merits study in progressive MS.

Considerations for future trials

The authors’ discussion of clinical trial design for progressive MS moving forward includes the following key points:

• A trial’s target patient population should be defined according to the proposed therapeutic mechanism and explicitly factor in the degree of inflammatory activity as well as patients’ MS subtype, race, ethnicity and comorbidities.
• In view of the range of disease processes that may be targeted in progressive MS, biomarkers should align with the underlying biology of the investigated therapy’s mechanism of action. Those pertinent for progressive MS include imaging, visual and biofluid markers. Efforts are continuing to identify intermediate outcomes that yield insights in phase 2 trials more efficiently than disability measures can.
• Among imaging biomarkers, whole brain atrophy has been widely used in trials. Its advantages include a good association with disability progression, although it has modest utility at the individual patient level and occurs relatively late after tissue injury. Regional brain volumes have also been proposed for use as outcome metrics, with cortical atrophy particularly well suited for studies assessing neuroprotective effect.
• Visual biomarkers include both functional measures, such as VEPs, and structural markers, such as optical coherence tomography (OCT). Whereas VEPs show the most promise in remyelination trials, OCT is likely to be most useful as a marker of neuroprotection.
• Among fluid biomarkers, neurofilament light chain (NfL) is a responsive marker for use with immunomodulatory therapies, due to its close association to inflammation, but less so with neuroprotective therapies. New fluid biomarkers of noninflammatory neurodegeneration are sorely needed.
• Nearly all phase 3 trials and many phase 2 trials continue to use standard two-arm, placebo-controlled designs with time to disability progression as the primary endpoint. While these methods are scientifically sound, alternate approaches like multi-arm and multistage trials could accelerate the evaluation of candidate therapies through time and cost efficiencies.
• Greater collaboration across all stakeholder groups is critical for the development of efficient trials focused on what matters most to those living with progressive MS.

“The need for therapies for progressive MS remains great,” says Dr. Fox, senior author of the review. “We have learned how to design, conduct and analyze trials much better, and that will help us test therapies more quickly and efficiently so we can address this urgent need.”