Title
Gene Transfer Clinical Study in X-Linked Myotubular Myopathy
ASPIRO: A Phase 1/2/3, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Efficacy of AT132, an AAV8-Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients
Phase
Phase 1/Phase 2Lead Sponsor
Audentes TherapeuticsStudy Type
InterventionalStatus
Active, not recruitingIndication/Condition
X-Linked Myotubular MyopathyIntervention/Treatment
AT132Study Participants
26This is a multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and efficacy of AT132 in subjects with X-Linked Myotubular Myopathy aged less than 5 years old. Subjects will receive a single dose of AT132 and will be followed for safety and efficacy for 10 years
This study will evaluate safety and efficacy of gene transfer in X-Linked Myotubular Myopathy. Subjects will receive a single dose of AT132 delivered intravenously.
ASPIRO is being conducted in two parts. Part 1 is a dose escalation phase that is evaluating the preliminary safety and efficacy of AT132 at doses of 1x10^14 vg/kg and 3x10^14 vg/kg. Part 2 of ASPIRO is a pivotal expansion cohort designed to confirm the safety and efficacy of AT132 at a dose of 3x10^14 vg/kg. The pivotal expansion cohort will enroll eight subjects, consisting of four age-matched pairs (within +/- 6 months of age). One subject from each pair will be randomized to receive a single dose of AT132 at 3x10^14 vg/kg, and the other will serve as a delayed treatment control. Eligible delayed treatment control subjects will be administered AT132 after that individual subject has completed the Week 24 visit as a delayed treatment control.
The primary efficacy endpoint measures will be assessed at Week 24. Subjects will be followed for a total of 10 years after administration of AT132.
This study utilizes an independent Data Monitoring Committee (DMC) that monitors subject safety and provides recommendations to Astellas regarding dose escalation, dose expansion, and safety matters.
1.0 x 10^14 vg/kg of AT132 defined with the use of 1st generation vg titer assay delivered intravenously one time. 1.3 x10^14 vg/kg of AT132 defined with the use of 2nd generation vg titer assay delivered intravenously one time.
3.0 x 10^14 vg/kg of AT132 defined with the use of 1st generation vg titer assay delivered intravenously one time. 3.5 x 10^14 vg/kg of AT132 defined with the use of 2nd generation vg titer assay delivered intravenously one time
Delayed-Treatment Control subjects will generally have the same assessments as treated subjects. After the follow up period, eligible delayed-treatment control subjects will be dosed with AT132 and initiate the same post-dose procedures as subjects who received AT132.
Inclusion Criteria: Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 gene as assessed by a Sponsor-approved testing facility. Subject is male. Subject is aged less than 5 years old at dosing Subject requires mechanical ventilatory support: Part 1: Subject requires some mechanical ventilatory support (e.g., ranging from 24 hours per day full time mechanical ventilation, to noninvasive support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) during sleeping hours). Part 2: Subject requires invasive mechanical ventilatory support ranging from 20 - 24 hours per day at screening (confirmed by daytime polysomnographic study). Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a cuffed tracheostomy tube for some respiratory assessments. Subject has ventilator maximum positive end-expiratory pressure (PEEP) <8 cm H2O at screening. UNIQUE to France: Subject's weight is ≥ 4.8 kg. Exclusion Criteria: Subject is participating in an interventional study designed to treat XLMTM. Subject born <35 weeks gestation who is still not term as per corrected age. Subject tests positive for AAV8 neutralizing antibody with titers above protocol specified threshold. Subject had recent surgery (<3 months before Day 1) or has planned surgery that may confound data collection during the first 48 weeks of the study. Subject has a clinically important condition other than XLMTM in the opinion of the investigator. Subject has a clinically significant underlying liver disease. Subject is currently experiencing a clinically important respiratory infection or other active infection. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1. Other than as required per protocol, subject has received immune-modulating agents within 3 months before Day 1 (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed); use of other concomitant medications to manage chronic conditions must have been stable for at least 4 weeks before dosing. Subject has a contraindication to prednisolone. Subject has a contraindication to study drug or ingredients. Subject has previous scoliosis repair surgery/procedure, or planned/expected scoliosis repair surgery/procedure in the 12 months following Day 1 (Part 2 including any subjects enrolled under protocol v8 and beyond). Subject has contractures, scoliosis, or other medical condition that would limit the potential to achieve unassisted sitting, in the opinion of the investigator (Part 2 including any subjects enrolled under protocol V8 and beyond). Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the investigator (Part 2 including any subjects enrolled under protocol V8 and beyond). Subject has a clinically important condition, including CTCAE v4.03 Grade ≥ 2 anemia (< 10 g/dL hemoglobin). Subject has a contraindication to ursodiol (ursodeoxycholic acid). UNIQUE to France: Subject has a prior diagnosis or history of cardiac arrhythmias, myocarditis, or any other cardiac disease. UNIQUE to France: Subject has a contraindication to general anesthesia and to muscle biopsy procedures.
