P.105INCEPTUS pre-phase 1, prospective, non-interventional, natural history run-in study to evaluate subjects aged 4 years and younger with X-linked myotubular myopathy (XLMTM)

Abstract

XLMTM is a rare disease caused by mutations in the MTM1 gene, leading to profound muscle weakness, respiratory failure and early death. INCEPTUS (NCT02704273) is a prospective, non-interventional study in patients (pts) ≤4 years old to characterize the course and natural history of XLMTM using neuromuscular and respiratory assessments and to identify adverse events (AEs). INCEPTUS will generate within-pt control data to support a Phase 1/2 gene therapy clinical trial (ASPIRO). As of 22MAR19, 32 male pts (0.3-4.6 years of age) have been enrolled and assessed every 3 months for up to 24 months. There were 3 deaths and 61 serious AEs, mainly due to respiratory tract infections. neuromuscular function is severely compromised. Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP INTEND) was performed in all pts. Mean CHOP INTEND scores show a 2.7-point annual decline from baseline (mean [SD, min-max]= 33.3 [8.1, 17-52]) to month 12 (30.6 [5.8, 19-40]). A healthy pt may score a maximum of 64 points. Developmental milestones (per Bayley-III scales) were evaluated if pts scored >45 points on the CHOP INTEND or if they were able to sit. In INCEPTUS, 27 pts (87%) have no or very poor head control, a motor milestone typically reached by 4 months of age in healthy pts. Similarly, while healthy pts can roll by 5 months, none of the INCEPTUS pts achieved this milestone. Only 3 pts (9%) in INCEPTUS were able to sit without assistance >30 seconds. Most pts (n=24, 75%) require invasive ventilatory support; 21 pts for 24h/day. Respiratory muscle strength measured as maximum inspiratory pressure (MIP, cmH2O) is very low at baseline (34.5 [12.2, 17.6-64.5]) and declines by 6.3 cmH2O over 12 months' follow-up (28.3 [7.9, 15.1-41.4]). INCEPTUS prospectively demonstrates that neuromuscular and respiratory functions are severely impaired and slowly worsen over time in pts ≤4 years old, reinforcing that XLMTM is a severe, life-threatening childhood disorder.