Efficacy, Biodistribution, and Safety of an AAV Gene Therapy in XLMTM Disease Model Mice and Juvenile Non-Human Primates

Topic:

Pre-Clinical Research

Poster Number: 410 O

Author(s):

Takeshi Soto, DVM, PhD, Astellas Pharma, Inc., San Francisco, CA, USA, Marie Stark, PhD, Astellas Pharma, Inc., San Francisco, CA, USA, Nakyo Heo, PharmD, Astellas Pharma, Inc., San Francisco, CA, USA, Tyler Holt, Astellas Pharma, Inc., San Francisco, CA, USA, Aamani Boyanapalli, PhD, Astellas Pharma, Inc., San Francisco, CA, USA, Hikaru Mitori, Astellas Pharma, Inc., San Francisco, CA, USA, Upasana Niyogi, PhD, Astellas Pharma, Inc., San Francisco, CA, USA, Eric Lau, Astellas Pharma, Inc., San Francisco, CA, USA, Fria Bolan, Astellas Pharma, Inc., San Francisco, CA, USA, Mario Guerrero, Astellas Pharma, Inc., San Francisco, CA, USA, Mo Baikoghli, Astellas Pharma, Inc., San Francisco, CA, USA, Samuel Sutton, Astellas Pharma, Inc., San Francisco, CA, USA, Tianbi Zhang, PhD, Astellas Pharma, Inc., San Francisco, CA, USA, Asish Nand, Astellas Pharma, Inc., San Francisco, CA, USA, Bala Medicherla, PhD, Astellas Pharma, Inc., San Francisco, CA, USA, Carlos Fonck, PhD, Astellas Pharmaceuticals

X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by mutations in MTM1, leading to severe skeletal muscle weakness, hypotonia, feeding and respiratory difficulties, and often early death. ASP2957 is an investigational gene therapy comprising a muscle-tropic MyoAAV3.8 capsid that contains the human MTM1 gene, a muscle-specific MHCK7 promoter, and a synthetic intron. ASP2957 received FDA investigational new drug clearance in 2025.

Efficacy, biodistribution, and safety of ASP2957 were evaluated in Mtm1 knockout mice and juvenile non-human primates (NHPs) following a single intravenous dose. Mice received 0, 1.0E11, 3.0E11, 2.0E12, 6.0E12, or 1.3E13 vg/kg, and NHPs received 0, 1.75E12, 6.84E12, or 2.24E13 vg/kg. Mice were observed for up to 10 weeks, and NHPs for up to 26 weeks. In mice, vehicle or ASP2957 doses ≤3E11 vg/kg resulted in XLMTM-like symptoms followed by death or early euthanasia. Survival improved in a dose-dependent manner in mice administered ≥2E12 vg/kg. Mice receiving these doses showed significant improvements in body weight gain and motor performance (rotarod). Histopathology revealed myofiber abnormalities in untreated knockout mice, with severity diminishing in a dose-dependent manner. Doseresponse modeling of rotarod performance yielded an ED₅₀ of 2.06E12 vg/kg. Minimal mononuclear cell infiltration was observed in knockout mouse cardiac and skeletal muscle, suggesting a non-adverse mild immune response. A high-sensitivity antibody assay was developed and tested to pre-screen NHPs. In juvenile NHPs, dose-dependent increases in muscle vector copy number and myotubularin were observed. Low or no myotubularin expression was detected in liver and spleen, supporting muscle-specific transgene expression. No findings suggesting ASP2957 toxicity were observed at any dose in NHPs, including functional and histological evaluations of the liver and DRG.

These data show that ASP2957 has a favorable safety profile, while producing potent, muscle-specific effects, supporting the dose window for a first-in-human trial in patients with XLMTM.