Genge, Angela

Background: Losmapimod is an orally administered small molecule and selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor able to reduce aberrant expression of DUX4 in vitro and thereby potentially slowing disease progression in patients with facioscapulohumeral muscular dystrophy (FSHD). Objective: This global, randomized, placebo-controlled, double-blind phase 3 study in patients with FSHD1 and FSHD2 examined the efficacy and safety of losmapimod over a 48-week treatment period compared to placebo (NCT05397470, EUDRACT 2022-000389-16). Methods: The primary endpoint was change in quantification of reachable workspace (RWS) expressed as relative surface area (RSA). Other endpoints included measures of muscle composition (fat content and lean muscle) using magnetic resonance imaging (MRI), muscle strength using quantitative dynamometry, and quality of life measures. Results: 130 participants received losmapimod and 130 participants received placebo, with 252 participants completing the 48-week treatment period. There were no statistically significant differences between groups in change in RSA and all secondary efficacy endpoints from baseline to Week 48. Losmapimod treatment was well-tolerated, and most adverse events were mild. Conclusions: Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies.

AbstractObjectiveDual leucine zipper kinase (DLK), which regulates the c‐Jun N‐terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first‐in‐human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC‐0134, a small‐molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC‐0134‐treated ALS patients and DLK conditional knockout (cKO) mice.MethodsThe study included placebo‐controlled, single and multiple ascending‐dose (SAD; MAD) stages, and an open‐label safety expansion (OLE) with adaptive dosing for up to 48 weeks.ResultsForty‐nine patients were enrolled. GDC‐0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug‐related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC‐0134 exposure was dose‐proportional (median half‐life = 84 h). Patients showed GDC‐0134 exposure‐dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild‐type littermates.InterpretationThis trial characterized GDC‐0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC‐0134‐treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on‐target drug effects. The safety profile of GDC‐0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.

Abstract Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.