Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial

Abstract

Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9 years, in wheelchairs for ≥1 to ≤4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population.

Clinical trials of exon skipping in Duchenne muscular dystrophy

“…On 7 January 2016, the US Food and Drug Administration (FDA), composed of a panel of outside advisors, voted that there was no conclusive benefit from Kyndrisa and a few months later Biomarin announced on 31 May 2016 that it was withdrawing Kyndrisa TM from clinical testing (www.BMRN.com). Any additional question about higher dosing of drisapersen to achieve greater benefit was addressed in a study assessing safety, tolerability and pharmacokinetics after a single subcutaneous dose ranging study (3-9 mg/kg) was completed in non-ambulatory DMD boys [13]. It was already known that AONs with phosphorothioate linkage had potential adverse effects that fall into four main categories: inflammation, thrombocytopenia, accumulation in the kidneys and liver,…”

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

“…[19][20][21] Even very small quantities of dystrophin, hardly detectable by immunohistochemistry (IHC) or Western blot (WB), might ameliorate the disease and delay LoA by several years. This is particularly relevant for the development of dystrophin-restoring treatments, such as exon skipping by antisense oligonucleotides (AONs) [22][23][24][25][26][27][28][29][30] and stop codon readthrough, [31][32][33] as variation in baseline levels of dystrophin may confound evaluations of efficacy in clinical trials.…”

Recent advances in the management of Duchenne muscular dystrophy

“…After 24 weeks but not at 48 weeks, the continuous regimen resulted in a statistically significant increase in walking distance (∼35 m) compared with placebo. Proteinuria was a common adverse effect 45 46. Eteplirsen is a morpholino drug that leads to removal of exon 51 during the RNA splicing process (excision of introns and joining of exons).…”