Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015–2020

Abstract

In the recent past, a plethora of drugs have been approved for the treatment of multiple sclerosis (MS). These therapeutics are mainly confined to immunomodulatory or immunosuppressive strategies but do not sufficiently address remyelination and neuroprotection. However, several neuroregenerative agents have shown potential in pre-clinical research and entered Phase I to III clinical trials. Although none of these compounds have yet proceeded to approval, understanding the causes of failure can broaden our knowledge about neuroprotection and neuroregeneration in MS. Moreover, most of the investigated approaches are characterised by consistent mechanisms of action and proved convincing efficacy in animal studies. Therefore, learning from their failure will help us to enforce the translation of findings acquired in pre-clinical studies into clinical application. Here, we summarise trials on MS treatment published since 2015 that have either failed or were interrupted due to a lack of efficacy, adverse events, or for other reasons. We further outline the rationale underlying these drugs and analyse the background of failure to gather new insights into MS pathophysiology and optimise future study designs. For conciseness, this review focuses on agents promoting remyelination and medications with primarily neuroprotective properties or unconventional approaches. Failed clinical trials that pursue immunomodulation are presented in a separate article.

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

“…Offering affected patients perhaps the most impressive series of therapeutic milestones over the past 28 years, MS research is a very encouraging example of bench-to-bedside success, at least for relapsing–remitting multiple sclerosis (RRMS). The progressive forms of MS—secondary progressive MS (SPMS) and primary progressive MS (PPMS)—have demonstrated a less encouraging response to novel treatments in clinical trials [ 7 , 8 ]. Of note, PPMS may be considered “active” if relapses occur, which would have been referred to as progressive-relapsing MS (PRMS) prior to the publication of the 2013 International Advisory Committee on Clinical Trials of MS guidelines [ 9 ].…”

Stem Cell Therapies for Progressive Multiple Sclerosis

“…Most likely, successful therapeutic agents will have to interact with multiple processes, modifying chronic inflammation while enhancing the intrinsic repair of the damaged CNS. While more rigorous clinical trial design with appropriate endpoints and longer follow-up times may aid in the successful identification of safe and efficacious PMS DMTs (Huntemann et al, 2021), the innate multifunctionality of stem cell therapies offer a promising alternative route toward addressing the unmet needs of neuroprotection and neuroregeneration.…”

Crosstalk of Microorganisms and Immune Responses in Autoimmune Neuroinflammation: A Focus on Regulatory T Cells

“…As already pointed out, HERV and HERVrelated proteins such as ENV exert an unfavorable effect on OPCs and myeloid cells and thus on remyelination and neurodegeneration (307)(308)(309). In view of the persistent lack of remyelinating therapies (338), it is particularly interesting that this inhibition can be reversed by the anti-HERV-W IgG4 monoclonal antibody GNbAC1 (temelimab) (309). Besides promotion of remyelination, GNbAC1 impedes the release of pro-inflammatory cytokines (339).…”