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.

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.

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.

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.

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.