Del-zota increases dystrophin in DMD patients, new trial data show
EXPLORE44 study shows safety, benefits of therapy formerly called AOC 1044
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Avidity Biosciences‘ delpacibart zotadirsen, or del-zota for short — formerly called AOC 1044 — was found to safely increase levels of dystrophin production to 25% of normal in people with Duchenne muscular dystrophy (DMD), according to new data from the EXPLORE44 trial.
In the Phase 1/2 clinical trial (NCT05670730), which enrolled DMD patients with mutations amenable to exon 44 skipping, the therapy also reduced blood levels of creatine kinase, a biomarker for muscle damage, to the near-normal range.
“This is an exciting moment as these data suggest del-zota has the potential to change the treatment paradigm and course of disease for patients with Duchenne muscular dystrophy mutations amenable to exon 44 skipping,” Diana Castro, MD, trial investigator, neuromuscular physician, and founder and director of the Neurology and Neuromuscular Care Center in Texas, said in a company press release.
“We have not seen this level of dystrophin production and reduction in creatine kinase with other … exon-skipping treatments [of this type],” Castro added, calling the new data “very encouraging.”
Del-zota designed for patients with mutations amenable to exon 44 skipping
In DMD, mutations in the DMD gene disrupt the production of dystrophin, a muscle protein that normally helps protect muscle cells against damage. Without dystrophin, muscles accumulate damage faster, leading to symptoms of progressive muscle weakness and damage.
Like most genes, the DMD gene contains exons, which are segments along the DNA chain that provide instructions to make proteins. Exon-skipping therapies are those that skip over one or more exons, resulting in the production of a shortened but functional version of dystrophin.
Del-zota is designed to promote the skipping of exon 44 in the DMD gene. It includes an antibody that targets muscle cells and a molecule called a phosphorodiamidate morpholino oligomer, or PMO, that promotes exon skipping.
“Children and adults living with Duchenne muscular dystrophy mutations amenable to exon 44 skipping are still in need of targeted treatment options to address this debilitating disease,” Castro said.
The first part of EXPLORE44 is evaluating single doses of the therapy in healthy volunteers. Data reported in 2023 showed that the treatment, at 10 mg/kg, promoted exon skipping, compared with a placebo, in all participants.
The trial’s second part is testing multiple doses of del-zota in patients, ages 7-27, with DMD mutations amenable to exon 44 skipping.
Dystrophin production seen to increase to 25% of normal in DMD patients
In this analysis, researchers reported on the safety and tolerability of the therapy in 25 participants across two dose levels: 5 mg/kg and 10 mg/kg. For the four-month assessment in the 5 mg/kg group, patients received three 5 mg/kg doses, or the placebo, every six weeks. Muscle delivery, exon skipping, dystrophin production, and creatine kinase levels were assessed in 10 participants in the 5 mg/kg group.
Data showed that del-zota treatment delivered high levels of PMO to muscles after three 5 mg/kg doses.
At four months, there was also a significant 37% increase in exon 44 skipping, which reached up to 66%. Dystrophin production significantly increased to 25% of normal and restored total dystrophin up to 54% of normal, the data showed.
At the same time, creatine kinase levels dropped to the near-normal range, representing a reduction of more than 80% compared with the study’s start.
The robust exon skipping, significant dystrophin production, and profound reduction of creatine kinase reinforce our belief in the potential of del-zota to be an effective treatment for people living with DMD44.
According to researchers, the therapy demonstrated a favorable safety and tolerability profile, and most treatment-emergent adverse events were mild or moderate in severity.
“The robust exon skipping, significant dystrophin production, and profound reduction of creatine kinase reinforce our belief in the potential of del-zota to be an effective treatment for people living with DMD44,” said Sarah Boyce, Avidity’s president and CEO. “These data support expediting the regulatory path for del-zota as quickly as possible.”
Del-zota was granted rare pediatric disease designation earlier this year by the U.S. Food and Drug Administration. The regulatory agency also has awarded the therapy candidate orphan drug designation and fast-track status. Rare pediatric disease designation supports treatments for rare disorders primarily affecting children and adolescents, while orphan drug designation incentivizes the development of treatments for rare disorders. Fast-track status helps to get medicines to market faster.
While sharing these new trial data, Avidity also announced delpacibart zotadirsen, or del-zota for short, as the international nonproprietary name of AOC 1044.
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