[en] [en] BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.
METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.
FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).
INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.
FUNDING: Astellas Gene Therapies.
Disciplines :
Pediatrics
Author, co-author :
Shieh, Perry B; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: pshieh@mednet.ucla.edu
Kuntz, Nancy L; Division of Neurology, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
Dowling, James J; Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada
Müller-Felber, Wolfgang; Department of Paediatric Neurology and Developmental Medicine, Hauner Children's Hospital, Ludwig Maximilian University of Munich, Munich, Germany
Bönnemann, Carsten G; Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, USA
Seferian, Andreea M; I-Motion, Hôpital Armand Trousseau, Paris, France
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques
Smith, Barbara K; Department of Physical Therapy, University of Florida, Gainesville, FL, USA
Muntoni, Francesco; NIHR, Great Ormond Street Hospital Biomedical Research Centre, University College London Institute of Child Health, London, UK
Blaschek, Astrid; Department of Paediatric Neurology and Developmental Medicine, Hauner Children's Hospital, Ludwig Maximilian University of Munich, Munich, Germany
Foley, A Reghan; Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, USA
Saade, Dimah N; Division of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Neuhaus, Sarah; Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, USA
Alfano, Lindsay N; Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
Beggs, Alan H; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Buj-Bello, Ana; Généthon, Evry, France, Integrare Research Unit UMR_S951, Université Paris-Saclay, Université d'Evry, Inserm, Généthon, Evry, France
Childers, Martin K; Department of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
Duong, Tina; Department of Neurology, Stanford University, Palo Alto, CA, USA
Graham, Robert J; Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Jain, Minal; Rehabilitation Medicine Department, NIH Hatfield Clinical Research Center, Bethesda, MD, USA
Coats, Julie; Astellas Gene Therapies, San Francisco, CA, USA
MacBean, Vicky; Department of Health Sciences, Brunel University London, London, UK
James, Emma S; Astellas Gene Therapies, San Francisco, CA, USA
Lee, Jun; Astellas Gene Therapies, San Francisco, CA, USA
Mavilio, Fulvio; Astellas Gene Therapies, San Francisco, CA, USA, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
Miller, Weston; Astellas Gene Therapies, San Francisco, CA, USA
Varfaj, Fatbardha; Astellas Gene Therapies, San Francisco, CA, USA
Murtagh, Michael; Astellas Gene Therapies, San Francisco, CA, USA
Han, Cong; Astellas Pharma Global Development, Northbrook, IL, USA
Noursalehi, Mojtaba; Astellas Gene Therapies, San Francisco, CA, USA
Lawlor, Michael W; Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA, Diverge Translational Science Laboratory, Milwaukee, WI, USA
Prasad, Suyash; Astellas Gene Therapies, San Francisco, CA, USA
Rico, Salvador; Astellas Gene Therapies, San Francisco, CA, USA
The ASPIRO trial was sponsored by Astellas Gene Therapies. We gratefully acknowledge the following investigators for their role in the data monitoring committee: Gregory M Enns, Philip Rosenthal, Gerald Lipshutz, David N Rosenthal, and Alex Fay. We thank the patients and families with X-linked myotubular myopathy who participated in the INCEPTUS and ASPIRO studies and are grateful for support from the X-linked myotubular myopathy patient advocacy community. We gratefully acknowledge the additional investigators involved in ASPIRO for their remarkable work in collecting part of the data: the outstanding therapists, nurses, study coordinators, and advisors involved in patient evaluation or data collection; the leading role of Généthon–Inserm in the design of the human MTM1-expressing vector; Généthon-Inserm and the University of Washington School of Medicine for the design and execution of preclinical studies; Jose Cancelas of the Cancer and Blood Diseases Institute of Cincinnati Children's Hospital Medical Center for contributions to understanding the pathophysiology of the thrombocytopenic events; Astellas Gene Therapies in the development of the good manufacturing practice vector production process; the clinical team at Astellas Gene Therapies; Bhargav Achanta, Neema Lakshman, and Aparna Shetty of Astellas Gene Therapies; Bryan Sepulveda, formerly of Astellas Gene Therapies, for critical contributions to the manuscript; and Laurie LaRusso of Chestnut Medical Communications for medical writing support funded by Astellas Gene Therapies.The ASPIRO trial was sponsored by Astellas Gene Therapies. We gratefully acknowledge the following investigators for their role in the data monitoring committee: Gregory M Enns, Philip Rosenthal, Gerald Lipshutz, David N Rosenthal, and Alex Fay. We thank the patients and families with X-linked myotubular myopathy who participated in the INCEPTUS and ASPIRO studies and are grateful for support from the X-linked myotubular myopathy patient advocacy community. We gratefully acknowledge the additional investigators involved in ASPIRO for their remarkable work in collecting part of the data: the outstanding therapists, nurses, study coordinators, and advisors involved in patient evaluation or data collection; the leading role of Généthon–Inserm in the design of the human MTM1-expressing vector; Généthon-Inserm and the University of Washington School of Medicine for the design and execution of preclinical studies; Jose Cancelas of the Cancer and Blood Diseases Institute of Cincinnati Children's Hospital Medical Center for contributions to understanding the pathophysiology of the thrombocytopenic events; Astellas Gene Therapies in the development of the good manufacturing practice vector production process; the clinical team at Astellas Gene Therapies; Bhargav Achanta, Neema Lakshman, and Aparna Shetty of Astellas Gene Therapies; Bryan Sepulveda, formerly of Astellas Gene Therapies, for critical contributions to the manuscript; and Laurie LaRusso of Chestnut Medical Communications for medical writing support funded by Astellas Gene Therapies.
