ASP2957 gene therapy for ventilator-dependent boys with X-linked myotubular myopathy

A Phase 1/2, Multicenter, Open-label, Dose Escalation and Expansion Clinical Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of ASP2957 in Male Participants With Invasive Ventilator-dependent X-linked Myotubular Myopathy

This trial will try a one-time AAV gene therapy, ASP2957, in infants and young boys with XLMTM who need a ventilator to breathe most of the day.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 9 (estimated)
• Ages: N/A to 36 Months
• Sex: Male
• Sponsor: Astellas Pharma Inc (Industry-sponsored)
• Locations: 4 sites (Chicago, Illinois and 3 other locations)
• Trial ID: NCT07052929 on ClinicalTrials.gov

What this trial studies

This Phase 1/2, first-in-human, open-label trial tests ASP2957, an adeno-associated virus (AAV) vector delivering a healthy MTM1 gene, in male participants with genetically confirmed XLMTM. Eligible participants are ≤36 months old, ventilator-dependent (≥20 hours/day) with a tracheostomy, and must have acceptable liver imaging; standard steroid and immunosuppressive medications (methylprednisolone, prednisolone, sirolimus) are included in the protocol to manage immune response. The study is being conducted at three U.S. pediatric centers and will follow treated children for safety and signs of improved muscle and respiratory function. Because this is the first time ASP2957 is given to people, safety monitoring is intensive and outcomes will guide further development.

Who should consider this trial

Good fit: Boys 36 months of age or younger with a pathogenic or likely pathogenic MTM1 variant who are ventilator-dependent (≥20 hours/day) and have a tracheostomy and normal liver ultrasound are ideal candidates.

Not a fit: Patients without a confirmed MTM1 pathogenic variant, females/carriers, those older than 36 months, or those with significant liver abnormalities are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the therapy could improve muscle strength and breathing and reduce dependence on ventilators in young children with XLMTM.

How similar studies have performed: AAV-based MTM1 gene replacement produced strong benefits in animal models and has shown early promise in human programs, but prior human efforts also raised serious safety concerns, so the approach is partly tested but not yet proven safe and effective.

Eligibility criteria

Inclusion Criteria:

* Participant is projected to be ≤ 36 months of age at dosing.
* Participant has molecular genetic report from a CAP-approved testing facility at screening that confirms a diagnosis of XLMTM and harbors a "pathogenic" or "likely pathogenic" variant in the MTM1 gene as classified using the American College of Medical Genetics (ACMG) standards and guidelines for interpretation of sequence variants. Although samples will be sent to the sponsor central laboratory during screening for exploratory testing, results of this testing are not required for enrollment.
* Participant is ventilator-dependent and meets the following criteria:

  * Required respiratory support at birth
  * Requires ≥ 20 hours per day of invasive ventilator support (confirmed during screening)
  * Has a tracheostomy tube
* Participant has no evidence of hepatic peliosis, increased echogenicity or any other clinically important abnormal finding on liver ultrasound.
* Participant can receive immunosuppression per protocol.
* Participant's hepatobiliary laboratory measurements must meet the criteria during screening and for the 2-month retrospective assessment of participant's medical history from the time of signing the ICF:
* Participant's hematological laboratory measurements must meet the criteria during screening:
* Participant's parent(s) or legally authorized representative LAR(s) must provide documentation of being current with recommended immunization schedule according to regional guidelines.

  * If any immunization has not been administered, the medical reasons must be documented by the investigator along with medical risk associated with ASP2957 and immunosuppression administration. The sponsor will review the risk assessment with the investigator and determine the participant's eligibility for the study.
  * Immunizations requiring administration after inclusion in the study must be administered in accordance with regional guidelines for live, live attenuated and inactivated immunization prior to, during and after stopping immunosuppression with methylprednisolone, prednisolone and sirolimus. For an example of guidelines, see Centers for Disease Control and Prevention (CDC) General Best Practices Guidelines for Immunization.
  * Immunization of household contacts can be considered based on regional standards of care of individuals receiving immunosuppression regimens.
* Participant and participant's parent(s) or LAR(s) are willing and able to comply with study visits and study procedures.
* Participant's parent(s) or LAR(s) agree that the participant will not participate in another interventional study from the time of signing the Informed Consent Form (ICF) through week 52.
* Participant's parent(s) or LAR(s) is willing to transition the participant to a separate long-term follow-up study after study completion.

