Assess the safety, tolerability and efficacy of GHF-201 in patients with Adult Polyglucosan Body Disease (APBD) in a pivotal phase 2/3 study.

APBD is an ultra-rare, adult-onset autosomal recessive leukodystrophy with no approved treatment. The disease is caused by glycogen branching enzyme (GBE1) deficiency leading to polyglucosan body (PB) accumulation and progressive neurodegeneration. GHF-201 is a novel small molecule demonstrated to enhance autophagic flux and improve survival and motor parameters in several mouse models of glycogen and lysosomal storage diseases (GSDs/LSDs), including APBD. Additionally, GHF-201 was associated with clinically meaningful benefit in 3 APBD patients participating in a compassionate use program with >10 patient-years of follow-up. GHF-201 also showed no safety issues in phase I study in healthy volunteers.

Study GHF-201-02-APBD will be a phase 2/3 double-tiered adaptive design study. The first tier will be a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of two doses of GHF-201 compared to placebo in APBD subjects over 24 weeks (Cohort 1). The second tier will be an interim analysis (IA) supporting a confirmatory open-label assessment to evaluate efficacy and safety of the optimal dose of GHF-201 for a treatment duration determined during the IA (Cohort 2). Various clinical endpoints, patient-reported outcomes, MRI, biomarkers (PB burden, neurofilament light chain) as well as natural history and registry data will be integrated into a totality-of-evidence analysis.

The safety, clinical efficacy, and biomarker results from the ongoing compassionate use program support the examination of GHF-201 in this pivotal study. An updated study design will be presented at the meeting.

This innovative, adaptive trial design maximizes statistical efficiency and incorporates real-world and biomarker data to detect clinically meaningful benefits in APBD. Findings may support regulatory approval of GHF-201 as the first targeted therapy for APBD.