VALOR study design: a phase 1/2 study assessing the safety and preliminary efficacy of ASP2957 gene therapy for X-linked myotubular myopathy (XLMTM)

Topic:

Clinical Trials

Poster Number: 117 S

Author(s):

Shannon Barrett, MS, CGC, Astellas Gene Therapies, Amitava Ganguli, MD, Astellas Pharma Global Development, Inc., Rahul R. Gentyala, MD, Astellas Pharma Global Development, Inc., Robert J. Graham, MD, Boston Children’s Hospital, Harvard Medical School, Oscar Mayer, MD, The Children's Hospital of Philadelphia, Ana Chaparro, MD, Astellas Pharma Global Development, Inc. (at the time the work was performed), Richard Shell, MD, Nationwide Children’s Hospital, Patricia Li, Astellas Gene Therapies, Julie Coats, DPT, Astellas Gene Therapies (at the time the work was performed), Francesco Muntoni, MD, Dubowitz Neuromuscular Centre, UCL and Great Ormond Street Hospital Trust, London, UK, Kristine Skjolaas, PhD, Astellas Gene Therapies, Michael Lawlor, MD PhD, Diverge, Nancy Kuntz, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, Anil Dhawan, MD, King's College Hospital, Jim Dowling, MD, PhD, University of Pennsylvania, Lucy James, Astellas Gene Therapies, Ha Tran, MD, Astellas Gene Therapies

XLMTM is a rare congenital disease caused by mutations in the MTM1 gene and characterized by severe muscle weakness and impaired pulmonary function. No disease-modifying therapies have been approved; however, results from the ASPIRO study suggest potential benefits from gene therapy. ASP2957 (MyoAAV3.8-MHCK7-hMTM1) is an investigational, nonreplicating recombinant adeno-associated virus with a muscle-tropic engineered capsid that contains a DNA sequence of the human MTM1 gene under the control of an MHCK7 muscle-specific promoter. VALOR, a first-in-human phase 1/2 study, will assess the safety and preliminary efficacy of a single intravenous administration of ASP2957. Study design was informed by experience from ASPIRO and preclinical studies. The study comprises 2 parts: dose escalation (phase 1: dose levels 1.0 x 10^12 and 2.0 x 10^12 vg/kg) and dose expansion (phase 2: dose to be selected based phase 1 results). Sentinel dosing and a sequential dosing interval of 8 weeks will be implemented. Participants will receive a robust prophylactic immunosuppression regimen to mitigate innate and adaptive immune responses after ASP2957 administration. Up to 9 male children with XLMTM aged ≤3 years who require invasive ventilatory support for ≥20 hours/day will be recruited (phase 1: 2–3 patients per dose; phase 2: 3–4 patients at the selected dose). Exclusion criteria include any history of hepatic dysfunction, including cholestatic liver disease. The primary endpoint will be safety and tolerability based on treatment-emergent adverse events and liver, cardiac, muscle, and hematologic assessments. Secondary/exploratory endpoints will include assessing the effects of ASP2957 on ventilation support, neuromuscular function and development, clinician- and caregiver-reported outcomes, and biodistribution, vector shedding, and immunogenicity of ASP2957. Participants will be followed for 52 weeks post-treatment, with the subsequent option to join a separate long-term follow-up study. The VALOR study design was previously presented at the 30th Annual World Muscle Society 2025 congress.