2026 American Academy of Neurology Abstract Website

Diego Cadavid¹, Robert Scannevin¹, Ines Hoffmann¹, Anil Tarachandani¹, Irene Choi¹, Ashwin Swami¹, Joanna Haas¹, Martin Schmidt¹, Brian Shook¹, Madelyn Rubenstein¹, Shane Raines², Philip Van Damme³, Pentti Tienari⁴, Eino Solje⁵, Manu Jokela⁶, Angela Genge⁷, Colleen O'Connell⁸, Ruben van Eijk⁹, Leonard Van den Berg¹⁰
¹Verge Genomics, ²2b Analytics, ³University Hospital Leuven, ⁴Helsinki University Hospital, ⁵University of Eastern Finland, Brain Research Unit, ⁶Turku University Hospital, ⁷The Neuro – Montreal Neurological Institute Hospital, ⁸Stan Cassidy Centre for Rehabilitation, ⁹Utrecht University Medical Center, ¹⁰University Medical Centre Utrecht

Objective:

Topline results of the safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) responses, and efficacy for treatment of amyotrophic lateral sclerosis (ALS) of VRG50635, a prodrug of the small molecule brain penetrant PIKfyve inhibitor VRG50468.

Background:

VRG50635, an oral prodrug of the brain-penetrant PIKfyve inhibitor VRG50468, was evaluated in a prospective single-arm, open-label, within-subject multiple ascending dose, proof of concept study in ALS.

Design/Methods:

Fifty-four participants (sporadic n=36; genetic n=17) completed an 8-week pretreatment run-in followed by three 8-week dosing periods at 400, 600, and 800 mg once daily, with escalation based on individual tolerability; participants then remained on the highest tolerated dose for up to 40 additional weeks.

Results:

Fifty study participants initiated treatment; approximately one-third discontinued before reaching 600 mg, and two-thirds escalated to 600 or 800 mg. Early discontinuation correlated with older age, more severe ALS, and higher baseline pNfL and GFAP; PK and PD responses were similar. VRG50635 was rapidly and nearly completely converted to VRG50468, producing time- and dose-dependent PD effects in plasma and peripheral blood mononuclear cells; in 11 participants undergoing lumbar puncture at week 32, CSF VRG50468 exceeded the PIKfyve IC₉₀. Treatment induced a rapid, sustained increase in pNfL (p<0.001) with higher plasma GFAP (p<0.001). ALSFRS-R declined gradually with comparable worsening during pretreatment run-in and treatment periods, without exposure-dependent improvement or worsening. The most common related adverse events were fatigue, decreased appetite, nausea, weakness, headache, and dizziness; eight participants had treatment-related serious adverse events. One third discontinued treatment early on.

Conclusions:

In this Phase 1b study, VRG50635 showed good oral bioavailability to the active metabolite, clear central and peripheral exposure and pharmacology, and a rapid and sustained pNfL and GFAP increase without evidence of sustained clinical change from the pretreatment period. The results are consistent with VRG50468-induced increase in secretory exocytosis of axonal pNfL and astrocytic GFAP.