X-linked myotubular myopathy (XLMTM) is a rare and serious condition present at birth where the muscles do not work properly. There are currently no approved therapies for XLMTM.
The protein myotubularin is needed for muscle development, movement and breathing. A gene called MTM1 tells the body to make myotubularin. XLMTM is caused by changes, or mutations, in the MTM1 gene. Changes in the MTM1 gene cause low or no levels of myotubularin to be made, so the muscles do not work properly.
Gene therapy is a way of getting a healthy copy of a gene into the body. This allows the body's cells to make a normal protein that may reduce disease symptoms. Researchers have developed ASP2957 to get a healthy MTM1 gene into the body. This could help improve muscle development and function in young children with XLMTM.
In this study, ASP2957 will be given to humans for the first time.
ASP2957 has the healthy MTM1 gene inside a type of empty (killed) virus. The virus delivers the healthy MTM1 gene directly into cells in the body. It's possible that some boys may have antibodies to the virus if they have previously been infected with a similar virus. The antibodies could stop ASP2957 from working properly and cause an immune reaction to ASP2957. To prevent this, the boys will also be given medicines to lower the immune system.
The main aims of this study are to check the safety of ASP2957, how well it is tolerated, and to find a suitable dose of ASP2957.
The study was designed in 2 phases. In Phase 1, different small groups of boys will receive lower to higher doses of ASP2957. Each boy will receive a single infusion of ASP2957. Any medical problems will be recorded for each dose. This is done to find a suitable dose of ASP2957 to use in Phase 2.
In Phase 2, another small group of young boys will receive a single infusion of ASP2957. The most suitable dose of ASP2957 worked out from Phase 1 will be used.
The boys will be checked for up to 1 year after their single infusion of ASP2957. After this, there will be the option for the boys to join another study so they will continue to be checked longer term.
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.
Required respiratory support at birth
Requires ≥ 20 hours per day of invasive ventilator support (confirmed during screening)
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.
Sequential
ASP2957
GeneticIntravenous infusion
Methylprednisolone
DrugIntravenous infusion
Prednisolone
DrugRoute of administration based on locally sourced product
Sirolimus
DrugRoute of administration based on locally sourced product
Number of participants with treatment emergent adverse events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of study intervention. This includes events related to the comparator, if applicable, and events related to the (study) procedures. A TEAE is defined as an AE observed after administration of ASP2957.
Number of participants with adverse events of special interest (AESIs)
AESIs include myocardial-associated events, muscle abnormalities, hepatobiliary disorders, thrombocytopenia, TMA and life-threatening infections.
Number of participants with laboratory value abnormalities and/or adverse events (AEs)
Number of participants with potentially clinically significant laboratory values.
Number of participants with electrocardiogram (ECG) abnormalities and/or AEs
Number of participants with potentially clinically significant ECGs.
Change from baseline in hours per day of ventilation support at week 52
The hours of ventilation support will be collected.
ASP2957 vector deoxyribonucleic acid (DNA) in serum through week 52
ASP2957 vector DNA will be recorded from serum samples collected.
ASP2957 vector DNA in muscle biopsy at week 52
ASP2957 vector DNA will be recorded from muscle biopsy collected.
ASP2957 vector DNA in saliva
ASP2957 vector DNA will be recorded from saliva samples collected.
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