Gene Transfer Clinical Study in X-Linked Myotubular Myopathy (ASPIRO)

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

This 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.

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.

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.

Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)

Time to reduction in required ventilator support to ≤ 16 hours a day (only in subjects who require invasive ventilation) at Week 24

Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) at Week 24

Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at Week 24

Change from baseline in quality of life Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) at Week 24

The ACEND questionnaire will be completed by the caregiver for subjects in the study. Scoring from 1 (needs full time assistance) to 6 (needs no assistance).

PedsQL Inventory Scale comprises of 15 items in 4 domains: physical functioning, emotional functioning, social functioning and school functioning. A Likert scale from 0 (Never/Not at all) to 4 (Almost always/A lot) will be used to record response. Higher scores indicate better quality of life. Scale is based on the participant's age and will be assessed by participant or caregiver.

Percentage of age-appropriate clinically relevant gross motor function milestones attained through Week 24

Percentage of subjects achieving full ventilator independence in the absence of acute illness and perioperatively at Week 24

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.

Kinderklinik und Kinderpoliklinik im Dr. Von Haunerschen Kinderspital Klinikum der Universitat Munchen

Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."