Progressive MS Alliance Seeks Change to Study Designs to Spur New Therapies

Advocates for patients with progressive multiple sclerosis (MS) want changes in study designs on emerging therapies to speed development and better align with the needs of researchers and patients.

The International Progressive MS Alliance recently released a proposal suggesting ways to alter and improve the clinical testing process to streamline treatment development for progressive multiple sclerosis (MS).

The group is a collaboration between patients with MS, clinicians, academics, physicians, industry leaders, and regulators across several countries. The Alliance said that it is creating a funding program that will focus on revamping experimental medicine trials. The proposal, published in Nature Reviews Neurology, featured a call to action to stakeholders and the research community to provide feedback to help shape the program and future plans.

Relapsing-remitting MS has several effective therapies available to patients that mostly target inflammatory responses. However, because progressive MS has multiple pathophysiological mechanisms interacting and causing myelin damage and neurodegeneration, treatment options are limited and clinical trials for new therapies often fail or get cancelled.

In order to expedite the clinical process, the Alliance pushed for the advancement of experimental medicine trials (ExMTs), defined as phase 2a trials that examine treatments while also providing information on disease mechanisms, even if they produce a negative outcome, through the use of a coherent pool of biological and clinical measures. ExMTs are conducted in tandem with drug screenings.

In progressive MS, ExMTs using high-throughput screenings have detected molecules that could be used in remyelination and neuroprotection. “Thanks to such advances, a substantial number of molecules for which robust preclinical data exist have been identified and deserve to be tested in neurodegenerative diseases, including progressive MS,” wrote the authors.

Additionally, to better target multiple pathophysiological mechanisms of progressive MS, the authors said that researchers should focus more on studying polytherapies over novel monotherapies. However, trials assessing polytherapies can bring about heterogeneity because different combinations of drugs may be tested in different trials.

Including peripheral blood transcriptomics in studies was another suggestion because they may provide information on surrogate markers that can demonstrate the efficacy of drugs targeted at the central nervous system. The authors also said that they strongly recommend biobanking samples to use for future analyses.

The proposal featured new trial design styles that could lead to shorter trials and limit the potential for false negative results that are often associated with short study durations or inadequate sensitivity outcome measures.

Further, trials should not be restrictive in the criteria needed for participation, such as patients who have MS that is progressing slower than others due to onset at a younger age.

“All people with progressive MS should have the opportunity to see their condition explored therapeutically and the mechanism of action of an experimental drug or specific hypotheses about disease pathophysiology should not dictate that only people with a specific disease duration or within a specific age range are included,” the authors argued.

The authors emphasized the importance of including people with MS into discussions on trial designs to ensure that trials are conducted with the patients’ interests in mind.

“The immediate availability of informed patient perspectives during critical discussions has steered us away from flawed decisions, for example, from overly restrictive inclusion criteria that might limit learning opportunities or the use of performance tests that are unnecessarily onerous and exhaust patients,” wrote the authors.

The potential for many testing proposals to be for drugs already indicated for other conditions and the possibility that most first in-human trials will continue to be conducted using traditional trial designs were identified as 2 factors limiting the Alliance’s ability to fully exploring the initiative. Reliance on a previously known drug can make getting patent registrations more difficult and traditional trial designs continuing to be used may cause difficulties in leveraging the information presented during the early stages of the clinical process.


Dangond F, Donnelly A, Hohlfeld R, et al. Facing the urgency of therapies for progressive MS — A Progressive MS Alliance proposal. Nat Rev Neurol. January 22, 2021. doi: 10.1038/s41582-020-00446-9