A Phase 2/3 Adaptive Design Study of GHF-201 as the First Potential Treatment of Adult Polyglucosan Body Disease
Michio Hirano1, Miguel Weil2, Or Kakhlon3, Anat Mordechai4, Nissim Garti5, Yossi Gilgun-Sherki6, Alexander Lossos3
1Columbia University Medical Center, 2Tel-Aviv University, 3Hadassah Hospital, 4Department of Neurology, Hadassah Hospital, 5Lyotropic Delivery Systems Ltd, 6Golden Heart Flower
Objective:

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

Background:

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 benefits in 3 APBD patients participating in a compassionate use program with ~12 patient-years of follow-up. GHF-201 also showed no safety issues in a phase I study in healthy volunteers.

Design/Methods:

Study GHF-201-02-APBD will be a phase 2/3 adaptive design study. The first stage will be a randomized, placebo-controlled, double-blind trial evaluating the efficacy and safety of two doses of GHF-201 compared to placebo in APBD patients over ~24 weeks (Cohort 1). The second stage is informed by a comparative interim analysis (IA) supporting a confirmatory assessment of the optimal dose of GHF-201 and treatment duration determined during the IA (Cohort 2). Various clinician/ observer-based (ClinRo; ObsRO), performance-based (PerfO), patient-reported (PRO) endpoints, as well as MRI, biomarkers (PB burden, neurofilament light chain) and natural history will provide a totality-of-evidence review.

Results:

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.

Conclusions:

This innovative, adaptive trial design is intended to maximize efficiency by leveraging advanced statistical methodologies and incorporating biomarker and real-world data to detect clinically meaningful benefits in APBD. Findings may support accelerated approval of GHF-201 as the first targeted therapy for APBD.

10.1212/WNL.0000000000215858
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