Dados do Trabalho

Título

INCEPTUS Multinational, Prospective, Natural History, Run-in Study of Males with X-Linked Myotubular Myopathy

Introdução

X-linked myotubular myopathy (XLMTM) is an ultra-rare, life-threatening congenital myopathy characterized by profound muscle weakness at birth. Approximately 1 in 40,000-50,000 newborn males are affected (Vandersmissen, 2018). XLMTM is a monogenic disorder, caused by mutations in the MTM1 gene, resulting in absent or dysfunctional myotubularin protein. XLMTM is characterized by respiratory and motor function impairments, dependence on mechanical ventilation and feeding support, and absent or delayed motor milestones. Approximately half of infants die before 18 months of age, and survival is highly dependent on intensive medical intervention, without which most patients would not survive (Graham 2020; McEntagart, 2002).

Objetivo

INCEPTUS (Trial registration number: NCT02704273) was a prospective, non-interventional study to evaluate male ventilator dependent XLMTM subjects under 4 years of age.

Métodos

34 participants were assessed for up to 33 months and 80% required invasive support, many for 24h/day. Median time from birth to tracheostomy was 3.5 months. The mean [SD] daily ventilation hours remained constant from baseline (21.4 [4.3]) to end of study (21.7 [4.4]).

Resultados

Neuromuscular function (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND, mean [SD]) remained essentially unchanged from baseline (35.1 [8.1]) to end of study (37.2 [6.7]). Seven participants (21%) could sit unsupported for ≥ 30 seconds, but one lost this ability during the study. There were three deaths due to cardiopulmonary failure; aspiration pneumonia; and hepatic hemorrhage. Overall, 61 serious adverse events occurred in 20 patients, mainly due to respiratory infections, and resulted in 52 hospitalizations with a mean (SD) duration of 8.1 (7.6) days. Overall, 91% of participants had a history of hepatobiliary disease at enrollment or showed at least one sign of hepatic disease during the prospective study period.

Conclusões

INCEPTUS data have increased our understanding of respiratory and neuromuscular insufficiency in XLMTM, reinforcing its life-threatening nature and heterogeneity of presentation. There are currently no approved treatments for XLMTM. Patients demonstrated minimal to no improvements in measures of respiratory or motor function, regardless of their MTM1 mutation type or age. Management requires a multidisciplinary approach to address the manifestations of chronic, profound muscle weakness. .

Palavras Chave

XLMTM; congenital myopathy, MTM1, prospective study

Referências (se houver)

Fonte de Fomento (se houver)

Declaração de conflito de interesses de TODOS os autores

ANO has received speaker, consulting or other fees from PTC Therapeutics and Astellas Gene Therapies. JJD has received research grants from Astellas Gene Therapies, Inc and has participated. BS and WM are employees and stockholders at Astellas Gene Therapies. PBS has received grants or personal fees from Audentes, Sarepta, AveXis, PTC Therapeutics, Pfizer, Biogen, Argenx, Catalyst, Roche, Ra Pharma, Grifols, Alexion, CSL Behring, Fulcrum Therapeutics, Fibrogen, Acceleron, Reveragen, Sanofi, Santhera.

Área

Doenças neuromusculares