Advances in oral immunomodulating therapies in relapsing multiple sclerosis

Area of Science:

• Neurology
• Immunology
• Pharmacology

Background:

• The last decade has seen a significant increase in oral disease-modifying therapies for relapsing multiple sclerosis (MS).
• Four oral compounds—fingolimod, dimethyl fumarate, teriflunomide, and cladribine—are currently approved.
• These therapies, while orally administered, possess distinct mechanisms of action, allowing for personalized treatment strategies based on patient comorbidities and offering varied approaches like immune cell trafficking inhibition or depletion.

Purpose of the Study:

• To review recent developments in oral disease-modifying therapies for relapsing multiple sclerosis.
• To discuss the implications of novel mechanisms of action and the challenges in selecting and sequencing treatments.
• To highlight the need for monitoring long-term effects of sequential therapies in real-world settings.

Main Methods:

• Review of recent clinical trial data and drug approvals for oral MS therapies.
• Analysis of novel mechanisms of action, including sphingosine-1-phosphate receptor modulation, matrix metalloproteinase inhibition, and tyrosine kinase inhibition.
• Discussion of treatment selection, sequencing, and safety considerations in clinical practice.

Main Results:

• New sphingosine-1-phosphate receptor modulators (siponimod, ozanimod) show promise with specific S1PR targets and improved safety profiles.
• Novel agents like minocycline and evobrutinib target matrix metalloproteinases and tyrosine kinases, respectively, with early positive results.
• Diroximel fumarate aims to improve gastrointestinal tolerability compared to dimethyl fumarate; laquinimod trials did not meet primary endpoints.

Conclusions:

• The expanding landscape of oral MS therapies necessitates careful consideration of individual patient needs, balancing efficacy and risk.
• The long-lasting effects of some oral treatments, like cladribine, raise questions about cumulative effects in sequential monotherapy regimens.
• Post-marketing surveillance through phase 4 studies, cohort studies, and registries is essential to understand the real-world outcomes and safety of sequential treatment strategies.