The antisense oligonucleotide casimersen will be branded as Amondys 45 and is currently being assessed in the ESSENCE phase 3 clinical trial (NCT02500381).
The FDA has approved casimersen (Amondys 45; Sarepta Therapeutics) for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 45 skipping.1
The ESSENCE trial (NCT02500381; also known as Study 4045-301)—a placebo-controlled confirmatory trial to support the Sarepta product’s approval—is ongoing and expected to conclude in 2024. Keeping with the accelerated approval pathway that casimersen is on, the continued approval is contingent on the confirmation of a clinical benefit in confirmatory trials.
Notably, the antisense oligonucleotide therapy has met the full statutory standards for safety and effectiveness and is, therefore, not considered investigational or experimental.
“This is an important day for Sarepta and, far more importantly, for the patients that we serve. After years of scientific commitment, investment, and development, the approval of AMONDYS 45, Sarepta’s third approved RNA therapy, offers treatment to the 8% of the DMD community who have a confirmed exon 45 amenable mutation,” said Doug Ingram, president and chief executive officer, Sarepta, in a statement. “Along with our other approved RNA therapies, we can now offer treatment options for nearly 30% of Duchenne patients in the US. And our commitment to bring therapies to the greatest percentage of the DMD community as soon as possible continues.”
Kidney toxicity has been observed after the administration of some antisense oligonucleotides—such as potentially fatal glomerulonephritis—though it has not been observed in clinical studies of casimersen to date. It is advised that kidney function should be monitored in patients administered the drug.
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In the clinical trial of casimersen, the most common adverse events observed in at least 20% of patients treated and at least 5% more frequently than in placebo were: Upper respiratory tract infections (casimersen: 65%; placebo: 55%), cough (casimersen: 33%; placebo: 26%), fever (casimersen: 33%; placebo: 23%), headache (casimersen: 32%; placebo: 19%), joint pain (casimersen: 21%; placebo: 10%), and pain in mouth and throat (casimersen: 21%; placebo: 7%).
“Decades of research and commitment have fueled and now accelerate our progress towards new treatments for Duchenne,” said Marissa Penrod, founder, Team Joseph, and a parent of a teenager with DMD. “The extraordinary diligence and persistence of the Duchenne community—patients and families, clinicians and researchers—have led us to today’s approval, where we now have exon-skipping treatments for almost a third of those with Duchenne.”
The agent is part of Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform. The company noted in its announcement that the indication was based on the observed statistically significant increase in dystrophin production in skeletal muscular in clinical study of the therapy.
Previously, Sarepta had submitted its new drug application (NDA) filing in June 2020 and requested a priority review, which was granted by the FDA.2 The NDA included data from the casimersen arm of the ESSENCE study, which is a global, randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and safety of casimersen in patients amenable to skipping exons 45.
An interim analysis from ESSENCE, announced in March 2019, implied that treatment was associated with a statistically significant increase in dystrophin production, as measured by western blot in patients who received casimersen compared to baseline and placebo. The study is ongoing and remains blinded to collect additional efficacy and safety data.3
In ESSENCE, patients amenable to exon 45 skipping were randomized to receive a once-weekly intravenous (IV) infusion of casimersen dosed at 30 mg/kg (n = 27) or placebo (n = 16) for 96 weeks. The interim analysis was performed on data from biopsies of the bicep muscle at baseline and on-treatment at Week 48. Key findings from the interim analysis showed mean dystrophin protein increased to 1.736% of normal compared to a mean baseline of 0.925% of normal (P <.001) in the casimersen arm. Additionally, there was a statistically significant difference in the mean change from baseline to week 48 in dystrophin protein between the casimersen-treated arm and the placebo arm (P = .009).
As well, there was a statistically significant positive correlation between exon 45 skipping and dystrophin production (Spearman rank correlation = 0.635; P <.001). At the time, 22 patients receiving casimersen who had been tested for increased exon-skipping mRNA using reverse transcription-polymerase chain reaction (RT-PCR), and all 22 of them displayed an increase in skipping exon 45 (P <.001) above baseline levels, representing a 100% response rate.