Laporte, J, Biancalana, V, Tanner, SM, et al. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 15 (2000), 393–409.
Vandersmissen, I, Biancalana, V, Servais, L, et al. An integrated modelling methodology for estimating the prevalence of centronuclear myopathy. Neuromuscul Disord 28 (2018), 766–777.
Beggs, AH, Byrne, BJ, De Chastonay, S, et al. A multicenter, retrospective medical record review of X-linked myotubular myopathy: the RECENSUS study. Muscle Nerve 57 (2018), 550–560.
McEntagart, M, Parsons, G, Buj-Bello, A, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord 12 (2002), 939–946.
Graham, RJ, Muntoni, F, Hughes, I, et al. Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis. Arch Dis Child 105 (2020), 332–338.
Amburgey, K, Tsuchiya, E, de Chastonay, S, et al. A natural history study of X-linked myotubular myopathy. Neurology 89 (2017), 1355–1364.
Annoussamy, M, Lilien, C, Gidaro, T, et al. X-linked myotubular myopathy: a prospective international natural history study. Neurology 92 (2019), e1852–67.
Dowling, JJ, Müller-Felber, W, Smith, BK, et al. INCEPTUS natural history, run-in study for gene replacement clinical trial in X-linked myotubular myopathy. J Neuromuscul Dis 9 (2022), 503–516.
Danièle, N, Moal, C, Julien, L, et al. Intravenous administration of a MTMR2-encoding AAV vector ameliorates the phenotype of myotubular myopathy in mice. J Neuropathol Exp Neurol 77 (2018), 282–295.
Raess, MA, Cowling, BS, Bertazzi, DL, et al. Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy. Hum Mol Genet 26 (2017), 3736–3748.
Gayi, E, Neff, LA, Massana Muñoz, X, et al. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. Nat Commun, 9, 2018, 4848.
Maani, N, Sabha, N, Rezai, K, et al. Tamoxifen therapy in a murine model of myotubular myopathy. Nat Commun, 9, 2018, 4849.
Mendell, JR, Al-Zaidy, S, Shell, R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377 (2017), 1713–1722.
Russell, S, Bennett, J, Wellman, JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390 (2017), 849–860.
Buj-Bello, A, Fougerousse, F, Schwab, Y, et al. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Hum Mol Genet 17 (2008), 2132–2143.
Childers, MK, Joubert, R, Poulard, K, et al. Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med, 6, 2014, 220ra10.
Elverman, M, Goddard, MA, Mack, D, et al. Long-term effects of systemic gene therapy in a canine model of myotubular myopathy. Muscle Nerve 56 (2017), 943–953.
Mack, DL, Poulard, K, Goddard, MA, et al. Systemic AAV8-mediated gene therapy drives whole-body correction of myotubular myopathy in dogs. Mol Ther 25 (2017), 839–854.
Prasad, S, Dimmock, DP, Greenberg, B, et al. Immune responses and immunosuppressive strategies for adeno-associated virus-based gene therapy for treatment of central nervous system disorders: current knowledge and approaches. Hum Gene Ther 33 (2022), 1228–1245.
