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Multicenter Study
. 2022;9(4):503-516.
doi: 10.3233/JND-210781.

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

James J Dowling  1 , Wolfgang Müller-Felber  2 , Barbara K Smith  3 , Carsten G Bönnemann  4 , Nancy L Kuntz  5 , Francesco Muntoni  6 , Laurent Servais  7   8 , Lindsay N Alfano  9 , Alan H Beggs  10 , Deborah A Bilder  11 , Astrid Blaschek  2 , Tina Duong  12 , Robert J Graham  10 , Minal Jain  13 , Michael W Lawlor  14 , Jun Lee  15 , Julie Coats  16 , Charlotte Lilien  7 , Linda P Lowes  9 , Victoria MacBean  17 , Sarah Neuhaus  4 , Mojtaba Noursalehi  15 , Teresa Pitts  18 , Caroline Finlay  15   18 , Sarah Christensen  15   18 , Gerrard Rafferty  19 , Andreea M Seferian  7 , Etsuko Tsuchiya  1 , Emma S James  15   18 , Weston Miller  16 , Bryan Sepulveda  15 , Maria Candida Vila  15 , Suyash Prasad  15 , Salvador Rico  15 , Perry B Shieh  20 ; INCEPTUS investigators
Affiliations
Multicenter Study

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

James J Dowling et al. J Neuromuscul Dis. 2022.

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.

Keywords: X-linked myotubular myopathy; centronuclear myopathy; mechanical; motor disorders; neuromuscular diseases; respiratory failure; ventilators.

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Conflict of interest statement

JJD reports research grants from Astellas Gene Therapies,* serving on advisory boards for Dynacure, Kate Therapeutics, and RYR1 Foundation, and serving as an editor of the Journal of Neuromuscular Diseases. BKS reports consulting fees from Astellas Gene Therapies* and Sarepta. CGB is editor-in-chief of the Journal of Neuromuscular Diseases. DAB reports former participation on the Scientific and Clinical Advisory Board for Astellas Gene Therapies* and receiving travel expenses for attending advisory board meetings. AB reports grants or personal fees from Biogene and Sanofi Genzyme; advisory or other board participation at Dynacure and CMD Scientific and Medical. LL reports consulting fees paid to her institution for training of evaluators in the INCEPTUS study. MWL reports research grants paid to his institution from Astellas Gene Therapies,* Solid Biosciences, Kate Therapeutics, Taysha Therapeutics, and Prothelia and consulting fees from Astellas Gene Therapies,* Encoded Therapeutics, Modis Therapeutics, Lacerta Therapeutics, AGADA Biosciences, Dynacure, Affinia, and Biomarin. TD reports personal consulting fees from Astellas Gene Therapies,* Biogen, Avexis, Roche, Novartis, Dynacure, Sarepta, Pfizer, and Genentech. GR reports consulting fees from Astellas Gene Therapies* paid to his institution. VM reports consulting fees from Astellas Gene Therapies* paid both directly to her and her institution. PBS reports grants or personal fees from Astellas Gene Therapies,* Sarepta, AveXis, PTC Therapeutics, Pfizer, Biogen, Argenx, Catalyst, Roche, Ra Pharma, Grifols, Alexion, CSL Behring, Fulcrum Therapeutics, Fibrogen, Acceleron, Reveragen, Sanofi, and Santhera. AHB reports sponsored research support from NIH, MDA (USA), AFM Telethon, Alexion Pharmaceuticals Inc., Astellas Gene Therapies,* Dynacure SAS, and Pfizer Inc. He has consulted and received compensation or honoraria from Astellas Gene Therapies,* Biogen, F. Hoffman-La Roche AG, Kate Therapeutics, GLG Inc, Guidepoint Global, and Novartis, holds equity in Kate Therapeutics and Kinea Bio, and is an inventor on a US patent describing a method for gene therapy of XLMTM. LNA reports grants or contracts from Astellas Gene Therapies* for clinical evaluator training and quality control in the INCEPTUS and ASPIRO studies. RJG reports limited consulting fees from Astellas Gene Therapies* for work on the ASPIRO study design and advisory board participation for Astellas Gene Therapies,* Biogen, and Genetech. CL reports consulting fees, payments or honoraria, and/or travel expenses from Roche, Biogen, ATOM, AFEHM, Sysnav, and PeerVoice. LS reports consulting fees from Astellas Gene Therapies* and Dynacure. NLK reports advisory board participation for Astellas Gene Therapies,* Biogen, Genentech, Novartis and Sarepta. AMS, ET, MJ, FM, SN, TP, and WMF report no conflicts of interest. JC, MN, WS, and BS are employees and/or stockholders of Astellas Gene Therapies.* JL, CF, SC, ES, MCV, SP, and SR are former employees and/or stockholders of Astellas Gene Therapies.*

*Formerly Audentes Therapeutics

Figures

Fig. 1
Fig. 1
Motor function over time for individual participants by mutation type. (A) CHOP INTEND total scores. (B) MFM-20 scores. The thick red lines represent LS means and standard errors from a mixed-effect model with fixed effect of time.
Fig. 2
Fig. 2
Respiratory function over time for individual participants by mutation type. (A) Ventilator dependence within the previous 24 hours. Higher ventilator dependence reflects more daily hours of ventilator use. The thick blue and red lines represent LS means and standard errors from a mixed-effect model with fixed effect of time for invasively ventilated participants (blue) and noninvasively ventilated participants (red). (B) Maximal inspiratory pressure (MIP). The thick red line represents LS means and standard errors from a mixed-effect model with fixed effect of time.
See this image and copyright information in PMC

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