New Phase 1/2 EXPLORE44 Trial Data Shows Continued Treatment Effect of AOC 1044 in Duchenne Muscular Dystrophy

Michael Kelly, PhD

Avidity Biosciences recently announced new positive data from EXPLORE44, its phase 1/2 trial assessing AOC 1044, an antisense oligonucleotide, as a potential therapy for patients with Duchenne muscular dystrophy (DMD). Treatment with the therapy, otherwise known as delpacibart zotadirsen (or del-zota), resulted in statistically significant increases in dystrophin production and reductions in creatine kinase levels along with a favorable safety and tolerability profile.¹

EXPLORE44, a randomized, placebo-controlled study, includes 25 patients with DMD across the US and Canada who are randomly assigned 3:1 to investigational AOC 1044 or placebo for a treatment period lasting approximately 12 or 16 weeks (dependent upon 6 or 8 week infusion schedule). In the study, AOC 1044 at 5 mg/kg demonstrated unsurpassed delivery of phosphorodiamidate morpholino oligomers (PMO) concentrations of 200 nM in skeletal muscle. This group also showed a statistically significant increase of 25% of normal in dystophin production and a statistically significant increase of 37% in exon 44 skipping in studied patients, which had DMD mutations amenable to exon 44 skipping.

"The results were very impressive. It showed high levels of exon-skipping, along with a substantial 25% increase in skipped dystrophin production in patients’ muscles after only the first 3 doses of Del-zota. This was accompanied by a remarkable 80% reduction in creatine kinase (to near normal levels) and taken together is highly suggestive of a potential significant clinical benefit for patients with Duchenne," Michael Kelly, PhD, the chief scientific officer at CureDuchenne, told NeurologyLive®. "Having recognized the limitations of the first approved exon-skipping drugs, CureDuchenne funded Avidity Biosciences a number of years ago to accelerate the development of the next generation of exon-skipping to specifically target all muscle groups and substantially improve efficacy. The new 'muscle-targeted' approaches are being closely followed by the Duchenne community, and the recent clinical results have built significant enthusiasm for this approach."

AOC 1044, a nonapproved treatment designed to deliver PMO to skeletal muscle and heart tissue to specifically skip exon 44 of the dystrophin gene to enable dystrophin production, has previously been granted orphan drug and fast track designation by the FDA. More recently, in May, the agency granted the therapy rare pediatric disease designation. These designations have underscored the urgent need for innovative treatments for patients with DMD and further validated the potential of AOC 1044 to address these unmet needs.

Diana Castro, MD

"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. We have not seen this level of dystrophin production and reduction in creatine kinase with other PMO exon-skipping treatments," lead investigator Diana Castro, MD, founder and director of the Neurology and Neuromuscular Care Center, said in a statement.¹ "These del-zota data are very encouraging as 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."

For the 4 month assessment in the 5 mg/kg cohort, participants received 3 doses of 5 mg/kg of AOC 1044 (PMO dose) or placebo every 6 weeks. Data on muscle delivery, exon skipping, dystrophin production, and creatine kinase levels were evaluated from 10 participants in the 5 mg/kg cohort. In the 5 mg/kg group, investigators observed up to 66% exon 44 skipping and a greater than 80% reduction in creatine kinase levels relative to baseline. Notably, reductions in creatine kinase were so substantial, they reached nearly normal levels in treated patients.

Above all, the treatment was considered safe, with adverse events that were mostly mild or moderate in treated patients. EXPLORE44, which lasts a total of 8 months when including screening and post-treatment follow-up, also has an additional open-label extension, in which all eligible participants who complete the study will receive active study drug for an ongoing period. Those who do not immediately take part in or decline the open-label extension will be followed for another 2 months in an extended follow-up period as part of the EXPLORE44 study.

Sarah Boyce

"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. These data support expediting the regulatory path for del-zota as quickly as possible," Sarah Boyce, president and chief executive officer at Avidity, said in a statement.¹ "Del-zota is the first AOC in development from our DMD franchise and with this data, we are also advancing additional exon-skipping DMD candidates."

EXPLORE44, designed to assess exon skipping and dystrophin protein levels of patients treated with AOC 1044, includes approximately 24 participants with DMD44, ages 7-27 years old. Coming into the study, patients must be clinically diagnosed or have a clear onset of DMD symptoms before the age of 6 years old. In addition, those included must weigh more than 23 kg (50.7 lbs), are either ambulatory or nonambulatory, and may currently be on a regimen of stable doses of steroids.

In December 2023, data from EXPLORE44 showed that AOC 1044 was safe among healthy volunteers and delivered 50-times greater concentrations of PMO in skeletal muscle following administration. At day 29, patients treated with a single dose of 10 mg AOC 1044 demonstrated statistically significant exon 44 skipping of up to 1.5% in comparison with placebo. The agent was considered safe, with all treatment-emergent AEs mild to moderate. Notably, there were no reports of symptomatic hemoglobin changes, no hypomagnesemia, and no renal events.²

"Exon skipping has the potential to treat up to 80% of patients with Duchenne and produces a protein that is significantly larger than that delivered by gene therapy," Kelly added. "Muscle-targeted and cell-penetrating approaches will play a very important role in future treatment options, offering high levels of skipped dystrophin production in all muscle groups, with less frequent dosing regimens (Q6W, etc. ) and acceptable safety and tolerability. CureDuchenne was an early investor in Avidity, and we’re thrilled to see this positive data. There’s a tremendous unmet need in the community, and as we move toward the second generation of exon-skipping drugs and other novel technologies, we’re hopeful that these drugs will reach even more of the population that still has no treatments."

REFERENCES
1. Avidity Biosciences Announces Positive AOC 1044 Data Demonstrated Significant Increase of 25% in Dystrophin Production and Reduction of Creatine Kinase Levels to Near Normal in People Living with Duchenne Muscular Dystrophy Amenable to Exon 44 Skipping in the Phase 1/2 EXPLORE44™ Trial. News release. Avidity Biosciences. August 9, 2024. Accessed August 12, 2024. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-aoc-1044-data-demonstrated-significant-increase-of-25-in-dystrophin-production-and-reduction-of-creatine-kinase-levels-to-near-normal-in-people-living-with-duchenne-muscular-dystrophy-amenab-302218647.html
2. Avidity Biosciences reports positive data demonstrating AOC 1044 delivers unprecedented concentrations of PMO in muscle following a single dose in healthy volunteers from phase 1/2 EXPLORE44 trial for Duchenne muscular dystrophy. News release. Avidity Biosciences. December 13, 2023. Accessed August 12, 2024. https://www.prnewswire.com/news-releases/avidity-biosciences-reports-positive-data-demonstrating-aoc-1044-delivers-unprecedented-concentrations-of-pmo-in-muscle-following-a-single-dose-in-healthy-volunteers-from-phase-12-explore44-trial-for-duchenne-muscular-dystrophy-302013456.html

To learn more, Cure Duchenne invites the community to attend its online webinar in partnership with Avidity held Friday, August 16 at 9:00am Pacific Time / 12:00pm Eastern Time. In the webinar, Diana Castro, MD, and a representative from Avidity will review the EXPLORE44 trial initial findings and provide insights on what these results mean for this development program and for the DMD44 community. Register HERE.