source: American Academy of Neurology
J Saoud, J Zhang, L Warner, C Kincaid, P Duda, E Kaye
The objective of this analysis is to examine the pharmacokinetic profiles of eteplirsen, a PMO designed to skip exon 51, following long-term administration in patients with DMD.
DMD is a rare, degenerative, recessive, X-linked genetic disease that results in progressive muscle loss and premature death. It is caused by mutations in the dystrophin gene that disrupt the reading frame of the encoded mRNA and prevent production of dystrophin protein. Exon skipping by PMOs is a promising, disease-modifying approach to DMD and eteplirsen is an investigational PMO designed to enable functional dystrophin production in boys amenable to exon 51 skipping (~13[percnt] of total DMD).
Twelve boys aged 7-10 years with eligible genotypes were randomized 1:1:1 to weekly IV eteplirsen 30 mg/kg, 50 mg/kg, or placebo for 24 weeks (4658-us-201). All patients transitioned into an ongoing open-label extension, 4658-us-202, with 30 or 50 mg/kg. Blood samples for determination of the pharmacokinetic properties of eteplirsen through up to 152 weeks of treatment as determined by HPLC/FL analysis of plasma samples. RESULTS:The plasma half-life of eteplirsen was found to be between 3-4 hours for both cohorts, similar to that observed at Week 12 in 4658-us-201. Due to rapid decline in concentrations over 24 hours, little if any accumulation due to weekly dosing was expected and none was observed. There were no notable differences in Cmax, AUC, and CL at Weeks 12 and 152. PK profiles were similar to those previously reported in the DMD population after a 1-hour IV infusion of eteplirsen in a phase Ib study (AVI-4658-28).
The pharmacokinetic profile of eteplirsen at 152 weeks showed concordance with previously conducted Phase I and II studies. Due to the short half-life and rapid decline in concentrations, accumulation was not observed with the current once weekly IV dosing schedule.
Sarepta Therapeutics, USA