Abstract Details

Title ASPIRO Gene Therapy Trial In X-Linked Myotubular Myopathy (XLMTM): Update on Preliminary Safety And Efficacy Findings up to 72 Weeks Post-Treatment

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S6 - Neuromuscular and Clinical Neurophysiology (EMG): Genetic Muscle Disorders (1:00 PM-1:12 PM)

Poster/Presentation
Number 001

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.

Authors/Disclosures
Perry Shieh, MD, PhD, FAAN (UCLA) PRESENTER	Dr. Shieh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sarepta. Dr. Shieh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Shieh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Shieh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Shieh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Shieh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Shieh has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for CSL Behring. Dr. Shieh has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Grifols. Dr. Shieh has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Shieh has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Biogen. Dr. Shieh has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Genentech. Dr. Shieh has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Argenx. Dr. Shieh has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Catalyst.
Nancy L. Kuntz, MD, FAAN (Ann & Robert H Lurie Children'S Hospital of Chicago)	Dr. Kuntz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Kuntz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Affinia Therapeutics. Dr. Kuntz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenyx. Dr. Kuntz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Audentes Therapeutics. Dr. Kuntz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Kuntz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Kuntz has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Kuntz has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta.
	No disclosure on file
James Dowling, MD, PhD (Hospital for Sick Children)	Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ikaika Therapeutics. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bain Consulting. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for RYR1 Foundation. Dr. Dowling has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Dechert LLP. The institution of Dr. Dowling has received research support from Astellas. The institution of Dr. Dowling has received research support from NIH. The institution of Dr. Dowling has received research support from CIHR. The institution of Dr. Dowling has received research support from Astellas. Dr. Dowling has received personal compensation in the range of $5,000-$9,999 for serving as a advisor with Ontario Ministry of Health.
	No disclosure on file
Carsten G. Bonnemann, MD	Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with RYR1 Foundation that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Genethon that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Sarepta Therapeutics that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Kate Therapeutics that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with CureCMD that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Seal Therapeutics that is relevant to AAN interests or activities.
Laurent Servais (John Radcliffe Hospital)	Laurent Servais has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Laurent Servais has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astellas. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Evox. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC. Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sysnav. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BioHaven. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dyne. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zentech. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MitoRx. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lupin. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fibrogen. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alltrana. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Illumina. Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Laurent Servais has received research support from Roche. The institution of Laurent Servais has received research support from Novartis. The institution of Laurent Servais has received research support from Biogen. The institution of Laurent Servais has received research support from Zentech. The institution of Laurent Servais has received research support from BioHaven. The institution of Laurent Servais has received research support from PerkinHalmers. The institution of Laurent Servais has received research support from Scholar Rock.
Francesco Muntoni, MD (UCL Institute of Child Health)	Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Muntoni has received research support from European Commission. The institution of Dr. Muntoni has received research support from Medical Research Council. The institution of Dr. Muntoni has received research support from Biogen. The institution of Dr. Muntoni has received research support from Muscular Dystrophy UK. The institution of Dr. Muntoni has received research support from MDA USA. The institution of Dr. Muntoni has received research support from Sarepta. The institution of Dr. Muntoni has received research support from Association Francoise Myopathies. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving as a Clinical expert with UK NICE Committee.
	No disclosure on file
Sarah B. Neuhaus, DO (Johns Hopkins Hospital)	Dr. Neuhaus has nothing to disclose.
Lindsay N. Alfano, PT (Nationwide Children'S Hospital)	Ms. Alfano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ATOM International, Ltd (Amicus Therapeutics, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics). Ms. Alfano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Novartis Gene Therapies. The institution of Ms. Alfano has received research support from Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Audentes Therapeutics/Astellas Gene Therapies. Ms. Alfano has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
Martin K. Childers, DO, PhD (Wake Forest University School of Med)	No disclosure on file
Tina Duong	Tina Duong has received personal compensation for serving as an employee of Roche. Tina Duong has received personal compensation for serving as an employee of Novartis. Tina Duong has received personal compensation for serving as an employee of Scholar Rock. Tina Duong has received personal compensation for serving as an employee of Genentech. Tina Duong has received personal compensation for serving as an employee of Novartis. Tina Duong has received personal compensation for serving as an employee of Sarepta. Tina Duong has received personal compensation for serving as an employee of Biogen. Tina Duong has received personal compensation for serving as an employee of Audentes. Tina Duong has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Tina Duong has received personal compensation in the range of $0-$499 for serving as a Consultant for Audentes. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genentech. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta. Tina Duong has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for biogen. The institution of Tina Duong has received research support from biogen. The institution of Tina Duong has received research support from scholar rock.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Jun Lee, MD (Yeungnam Univ Hospital)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Suyash Prasad, MBBS (Suyash Prasad Consulting LLC)	Dr. Prasad has received personal compensation for serving as an employee of Audentes Therapeutics. Dr. Prasad has received stock or an ownership interest from Audentes.
Salvador Rico	Salvador Rico has received personal compensation for serving as an employee of Audentes Therapeutics. Salvador Rico has received personal compensation for serving as an employee of Encoded Therapeutics. Salvador Rico has received stock or an ownership interest from Audentes Therapeutics.

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