Day, JW, Finkel, RS, Chiriboga, CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol 20 (2021), 284–293.
Duong, T, Harding, G, Mannix, S, et al. Use of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-linked myotubular myopathy: content validity and psychometric performance. J Neuromuscul Dis 8 (2021), 63–77.
Glanzman, AM, McDermott, MP, Montes, J, et al. Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther 23 (2011), 322–326.
Bayley, N, Bayley scales of infant and toddler development. 3rd edn., 2006, Harcourt Assessment, San Antonio, TX.
Matsumoto, H, Clayton-Krasinski, DA, Klinge, SA, et al. Development and initial validation of the assessment of caregiver experience with neuromuscular disease. J Pediatr Orthop 31 (2011), 284–292.
Iannaccone, ST, Hynan, LS, Morton, A, Buchanan, R, Limbers, CA, Varni, JW, The PedsQL in pediatric patients with spinal muscular atrophy: feasibility, reliability, and validity of the Pediatric Quality of Life Inventory Generic Core Scales and Neuromuscular Module. Neuromuscul Disord 19 (2009), 805–812.
Heinzmann-Filho, JP, Vasconcellos Vidal, PC, Jones, MH, Donadio, MV, Normal values for respiratory muscle strength in healthy preschoolers and school children. Respir Med 106 (2012), 1639–1646.
Shardonofsky, FR, Perez-Chada, D, Carmuega, E, Milic-Emili, J, Airway pressures during crying in healthy infants. Pediatr Pulmonol 6 (1989), 14–18.
WHO Multicentre Growth Reference Study Group. WHO motor development study: windows of achievement for six gross motor development milestones. Acta Paediatr 450:suppl (2006), 86–95.
Bertini, E, Burghes, A, Bushby, K, et al. 134th ENMC International Workshop: outcome measures and treatment of spinal muscular atrophy, 11-13 February 2005, Naarden, the Netherlands. Neuromuscul Disord 15 (2005), 802–816.
BioMarin International. Summary of product characteristics. ROCTAVIAN 2 × 1013 vector genomes/mL solution for infusion. https://www.ema.europa.eu/en/documents/product-information/roctavian-epar-product-information_en.pdf, 2022. (Accessed 11 October 2023)
CSL Behring. Prescribing information. HEMGENIX (etranacogene dezaparvovec-drlb) suspension, for intravenous infusion. https://labeling.cslbehring.com/PI/US/Hemgenix/EN/Hemgenix-Prescribing-Information.pdf, 2022. (Accessed 11 October 2023)
Novartis Gene Therapies. Prescribing information. ZOLGENSMA (onasemnogene abeparvovec-xioi) suspension, for intravenous infusion. https://www.fda.gov/media/126109/download, 2021. (Accessed 11 October 2023)
Horton, RH, Saade, D, Markati, T, et al. A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment. J Neurol Neurosurg Psychiatry 93 (2022), 1276–1288.
Herman, GE, Finegold, M, Zhao, W, de Gouyon, B, Metzenberg, A, Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr 134 (1999), 206–214.
Molera, C, Sarishvili, T, Nascimento, A, et al. Intrahepatic cholestasis is a clinically significant feature associated with natural history of X-linked myotubular myopathy (XLMTM): a case series and biopsy report. J Neuromuscul Dis 9 (2022), 73–82.
D'Amico, A, Longo, A, Fattori, F, et al. Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies. Orphanet J Rare Dis, 16, 2021, 425.
Gangfuss, A, Schmitt, D, Roos, A, et al. Diagnosing X-linked myotubular myopathy—a German 20-year follow up experience. J Neuromuscul Dis 8 (2021), 79–90.
Neese, JM, Yum, S, Matesanz, S, et al. Intracranial hemorrhage secondary to vitamin K deficiency in X-linked myotubular myopathy. Neuromuscul Disord 31 (2021), 651–655.
Freitag, C, Dynacure letter to CNM-MTM community. https://myotubulartrust.org/wp-content/uploads/PatientCommunicationsFinalJuly.pdf, July 6, 2022. (Accessed 18 July 2022)
Mingozzi, F, High, KA, Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122 (2013), 23–36.
Nathwani, AC, Tuddenham, EG, Rangarajan, S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365 (2011), 2357–2365.
Karolczak, S, Deshwar, AR, Aristegui, E, et al. Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy. J Clin Invest, 133, 2023, e166275.
