P.340Viltolarsen, exon 53 skipping drug, in patients with Duchenne muscular dystrophy: additional analysis of Japanese phase I/II study

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked inherited progressive disease, caused by a mutation in the dystrophin gene. Exon skipping therapy uses a synthesized antisense oligonucleotide designed to skip the specific exon to change out-of-frame to in-frame in the dystrophin mRNA, thereby inducing the expression of functional dystrophin protein. Viltolarsen is a novel morpholino oligomer discovered by NCNP and Nippon Shinyaku Co.,Ltd. Viltolarsen targets exon 53, to serve as effective treatment for DMD patients with deletion of exons 43-52, 45-52, 48-52, 49-52, 50-52 or 52 of dystrophin gene. First-in-human study was conducted as an investigator-initiated clinical study by NCNP. Viltolarsen was well tolerated at 3 dose group (1.25, 5 and 20 mg/kg) and one patient in 20 mg/kg group showed high efficiency of exon 53 skipping and expression of dystrophin protein (Sci Transl Med. 10, eaan0713 (2018)). Phase I/II dose-finding, multicenter study (Study No: NS065/NCNP-01-P1/2, JapicCTI-163291) enrolled 16 Japanese DMD patients, age of 5-12 years, amenable to exon 53 skipping. Patients were assigned to 40 or 80mg/kg dose group and received weekly infusions of viltolarsen for 24 weeks. We previously reported that 40 and 80 mg/kg of viltolarsen was well tolerated and no adverse event leading to discontinuation. In addition, western blotting analysis of dystrophin protein in muscle demonstrated significant dystrophin protein expression and Exon 53 skipping level showed tendency to increase depend on dose and treatment duration, which corresponded to mechanism of action of viltolarsen. And the correlation analysis showed higher dystrophin tended to suppress the decrease of motor functions (Time to stand and 10m Run/walk). In order to investigate further clinical benefit of viltolarsen, we exploratory performed additional analysis including the assessment of relationships between change of dystrophin and quantitative muscle strength.