Eteplirsen (Exondys 51): A Comprehensive Analysis of a First-in-Class Exon-Skipping Therapy for Duchenne Muscular Dystrophy

Abstract

Eteplirsen, marketed as Exondys 51, represents a seminal advancement in the field of genetic medicine, establishing a new therapeutic paradigm for Duchenne Muscular Dystrophy (DMD). As a first-in-class antisense oligonucleotide, Eteplirsen is specifically indicated for the approximately 13-14% of DMD patients who possess a genetic mutation amenable to the skipping of exon 51 in the dystrophin gene. Its novel phosphorodiamidate morpholino oligomer (PMO) chemistry and targeted mechanism of action, which aims to restore the dystrophin messenger RNA reading frame and permit the synthesis of a truncated, partially functional protein, offered the first tangible hope for a disease-modifying therapy targeting the underlying cause of this devastating disorder. However, the clinical development and regulatory trajectory of Eteplirsen have been characterized by profound scientific debate and unprecedented divergence in regulatory interpretation. This report provides a comprehensive analysis of Eteplirsen, from its molecular architecture and pharmacological profile to a critical appraisal of the clinical evidence that supported its regulatory submissions. The central narrative of Eteplirsen is one of conflict: its controversial accelerated approval by the U.S. Food and Drug Administration (FDA), which was granted based on a surrogate endpoint of dystrophin production despite a negative recommendation from its own advisory committee, stands in stark contrast to the subsequent refusal of marketing authorization by the European Medicines Agency (EMA), which deemed the same evidence base insufficient to establish a positive benefit-risk balance. Through this detailed examination, Eteplirsen emerges not only as a therapeutic agent but as a critical case study in modern regulatory science, illuminating the complex interplay between evide