Emerging targeted therapies in LOPD

By Agata Buczak

Three studies presented at WORLDSymposium 2026 (We’re Organizing Research on Lysosomal Diseases) highlight emerging approaches designed to target the underlying biology of late-onset Pompe disease (LOPD) with greater precision.

Updated data from FORTIS, a phase 1/2 study evaluating the gene replacement therapy AT845 in adults with LOPD, was reported by David Viskochil (University of Utah, Salt Lake City, USA). Eleven participants received a single intravenous dose and long-term follow-up. Muscle biopsies showed AT845 transduction, with increases in GAA protein and enzyme activity within 3 months. At the time of analysis, nine of 11 participants had discontinued enzyme replacement therapy (ERT) between 10 and 48 weeks after dosing, with one participant later restarting.

Most treatment-emergent adverse events (TRAEs) were mild or moderate; asymptomatic liver enzyme elevations were the most common and were managed with corticosteroids. Viskochil described functional measures, including forced vital capacity and 6-minute walk distance, as “variable but stable following dosing and ERT withdrawal.”

Samuel Hopkins (Asklepios BioPharmaceutical, Durham, North Carolina, USA) presented preclinical and early clinical findings for AB‑1009, a next‑generation adeno-associated virus (AAV) gene therapy incorporating an engineered capsid and GAA transgene. In preclinical studies, AB‑1009 produced sustained serum GAA activity with cross‑correction of glycogen in cardiac and skeletal muscle. In non‑human primate studies, only mild, transient alanine aminotransferase elevations were observed, resolving without intervention.

Early clinical data from three adults enrolled in an investigator‑initiated trial showed no dose‑limiting toxicities or serious adverse events through 52 weeks. Secretion of GAA and reductions in the biomarker hexatetrasaccharide (Hex4) were observed throughout follow‑up without capsid‑specific T‑cell reactivity. Hopkins concluded: “We believe that ongoing clinical studies support further clinical evaluation of AB‑1009 in adults.”

The third presentation introduced a different therapeutic modality – substrate reduction therapy. Ozlem Goker‑Alpan (Lysosomal & Rare Disorders Research & Treatment Center, Fairfax, Virginia, USA) presented data from the ongoing phase 1b study of ABX1100, a CD71‑targeted centyrin linked to glycogen synthase 1 (GYS1) as a substrate reduction therapy (SRT). The investigational therapy is designed to reduce glycogen synthesis.

In three adults enrolled, ABX1100 was described as well tolerated, with only mild or moderate TRAEs and no serious events. Muscle biopsies taken at weeks 6 and 10 showed sustained 60% GYS1 mRNA knockdown at both time points. Average creatine kinase levels decreased by 25% and Hex4 levels by 18% at week 10. Goker‑Alpan noted: “Collectively, these data provide a strong foundation for advancing ABX1100 into further development.”

All three presenters highlighted ongoing follow-up and further planned analyses, including extended observation in FORTIS, continued clinical investigation of AB-1009, and expansion of the ABX1100 study cohort.

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