EVOLVING THERAPIES, BIOMARKERS, AND REGULATORY PATHWAYS IN AMYOTROPHIC LATERAL SCLEROSIS

Abstract

Amyotrophic lateral sclerosis [ALS] remains a devastating neurodegenerative disease with historically limited therapeutic options, yet recent advances signal a paradigm shift toward precision medicine and multimodal intervention. In this multi-dimensional synthesis, we systematically review the evolving treatment landscape across five discrete domains: multi-stakeholder preference divergence, biomarker trajectories in gene-targeted therapy, formulation innovations of approved drugs, cross-national regulatory pathways, and Bayesian network meta-analysis frameworks for combination regimens. Our methodological framework integrates structured document analysis of FDA, EMA, and PMDA regulatory histories, systematic extraction of serial neurofilament light chain measurements from real-world cohorts, comparative pharmacokinetic modeling of riluzole formulations, and a living systematic review design for future comparative effectiveness research. The evidence synthesis reveals substantial conceptual progress but significant empirical gaps. For instance, multi-stakeholder analysis demonstrates moderate but consistent divergence: clinicians and regulators prioritize survival and tracheostomy delay, whereas patients emphasize quality of life and care burden. In SOD1-ALS patients treated with tofersen, we observe a median serum neurofilament light decline from 78.0 to 36.0 pg/ml—a reduction exceeding 50%—accompanied by an ALSFRS-R progression rate of only 0.11 points per month; nevertheless, the pivotal phase 3 trial missed its primary functional endpoint. Furthermore, riluzole oral film and suspension formulations are bioequivalent to the 50 mg tablet under fasting conditions, offering alternative delivery for dysphagic patients, albeit with higher oral hypoesthesia incidence [38% vs. 10%]. Regulatory analysis uncovers a 23-month lag between U.S. and Japanese approvals for tofersen, underscoring persistent access inequities. Critically, no randomized trial has tested dual or triple combination regimens against monotherapy, leaving a void in evidence that our living network meta-analysis framework is designed to fill. This synthesis therefore not only confirms a transition from a riluzole-edaravone paradigm to a precision framework anchored by tofersen, but also identifies actionable priorities for future clinical trial design, biomarker validation, and global regulatory harmonization.