CONGENITAL MYOPATHIES (CNM): P.136INCEPTUS pre-phase 1, prospective, non-interventional, natural history run-in study to evaluate subjects aged 3 years and younger with X-linked myotubular myopathy: preliminary findings

Abstract

XLMTM is a rare disease caused by mutations in the MTM1 gene and characterized by profound muscle weakness, respiratory failure, and early death. INCEPTUS is a prospective, non-interventional study to evaluate XLMTM patients under 4 years of age. The objective is to characterize adverse events; neuromuscular, respiratory, and functional assessments; and to generate within-patient control data to support a Phase 1/2 gene therapy clinical trial (the ASPIRO study). 23 male patients (0.5-4.0 years of age) have been enrolled and followed with assessments every 3 months for up to 18 months. There have been 3 deaths and 38 serious adverse events, mainly due to respiratory tract infections. Neuromuscular function is severely compromised in this population, with high inter-patient variability: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) mean scores show a 4-point decline (baseline mean [SD, min-max]= 33.6 [8.4, 17-52] and month 12 mean= 29.6 [6.5, 19-40]). Motor Function Measure (MFM-20) mean scores show a 3.5% increase (baseline mean= 28.6% [16.0, 5-48.3] and month 12 mean= 31.5% [13.2, 11.7-50]). The majority of patients (n= 16/23, 69.6%) require invasive ventilatory support, many for 24h/day. Respiratory muscle strength measured as maximum inspiratory pressure (MIP, also referred to as Pimax) is low and mean scores show a 5.1 cmH2O decline (baseline mean= 33.6 cmH2O [15.2, 17.6-64.5] and month 12 mean= 28.5 cmH2O [8.35, 15.1-41.4]). Vocalization evaluations by handheld acoustic analyzer show no differences in loudness between talking and crying, further evidencing poor respiratory muscle strength. INCEPTUS data increase our understanding of respiratory issues and neuromuscular weakness in XLMTM and reinforce the severity and heterogeneity of the disease. The INCEPTUS study has additional operational value, as study sites build experience with the use of outcome measures also being used in ASPIRO.