Exclusion Criteria:

* Participant born \< 35 weeks gestation is still not term as per corrected age.
* Participant is nutritionally unstable with weight less than fifth percentile for age or has a vitamin A, E or K deficiency.
* Participant requires supplemental oxygen on a routine or chronic basis.

  * Note: The use of supplemental oxygen for acute, self-limited illnesses (for example, during hospitalization for pneumonia) shall not be exclusionary, provided the participant is neither acutely ill nor using supplemental oxygen at the time of screening.
* Participant currently has a clinically important respiratory infection or other clinically important active infection of any kind.
* Participant has an active viral or bacterial infection including, but not limited to, positive testing for the following:

  * tuberculosis (TB) using the QuantiFERON-TB test
  * Active hepatitis A virus (HAV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
  * Prior HBV or HCV virus infection due to the risk of reactivation associated with immunosuppression
  * human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2)
  * coronavirus disease 2019 (COVID-19)
  * cytomegalovirus (CMV), viral loads ≥ 500 IU/mL or attributable symptoms or evidence of end-organ disease due to CMV.
* Participant has any history of cholestatic liver dysfunction and/or treatment for cholestasis. If the participant is taking prophylactic treatment for cholestasis (e.g., ursodiol, cholestyramine, rifampin or other therapies) which has not been prescribed for cholestatic liver dysfunction, treatment must be discontinued for at least 4 weeks prior to signing the ICF.

  * Neonatal hyperbilirubinemia resolving within 4 weeks of birth in a full-term infant is not an exclusion.
* Participant has prior history of abnormal transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) and/or abnormal bilirubin metabolism associated with ascites, jaundice (aside from neonatal hyperbilirubinemia) or gastrointestinal bleeding.
* Participant has a significant medical condition or life-threatening disease other than XLMTM that would interfere with adhering to protocol requirements or would increase the risk of immunosuppression and/or recombinant adeno-associated virus (rAAV) administration.
* Participant has musculoskeletal complications such as severe contractures and/or scoliosis that would limit the ability to observe improvements in neuromuscular function.

  * In participants with scoliosis, the Cobb angle must be \< 40 degrees for study eligibility.
* Other than as required per protocol, participant has received or plans to receive systemic immunomodulating agents within 90 days before day 1 (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed).
* Participant has previously received monoclonal antibodies of any type.

  * Exception: Monoclonal antibodies to prevent RSV are permitted, except for during the 4 weeks prior to the initiation of immunosuppression.
* Participant plans to have surgery within 12 weeks prior to day 1 through week 52 that may confound safety and efficacy data interpretation of the study intervention.

  * Exception: Standard of care surgical interventions such as gastrostomy, jejunostomy and Nissen fundoplication procedures are allowed.
* Participant received any treatment for cholestasis (e.g., ursodiol, cholestyramine, rifampin or other therapies) prior to signing the ICF.
* Participant is participating in another interventional study or has received an adeno-associated virus (AAV)-based gene therapy.
* Participant tests positive for anti-MyoAAV3.8 TAb, as determined by central laboratory testing.

  * Since very young children may have passive antibodies transferred in utero from the mother, participants ≤ 6 months of age who initially test positive for anti-MyoAAV3.8 total antibody (TAb) may be rescreened for study eligibility.
* Participant has a known or suspected contraindication or hypersensitivity to methylprednisolone, prednisolone, sirolimus or any components of the ASP2957 formulation.
* Participant has a contraindication to general anesthesia, magnetic resonance imaging (MRI) or muscle biopsy procedures.
* Any other reason that would render the participant unsuitable for participation in the study, including risk of non-adherence to the study assessments and protocol.

Where this trial is running

Chicago, Illinois and 3 other locations

• Lurie Children's Hospital — Chicago, Illinois, United States (Recruiting)
• Boston Children's Hospital — Boston, Massachusetts, United States (Recruiting)
• Oregon Health & Science University — Portland, Oregon, United States (Recruiting)
• The Hospital for Sick Children — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Study coordinator: Astellas Gene Therapies

Conditions X-Linked Myotubular Myopathy; XLMTM; Recombinant Adeno-Associated Virus