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 5 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 1x1014 vg/kg and 3x1014 vg/kg. Part 2 of ASPIRO is a pivotal expansion cohort designed to confirm the safety and efficacy of AT132 at a dose of 3x1014 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 3x1014 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 5 years after administration of AT132. This study utilizes an independent Data Monitoring Committee (DMC) that will monitors subject safety and provides recommendations to Audentes regarding dose escalation, dose expansion, and safety matters.
- Treatment-emergent adverse events (safety and tolerability) [ Time Frame: Baseline through Week 24 ]
- Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)
- Change from baseline in hours of ventilation support over time through Week 24 [ Time Frame: Baseline to Week 24 ]
- Change in hours of ventilation
- Percentage of subjects achieving functionally independent sitting for at least 30 seconds by Week 24 as assessed by an independent blinded Physical Therapy Adjudication Panel [ Time Frame: Baseline to Week 24 ] Achieve functionally independent sitting for at least 30 seconds
- Time to reduction in required ventilator support to ≤ 16 hours a day (only in subjects who require invasive ventilation) by Week 24 as assessed by independent blinded Pulmonary Adjudication Panel [ Time Frame: Baseline to Week 24 ] Reduction in required ventilator support
- Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) by Week 24 [ Time Frame: Baseline to Week 24 ] Change in CHOP-INTEND
- Change from baseline in maximal inspiratory pressure (PImax) by Week 24 [ Time Frame: Baseline to Week 24 ] Change in respiratory endurance
- Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at Week 24 [ Time Frame: Baseline to Week 24 ] Change in myotubularin expression
Ages Eligible for Study: Up to 5 Years (Child)
Sexes Eligible for Study: Male
Accepts Healthy Volunteers: No
- 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 Day 1 and/or participated in the ATX-MTM-009 (INCEPTUS) study.
- 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.
- 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 contractures, scoliosis, or other medical condition that would limit the potential to achieve unassisted sitting, in the opinion of the investigator (Part 2 only).
- Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the investigator (Part 2 only).
United States, California - UCLA Medical Center - Los Angeles, California, United States, 90095
United States, Florida - Powell Center for Rare Disease Research, Univ. of Florida - Gainesville, Florida, United States, 32610
United States, Illinois - Ann & Robert H Lurie Children's Hospital of Chicago - Chicago, Illinois, United States, 60611
United States, Maryland - National Institute of Neurological Disorders and Stroke/NIH Porter - Bethesda, Maryland, United States, 208892
Canada, Ontario - Hospital for Sick Children - Toronto, Ontario, Canada, M5G0A4
France - Hopital Armad Trousseau - Paris, France, 75012
Germany - Kinderklinik und Kinderpoliklinik im Dr. Von Haunerschen Kinderspital Klinikum der Universitat Munchen - München, Germany, 80337
Salvador Rico, MD, PhD