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

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

doi:10.3233/JND-210781

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

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 MacBeanSarah 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

^*Corresponding author for this work

Centre for Human & Applied Physiological Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Pages (from-to)	503-516
Number of pages	14
Journal	Journal of Neuromuscular Diseases
Volume	9
Issue number	4
DOIs	https://doi.org/10.3233/JND-210781
Publication status	Published - 2022

Keywords

centronuclear myopathy
mechanical
motor disorders
neuromuscular diseases
respiratory failure
ventilators
X-linked myotubular myopathy

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10.3233/JND-210781

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Dowling, J. J., Müller-Felber, W., Smith, B. K., Bönnemann, C. G., Kuntz, N. L., Muntoni, F., Servais, L., Alfano, L. N., Beggs, A. H., Bilder, D. A., Blaschek, A., Duong, T., Graham, R. J., Jain, M., Lawlor, M. W., Lee, J., Coats, J., Lilien, C., Lowes, L. P., ... Shieh, P. B. (2022). INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy. Journal of Neuromuscular Diseases, 9(4), 503-516. https://doi.org/10.3233/JND-210781

@article{a990ed9ee5964afeae54a3e54417705f,

title = "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. ",

keywords = "centronuclear myopathy, mechanical, motor disorders, neuromuscular diseases, respiratory failure, ventilators, X-linked myotubular myopathy",

author = "Dowling, {James J.} and Wolfgang M{\"u}ller-Felber and Smith, {Barbara K.} and B{\"o}nnemann, {Carsten G.} and Kuntz, {Nancy L.} and Francesco Muntoni and Laurent Servais and Alfano, {Lindsay N.} and Beggs, {Alan H.} and Bilder, {Deborah A.} and Astrid Blaschek and Tina Duong and Graham, {Robert J.} and Minal Jain and Lawlor, {Michael W.} and Jun Lee and Julie Coats and Charlotte Lilien and Lowes, {Linda P.} and Victoria MacBean and Sarah Neuhaus and Mojtaba Noursalehi and Teresa Pitts and Caroline Finlay and Sarah Christensen and Gerrard Rafferty and Seferian, {Andreea M.} and Etsuko Tsuchiya and James, {Emma S.} and Weston Miller and Bryan Sepulveda and Vila, {Maria Candida} and Suyash Prasad and Salvador Rico and Shieh, {Perry B.}",

note = "Funding Information: The INCEPTUS and ASPIRO studies are sponsored by Astellas Gene Therapies. The authors thank the children and families with XLMTM who allowed their data to be collected for the INCEPTUS and ASPIRO studies, and the entire XLMTM patient community for their cooperation and participation in the development of the studies, including: the Joshua Frase Foundation, MTM-CNM Family Connection, The Myotubular Trust, Where There{\textquoteright}s a Will There{\textquoteright}s A Cure Foundation for Myotubular Myopathy, and ZNM – Zusammen Stark! Clinical site management 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, Gri-fols, Alexion, CSL Behring, Fulcrum Therapeutics, Fibrogen, Acceleron, Reveragen, Sanofi, and San-thera. 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 Astel-las 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 Publisher Copyright: {\textcopyright} 2022-The authors. Published by IOS Press.",

year = "2022",

doi = "10.3233/JND-210781",

language = "English",

volume = "9",

pages = "503--516",

journal = "Journal of Neuromuscular Diseases",

issn = "2214-3599",

publisher = "IOS Press",

number = "4",

}

Dowling, JJ, Müller-Felber, W, Smith, BK, Bönnemann, CG, Kuntz, NL, Muntoni, F, Servais, L, Alfano, LN, Beggs, AH, Bilder, DA, Blaschek, A, Duong, T, Graham, RJ, Jain, M, Lawlor, MW, Lee, J, Coats, J, Lilien, C, Lowes, LP, MacBean, V, Neuhaus, S, Noursalehi, M, Pitts, T, Finlay, C, Christensen, S, Rafferty, G, Seferian, AM, Tsuchiya, E, James, ES, Miller, W, Sepulveda, B, Vila, MC, Prasad, S, Rico, S & Shieh, PB 2022, 'INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy', Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 503-516. https://doi.org/10.3233/JND-210781

TY - JOUR

T1 - INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy

AU - Dowling, James J.

AU - Müller-Felber, Wolfgang

AU - Smith, Barbara K.

AU - Bönnemann, Carsten G.

AU - Kuntz, Nancy L.

AU - Muntoni, Francesco

AU - Servais, Laurent

AU - Alfano, Lindsay N.

AU - Beggs, Alan H.

AU - Bilder, Deborah A.

AU - Blaschek, Astrid

AU - Duong, Tina

AU - Graham, Robert J.

AU - Jain, Minal

AU - Lawlor, Michael W.

AU - Lee, Jun

AU - Coats, Julie

AU - Lilien, Charlotte

AU - Lowes, Linda P.

AU - MacBean, Victoria

AU - Neuhaus, Sarah

AU - Noursalehi, Mojtaba

AU - Pitts, Teresa

AU - Finlay, Caroline

AU - Christensen, Sarah

AU - Rafferty, Gerrard

AU - Seferian, Andreea M.

AU - Tsuchiya, Etsuko

AU - James, Emma S.

AU - Miller, Weston

AU - Sepulveda, Bryan

AU - Vila, Maria Candida

AU - Prasad, Suyash

AU - Rico, Salvador

AU - Shieh, Perry B.

N1 - Funding Information: The INCEPTUS and ASPIRO studies are sponsored by Astellas Gene Therapies. The authors thank the children and families with XLMTM who allowed their data to be collected for the INCEPTUS and ASPIRO studies, and the entire XLMTM patient community for their cooperation and participation in the development of the studies, including: the Joshua Frase Foundation, MTM-CNM Family Connection, The Myotubular Trust, Where There’s a Will There’s A Cure Foundation for Myotubular Myopathy, and ZNM – Zusammen Stark! Clinical site management 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, Gri-fols, Alexion, CSL Behring, Fulcrum Therapeutics, Fibrogen, Acceleron, Reveragen, Sanofi, and San-thera. 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 Astel-las 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 Publisher Copyright: © 2022-The authors. Published by IOS Press.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - centronuclear myopathy

KW - mechanical

KW - motor disorders

KW - neuromuscular diseases

KW - respiratory failure

KW - ventilators

KW - X-linked myotubular myopathy

UR - http://www.scopus.com/inward/record.url?scp=85133659377&partnerID=8YFLogxK

U2 - 10.3233/JND-210781

DO - 10.3233/JND-210781

M3 - Article

C2 - 35694931

AN - SCOPUS:85133659377

SN - 2214-3599

VL - 9

SP - 503

EP - 516

JO - Journal of Neuromuscular Diseases

JF - Journal of Neuromuscular Diseases

IS - 4

ER -

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

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