INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy.

Abstract

BACKGROUND:

X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death.

OBJECTIVE:

We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study.

METHODS:

Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed.

RESULTS:

During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort.

CONCLUSIONS:

INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

• Authors: James J Dowling, Wolfgang Müller-Felber, Barbara K Smith, Carsten G Bönnemann, Nancy L Kuntz, Francesco Muntoni, Laurent Servais, Lindsay N Alfano, Alan H Beggs, Deborah A Bilder, Astrid Blaschek, Tina Duong, Robert J Graham, Minal Jain, Michael W Lawlor, Jun Lee, Julie Coats, Charlotte Lilien, Linda P Lowes, Victoria MacBean, Sarah Neuhaus, Mojtaba Noursalehi, Teresa Pitts, Caroline Finlay, Sarah Christensen, Gerrard Rafferty, Andreea M Seferian, Etsuko Tsuchiya, Emma S James, Weston Miller, Bryan Sepulveda, Maria Candida Vila, Suyash Prasad, Salvador Rico, Perry B Shieh, INCEPTUS investigators
• Journal: Journal of neuromuscular diseases (J Neuromuscul Dis) Vol. 9 Issue 4 Pg. 503-516 ( 2022) ISSN: 2214-3602 [Electronic] Netherlands
• PMID: 35694931 (Publication Type: Journal Article, Multicenter Study)

Topics

• Child, Preschool
• Genetic Therapy
• Humans
• Longitudinal Studies
• Male
• Myopathies, Structural, Congenital (genetics, therapy)
• Prospective Studies
• Quality of Life