International collaborators led by Professor Jeremy Chataway (University College London) have published an overview of recently completed and ongoing clinical trials involving people with progressive forms of multiple sclerosis. The paper reviews recent progress, remaining issues to be resolved, and potential pathways forward to improve trials and speed more effective treatments to people with progressive MS for whom there are few treatment options.
Details: Authors Prof. Jeremy Chataway PhD, FRCP, Thomas Williams PhD, Vivien Li FRACP, Prof. Ruth Ann Marrie MD, Prof. Daniel Ontaneda MD and Prof. Robert J. Fox MD discuss changes in the landscape since they published a previous review on the same topic in 2015 and some emerging concepts with relevance to the treatment of people in progressive phases of MS. These include:
- If progressive MS is found to be “active,” with signs of inflammation such as new MRI activity or relapses, it may be responsive to currently available disease-modifying therapies.
- Disease worsening can occur in the absence of recent relapses (called Progression Independent of Relapse Activity, or PIRA) and this recognition helps to focus questions around how to treat it.
- Biologic mechanisms driving progressive MS may include inflammation compartmentalized within the brain and spinal cord, abnormal metabolic processes and stress, and inadequate compensatory responses such as remyelination, and each of these processes may need a different treatment approach.
- A new framework for describing phases of MS is needed, based on the underlying biology rather than just clinical manifestations of MS.
The paper contains tables that outline details of recently completed (Table 1) and ongoing (Table 2) clinical trials in progressive MS.
- Many completed and ongoing trials test approaches that alter immune processes to interrupt MS activity and progression.
- Some trials focus on “neuroprotective” strategies that attempt to defend against further nervous system injury.
- Other trials test therapies to stimulate cells that can restore the myelin coating on nerve fibers with the aim of restoring nerve signals and functions.
There are 12 ongoing phase 3 trials listed in Table 2 that are expected to be completed over the next several years. Phase 3 results are what is needed to apply for approval from drug regulatory agencies. Just a few examples include:
- The Phase 3 “MS-STAT2” trial of simvastatin in secondary progressive MS is testing whether this cholesterol-lowering therapy can slow progression. It is expected to be completed in 2024.
- Three Bruton tyrosine kinase inhibitor (BTKi) trials in primary/secondary progressive MS.
- The Phase 2/3, multi-arm multi-stage “OCTOPUS” trial in primary and secondary progressive MS is testing several therapies including metformin (a diabetes drug) and alpha lipoic acid (an antioxidant) can slow the rate of brain atrophy and progression. It is expected to be completed in 2028.
- BEAT-MS to look at Autologous stem cell transplantation (estimated 2029).
At phase 2 level several promising emerging approaches are highlighted, such as vidofludimus (an enzyme inhibitor), hydroxychloroquine (reduces the activation of human microglia), and N-acetyl cysteine (precursor to the antioxidant glutathione).
Remaining Issues: The authors discuss the need for changes that will speed the testing of experimental therapies and make trials more informative about how a therapy will work in the real world. These include:
Trial Design
- The input of people with MS should be sought during the design of trials to ensure the study is feasible and is relevant to people’s needs. Polling trial participants about how a therapy makes them feel (Patient Reported Outcome Measures) is a relevant tool and work is underway to standardize it use.
- Testing multiple therapies at one time, such as in the new OCTOPUS trial, is an innovation that could speed progress.
- Finding ways to track progression and restoration more quickly would accelerate the ability to do early testing on more potential therapies. Better tools being investigated include imaging, fluid biomarkers and tech devices that can serve as indirect indicators of treatment response.
Trial Participants
- Including a more diverse population among those recruited to participate in clinical trials would better reflect the races, ethnicities and ages of people affected by MS and who may one day consider taking the therapy if it is approved.
- Trials could be more inclusive of participants with MS plus another disorder (called a comorbidity), but comorbidities need to be accounted for as they could change how people respond to the treatment.
Efforts are already underway to find solutions for these and other issues that stand in the way of improving therapy options for people with progressive MS.
Moving Forward: The authors paint an optimistic picture of better treatments for progressive MS on the horizon. “Further success is expected as novel immunomodulatory mechanisms – particularly those targeting elements within the central nervous system – complete trials over the next 2 years.”
They particularly reference progress that has been made in the MS research landscape, including advances in global collaboration such as the
International Progressive MS Alliance and several international teams working together on clinical and imaging protocols.
As understanding of MS and its underlying mechanism deepens, it points to potential new targets for therapies that can stop disease activity, protect against further nervous system injury, and stimulate repair to restore lost functions.
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Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges,” by Prof Jeremy Chataway, PhD, FRCP; Thomas Williams, PhD; Vivien Li, FRACP; Prof Ruth Ann Marrie, MD; Prof Daniel Ontaneda, MD; and, Prof Robert J. Fox, MD, was published in the March 2024 issue of
Lancet Neurology.