204P A phase 1 study of antisense oligonucleotide NS-035 in patients with Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is an autosomal recessive disease that primarily affects the skeletal muscles, brain, and eyes. FCMD is most commonly caused by a 3-kb retrotransposal insertion into the 3′ untranslated region of the fukutin gene, resulting in aberrant mRNA splicing (exon-trapping). In collaboration with Nippon Shinyaku, we discovered an antisense oligonucleotide, NS-035, that can prevent this exon-trapping, recovering normal fukutin mRNA expression and protein function in both mouse models and cells of FCMD patients. To obtain regulatory approval for NS-035, we initiated the first-in-human phase 1 study of NS-035 in patients with FCMD. This was a two-center, open-label, uncontrolled, dose-escalation clinical trial comprising four cohorts. Twelve patients with FCMD (aged 5–10 years) carrying homozygous or compound heterozygous variants in the fukutin gene were included, with three patients in each cohort. The study was initiated in cohort 1. D-mannitol alone was administered intravenously once during the premedication phase, followed by simultaneous doses of NS-035 and D-mannitol administered intravenously once weekly for 12 weeks during the treatment phase. The dose of D-mannitol was fixed at 500 mg/kg in all cohorts, while NS-035 was increased stepwise from cohorts 1 to 4 (1.6, 6.0, 20, and 40 mg/kg). The primary endpoint was safety, and the secondary endpoints were pharmacokinetics and efficacy (glycosylation rate of alpha-dystroglycan [DG], expression of glycosylated alpha-DG, exon-trapping inhibition efficiency, evaluation of gross motor function, and changes in blood CK value). Following institutional review board approval in June 2021, the trial was initiated in August 2021. This study is currently in progress with the final patient (patient 12). This study is progressing smoothly and is scheduled for completion in 2024.