Phase 1/2 VALOR Study to Assess ASP2957 Gene Therapy in Infants With X-Linked Myotubular Myopathy

A first-in-human clinical trial is underway to evaluate ASP2957 (MyoAAV3.8-MHCK7-hMTM1), an investigational adeno-associated virus (AAV)–based gene therapy designed to restore MTM1 expression in infants with X-linked myotubular myopathy (XLMTM), a rare congenital neuromuscular disorder associated with severe muscle weakness and respiratory failure. Otherwise known as the phase 1/2 VALOR trial, this study will assess the safety and preliminary efficacy of a single intravenous administration of the gene therapy in young children with advanced XLMTM who require substantial ventilatory support.¹

VALOR Trial Design

The VALOR study is a first-in-human phase 1/2 trial designed to build on prior clinical and preclinical experience with gene replacement strategies for XLMTM, including findings from the ASPIRO trial, which investigated another MTM1-targeted gene therapy candidate. The VALOR trial will enroll up to 9 male children aged 3 years or younger who require invasive ventilatory support for at least 20 hours per day, reflecting the severe end of the disease spectrum.

Led by Shannon Barrett, MS, CGC, regional medical director at Astellas Gene Therapies in Sanford, North Carolina, the study includes two sequential phases. The initial dose-escalation phase will evaluate two dose levels—1.0 × 10¹² vector genomes (vg)/kg and 2.0 × 10¹² vg/kg—with 2 to 3 participants treated at each dose level. Following safety evaluation, a dose-expansion phase will enroll an additional 3 to 4 participants at the selected dose.

Sentinel dosing and an 8-week sequential dosing interval between participants are incorporated into the design to allow for monitoring potential safety signals. Participants will also receive a prophylactic immunosuppression regimen intended to mitigate innate and adaptive immune responses to the AAV vector.¹

Safety and Efficacy Assessments

The primary endpoint of the VALOR study is safety and tolerability following gene therapy administration. Investigators will evaluate treatment-emergent adverse events and conduct detailed assessments of liver function, cardiac parameters, muscle biomarkers, and hematologic measures. Of note, the trial excludes participants with a history of hepatic dysfunction, including cholestatic liver disease.

Secondary and exploratory endpoints will assess potential clinical effects of ASP2957 across several domains relevant to disease progression. These include changes in ventilatory support requirements, neuromuscular function and developmental milestones, and clinician- and caregiver-reported outcomes. Investigators will also evaluate vector biodistribution, shedding, and immunogenicity to better understand the biological behavior of the gene therapy.

Limitations and Future Directions

Because the VALOR study is an early-phase clinical trial with a small planned sample size, the results will primarily inform safety and feasibility rather than definitive clinical efficacy. The inclusion of sentinel dosing and a sequential enrollment approach reflects the cautious development pathway typical for first-in-human gene therapy studies.

Additional research, including larger controlled studies and long-term follow-up, will likely be necessary to determine whether ASP2957 can produce sustained clinical benefits and improve survival or quality of life for patients with XLMTM. Furthermore, participants will be followed for 52 weeks after treatment to evaluate safety and efficacy outcomes.¹

Clinical Context

XLMTM is a rare congenital myopathy that primarily affects male infants because of its X-linked inheritance pattern. The disease leads to severe muscle weakness and respiratory insufficiency early in life, often requiring prolonged ventilatory support and intensive medical care.¹

Management currently focuses on supportive measures, including respiratory assistance, nutritional support, and physical therapy. Because the disease results from loss of functional MTM1 protein, gene replacement therapy has been considered a promising strategy for addressing the underlying genetic defect.

Early clinical research in this area has included the ASPIRO trial, which evaluated an AAV-mediated MTM1 gene therapy and reported improvements in respiratory function and motor milestones in some treated patients. However, safety concerns—including treatment-related hepatotoxicity observed in some participants—have highlighted the need for careful dose selection and monitoring in subsequent gene therapy programs.²

REFERENCES
1. Barrett S, Ganguli A, Gentyala R, et al. VALOR study design: a phase 1/2 study assessing the safety and preliminary efficacy of ASP2957 gene therapy for X-linked myotubular myopathy (XLMTM). Presented at 2026 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference; March 8-11, 2026; Orlando, Florida
2. Shieh P, Kuntz N, Dowling J, et al. Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial. Lancet Neurol. 2023; 22(12): 1125 – 1139. doi: 10.1016/S1474-4422(23)00313-7