Charting a global research strategy for progressive MS—An international progressive MS Alliance proposal

Abstract

Background: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term ‘active’ secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. Objective: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. Methods: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms “progressive multiple sclerosis”, “primary progressive multiple sclerosis”, “secondary progressive MS”. Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. Results: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. Conclusion: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

Molecular mechanisms associated with multiple sclerosis progression, severity and phenotype

“…The most surprising result of current study is the dominance of neuroinflammation-related pathways among biological processes that correlate with both MS progression and MS severity. As current MS drugs inhibit inflammation and formation of inflammatory CELs, their decreasing efficacy in later stages of MS, characterized by PIRA, led to broad belief that progressive MS (PMS) is less inflammatory than relapsing-remitting MS (RRMS) and that neurodegenerative mechanisms drive disability accumulation in PMS (29). In contrast, our results show that intrathecal activation of (some) neuroinflammation-related pathways increases with MS progression.…”

“…2) The same workflow was applied to comparison between BD and CombiWISE, by regressing out disability measured by CombiWISE and calculating BD residuals. 29 To identify differences in biology representing MS progression vs severity, the canonical pathways z-scores and -log 10 p-values were summed up across the four MS progression and four MS severity outcomes. Differentially activated pathways were identified as those with absolute sum of z-scores greater than 4, sum of -log 10 p-value greater than 1.33 and the difference between sum of z-scores for severity and sum of z-scores for progression greater than 2.…”

Researching COVID-19 in progressive MS requires a globally coordinated, multi-disciplinary and multi-stakeholder approach—perspectives from the International Progressive MS Alliance

“…[6][7][8][9][10] So far, several risk factors for more severe outcomes from SARS-CoV-2 infection have been identified, 4 including older age, higher disability, cardiovascular comorbidities, obesity and possibly male gender. Since 2012 the Alliance has been investing in a global research strategy 11 to expedite the development of disease-modifying and symptom-management therapies for people living with progressive MS. It will be critical for short term decision making that PwMS and their care providers understand the interactions between SARS-CoV-2 infection, vaccination and Disease Modifying Therapies (DMTs) on disease progression, as well as being vital for Industry's continued efforts to discover and develop therapies for PwPMS.Within this framework, the Alliance Industry Forum, 12 in its advisory role to the Alliance's Scientific Steering Committee, organized a meeting (April 2021) to discuss with major Alliance stakeholders and experts what we have learned about SARS-CoV-2 infection, the Covid-19 pandemic and progressive MS.…”

Editorial: Advances in Multiple Sclerosis

“…While clinicians now have a large armamentarium of disease modifying treatments available for use in relapsing MS, the situation is different in progressive MS. There are multiple reasons for this [20]. The pathobiology remains incompletely understood.…”