Casimersen (AMONDYS 45™): An Antisense Oligonucleotide for Duchenne Muscular Dystrophy

Abstract

Casimersen (AMONDYS 45^TM) is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer subclass developed by Sarepta therapeutics. It was approved by the Food and Drug Administration (FDA) in February 2021 to treat Duchenne muscular dystrophy (DMD) in patients whose DMD gene mutation is amenable to exon 45 skipping. Administered intravenously, casimersen binds to the pre-mRNA of the DMD gene to skip a mutated region of an exon, thereby producing an internally truncated yet functional dystrophin protein in DMD patients. This is essential in maintaining the structure of a myocyte membrane. While casimersen is currently continuing in phase III of clinical trials in various countries, it was granted approval by the FDA under the accelerated approval program due to its observed increase in dystrophin production. This article discusses the pathophysiology of DMD, summarizes available treatments thus far, and provides a full drug review of casimersen (AMONDYS 45^TM).

Keywords: AMONDYS 45; Duchenne muscular dystrophy; antisense oligonucleotide; casimersen; dystrophin; exon skipping; neuromuscular disorders; phosphorodiamidate oligomer.

Figure 1

(a) The structure of the dystrophin gene is shown with all 79 exons and corresponding domains: N terminus (Actin binding), central rod domain, cysteine-rich domain, and C-terminal domain. (b) Antisense-induced exon skipping in DMD patients. Deletion of exons 49 and 50 resulted in premature stop codon and disrupted the production of dystrophin. Exon skipping of 51 in this case produced a truncated and partly functional dystrophin protein. (c) Structure of casimersen.