Exon skipping trial for Duchenne muscular dystrophy did not meet primary end point
Pharmaceutical company Sarepta Therapeutics has announced the completion of the ESSENCE study for its Exon 45 and 53 skipping therapies, AMONDYS 45 (known as the brand casimersen) and VYONDYS 53 (known as the brand golodirsen).
Sarepta published topline results from ESSENCE, which show that at 96 weeks, the phase 3 trial, didn’t achieve a statistically significant difference in the key measure chosen to test its effectiveness (primary endpoint), 4-step ascend velocity, which was used to measure participants’ mobility.
Sarepta note that the topline results from the study show that numerical trends did favour treatment versus placebo (a substance that has no therapeutic effect) but the observed difference did not reach statistical significance.
In the press release, the company notes that if trial participants whose participation in the trial overlapped with the COVID-19 pandemic were excluded, the study demonstrated a clinically meaningful slowing of disease progression. Sarepta report that 43% of COVID-19-impacted participants missed consecutive doses of exon skipping therapy.
The company says the results also reinforced the safety of both AMONDYS 45 and VYONDYS 53 (supporting the favourable safety profiles of the two treatments), with any side effects or so-called adverse events, being mostly mild or moderate and comparable between treatment and placebo groups.
The ESSENCE study
ESSENCE was a global, randomized double-blind, placebo-controlled Phase 3 confirmatory study evaluating the efficacy and safety of AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen) in individuals living with Duchenne amenable to skipping exons 45 or 53, respectively.
Participants were recruited for the trial at sites around the UK.
Many boys and their families bravely took part in and committed their time to this important study in the UK, helping investigators to learn more about exon skipping and how it can be optimised as a treatment.
If you participated in the trial and have any questions or concerns about this announcement, please contact your clinical trial team, who will be best placed to advise you.
Exon skipping treatments in the US
Sarepta Therapeutics received accelerated approval from US regulator the FDA for VYONDYS 53 and AMONDYS 45 in 2019 and 2021 respectively, making them approved treatments in US, alongside Sarepta’s EXONDYS 51 (previously known as eteplirsen) an exon skipping treatment for those amenable to skipping exon 51.
None of these treatments are currently approved for use in the UK outside of clinical trials.
A condition of FDA accelerated approval is completion of a confirmatory study such as ESSENCE. The FDA may withdraw a product if a study fails to verify its clinical benefit.
Sarepta has indicated that the completion of the ESSENCE study is expected to fulfil the FDA’s primary postmarketing requirement. The company plans to meet with the FDA to discuss converting AMONDYS 45 and VYONDYS 53 from accelerated approval to traditional approval. They will submit complete ESSENCE data and real-world evidence to support this.
We will share further updates on the status of these medicines in the US and what it means for the UK, as we know more.
What is Exon Skipping?
The active part of the dystrophin gene is made up of 79 pieces called exons. These exons link together to form a code that is read in the cells so that the protein dystrophin can be made.
In DMD, some of the exons are not readable. The result is that very little or no dystrophin is made.
Exon skipping drugs hide or ‘patch’ the missing piece so that the exons fit together again and can be read. This means that a functional, although shorter, dystrophin protein can be produced by the body.
As the exon skipping drug is designed to skip over a particular exon, different versions need to be made depending on which exons needs to be skipped. This is because people with DMD have different genetic mutations that cause the disease. The most common mutation is around exon 51 and accounts for approximately 13% of cases of Duchenne.