ASPIRO Gene therapy trial in X-linked myotubular myopathy (XLMTM): Update on preliminary safety and efficacy findings up to 72 weeks post-treatment

Objective: ASPIRO is an ongoing, open-label, randomized study (NCT03199469) evaluating safety/efficacy of AT132, an investigational gene therapy for delivery of functional MTM1 gene copies. Background: XLMTM, a rare monogenic disease caused by mutations in the MTM1 gene, is characterized by profound muscle weakness, respiratory failure, and early death. Design/Methods: XLMTM patients, ≤7 years old, were randomized to treatment or delayed-treatment control and enrolled into ascending dose cohorts to receive a single AT132 infusion. Safety/efficacy data are available for 12 patients with 4–72 weeks’ follow-up: 6, Cohort 1 (1x1014 vg/kg); 4, Cohort 2 (3x1014 vg/kg); 2, untreated controls. Muscle biopsy data are available for 9 treated patients: 6, Cohort 1; 3, Cohort 2. Results: Since study initiation (Sep17) there were 82 AEs considered related/possibly related (14 serious AEs; 68 non-serious). At baseline, all patients required 12–24 hours/day ventilatory support, and missed critical motor milestones. As of 7Aug19, clinically meaningful changes from baseline in CHOP-INTEND and MIP scores were observed in all but one treated patient. Treated patients also achieved important motor milestones: ability to sit unassisted, raise self to stand, and walk supported or independently. There was significant and rapid reduction in ventilator use in all but one treated patient, with 7 treated patients reaching ventilator independence. These improvements contrast with the two untreated ASPIRO controls and the INCEPTUS contemporaneous external control subjects (NCT02704273) in whom gains of motor skills and achievement of ventilator independence were not observed. Muscle biopsies demonstrated robust dose-dependent tissue transduction and myotubularin expression with considerable improvement in histopathology. Conclusions: AT132 has shown a manageable safety profile across dose cohorts. Clinically meaningful improvements in neuromuscular and respiratory function continue through 72 weeks post-dose. An optimal dose (3x1014 vg/kg) has been selected for the study’s confirmatory phase. Updated data will be presented at the 2020 AAN Annual Congress. Disclosure: Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes, Sarepta, Pfizer, Genentech, Avexis, Biogen, Catalyst, Argenyx, Alexion, CSL Behring, Grifols. Dr. Shieh has received research support from Sarepta, Pfizer, Audentes, Avexis, Biogen, PTC, Roche, Sanofi, Reveragen, Acceleron.Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Argenyx, Audentes, AveXis, Biogen, Cytokinetics, PTC, Roche, and Sarepta.. Dr. Kuntz has received research support from Clinical trial research contracts with Audentes, AveXis, Biogen, Pfizer, Roche, and Sarepta.. Dr. Smith has nothing to disclose. Dr. Dowling has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dynacure, RYR1 Foundation, MD Canada, MDA USA, Deep Genomics. Dr. Mueller-Felber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes, Avexis, Biogen, Cytokinetics, PTC, Roche, Sanofi-Aventis. Dr. Bonnemann has nothing to disclose. Dr. Servais has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Inc., Biogen, Biophytis, Cytokinetics, Dynacure, Roche, Santhera, Sarepta Therapeutics. Dr. Servais has received research support from Avexis, Inc., Biogen, Dynacure, and Roche. Dr. Muntoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for AveXis, Biogen, Cytokinetics, Novartis, Pfizer, PTC, Roche, Sarepta, Summit, and Wave. Dr. Muntoni has received research support from Principal Investigator for ongoing Ionis Pharmaceuticals, Inc./Biogen and Roche clinical trials; funding from Muscular Dystrophy UK, SMA Europe, and SMA Trust UK. Dr. Blaschek has nothing to disclose. Dr. Neuhaus has nothing to disclose. Dr. Alfano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Alfano has received research support from Sarepta Therapeutics. Dr. Beggs has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics, Dynacure, Roche Pharmaceuticals, Guidepoint. Dr. Beggs has received research support from NIH, MDA, Joshua Frase Foundation, Lee and Penny Anderson Family Foundation, AFM-Telethon. Dr. Buj-Bello has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Childers has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics, AskBio. Dr. Duong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, Sarepta. Dr. Duong has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, Sarepta. Dr. Graham has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Jain has nothing to disclose. Dr. James has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Lawlor has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics, Solid Biosciences, Dynacure, AGADA Biosciences. Dr. Lawlor has received research support from Audentes Therapeutics, Solid Biosciences. Dr. Lee has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. MacBean has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Mavilio has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Murtagh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Noursalehi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Prasad has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics. Dr. Rico has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes Therapeutics.