Indications
Eteplirsen is indicated for the management of Duchenne muscular dystrophy (DMD) in individuals with a confirmed mutation in the DMD gene amenable to exon 51 skipping. This therapeutic indication has been granted accelerated approval based on observed increases in dystrophin in skeletal muscle tissue in certain patients receiving eteplirsen.
Pharmacodynamics
As a disease-modifying agent, eteplirsen is designed to decelerate the progression of Duchenne muscular dystrophy, although it does not provide a cure. While precise estimates of dystrophin production in muscle tissue during clinical evaluations remain elusive, eteplirsen's administration leads to increased levels of dystrophin protein in patients. The treatment facilitates the production of mRNA coding for a truncated dystrophin protein, similar to what is observed in Becker muscular dystrophy. This less severe muscular disorder is caused by specific DMD gene mutations resulting in the creation of functional, albeit truncated, dystrophin. Eteplirsen thus aims to mitigate the severity of the disease and slow the progression of functional impairment.
Absorption
Upon single or repeated intravenous infusions, eteplirsen reaches peak plasma concentration (Cmax) approximately at the conclusion of the infusion process, usually within 1.1 to 1.2 hours, across a dosage spectrum of 0.5 mg/kg/week to 50 mg/kg/week. The variability in peak plasma concentration and area under the curve (AUC) among different subjects ranges from 20% to 55%.
Metabolism
Eteplirsen is not metabolized by the liver. As with other phosphorodiamidate morpholino oligomers, it has minimal metabolic transformation, allowing it to maintain stability in the body without undergoing significant hepatic metabolism.
Mechanism of Action
Eteplirsen functions by facilitating exon skipping in specific defective genetic variants to address the underlying cause of Duchenne muscular dystrophy (DMD). The drug specifically targets and binds to exon 51 of the dystrophin pre-mRNA. This targeted binding results in the exclusion of exon 51 during the mRNA splicing process for patients with mutations that can benefit from exon 51 skipping. By inducing this exon skipping, eteplirsen reinstates the open reading frame of the DMD gene, thereby enabling the synthesis of functional dystrophin. This mechanism seeks to mitigate the effects of dystrophin deficiency, which is central to the pathogenesis of DMD.
