AOC 1020 Shows Significant Impact on Underlying Pathology of Facioscapulohumeral Muscular Dystrophy

Jeffrey M. Statland, MD

In the phase 1/2 FORTITUDE (NCT05747924), newly announced data showed that treatment with investigational AOC 1020 (Avidity Biosciences) resulted in pronounced reduction in DUX4 regulated genes, otherwise considered the root cause of facioscapulohumeral muscular dystrophy (FSHD). In addition, investigators observed trends of functional improvement, coupled with strong safety and tolerability that further support the therapy’s development going forward.¹

FORTITUDE is a randomized, double-blind, placebo-controlled trial assessing single and multiple doses of AOC 1020, or del-brax, in approximately 39 adult participants with FSHD. Though the trial is not statistically powered to assess functional benefit, it explores the clinical activity of the therapy, including measures of mobility and muscle strength as well as patient-reported outcomes and quality of life measures.

Presented at the 31st Annual FSHD Society International Research Congress, held June 13-14, in Denver, Colorado, the initial data included safety and tolerability from participants in both the 2 mg/kg and 4 mg/kg groups after 4 months of treatment. Data on DUX4 regulated genes, circulating biomarkers and muscle strength and function, were assessed from 12 participants in the 2 mg/kg cohort. In that smaller subgroup, greater than 50% mean reductions in DUX4 regulated genes were observed across multiple panels for DUX4 regulated gene expression in muscle.

"As the first therapy to directly target DUX4, it is very encouraging to see that the del-brax data demonstrate consistent reductions in DUX4 regulated genes and provided trends of functional improvement in patients with FSHD at the four-month timepoint. These early data would support the notion that del-brax has the potential to change the course of disease for people living with FSHD," trial investigator Jeffrey M. Statland, MD, professor of neurology at the University of Kansas Medical Center, said in a statement.¹ "Early data showing trends in del-brax to improve muscle strength and function are very encouraging for patients with FSHD who are in need of treatments to prevent the muscle weakness and disability that is associated with this relentlessly, progressive disease."

FSHD, a rare, hereditary disorder, is caused by an abnormal expression of DUX4. To date, there are no approved therapies to treat the condition. AOC 1020, which has been granted orphan drug and fast track designations from the FDA, consists of a monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DUX4 mRNA. In preclinical studies, a single intravenous dose with the murine version of the agent prevented development of muscle weakness across 3 functional assays.

In the 4-month assessment of FORTITUDE, those in the 2 mg/kg cohort received a single-dose of 1 mg/kg of AOC 1020 followed by 2 doses of 2 mg/kg AOC 1020 (siRNA dose), or placebo. Within the 2 mg/kg cohort, all participants treated with the investigational therapy showed reductions greater than 20% in DUX4 regulated genes. In addition, investigators reported mean reductions of at least 25% in novel circulating biomarker and creatine kinase.

READ MORE: Pfizer’s Duchenne Gene Therapy Fails to Meet Primary End Point in Phase 3 CIFFREO Trial

All told, AOC 1020-treated patients showed trends of functional improvements including increased strength in upper and lower limb muscles, as well as trends of improvement in patient and clinician reported outcomes. In terms of safety, the therapy was considered well tolerated, with no serious adverse events (AEs) or discontinuations. Notably, all AEs were considered mild or moderate in nature. Notably, muscle function was improved in treated patients, demonstrated through comparison analysis against placebo and the ReSolve natural history study.

"Data from the FORTITUDE trial are very promising for people living with FSHD as the progression of the disease can make it increasingly difficult to perform critical day-to-day activities, pursue work and can affect many aspects of life, including family and social life,” Mark Stone, president and chief executive officer at FSHD Society, said in a statement.¹ “FSHD is one of the most prevalent forms of muscular dystrophy and currently, there are no treatment options. The initial del-brax data offers real hope for those living with the disease, their families, and their caregivers, who are desperately waiting for a treatment."

In addition to AOC 1020, Avidity is developing 2 other agents—AOC 1044 and AOC 1001—for the potential treatment of Duchenne muscular dystrophy and myotonic dystrophy type 1 (DM1), respectively. Following positive results from the phase 2 MARINA trial (NCT05479981), Avidity initiated the phase 3 HARBOR study to continue to study the effects of AOC 1001 in patients with DM1. The study, which is supposed to begin in the second quarter of 2024, spans more than 40 global sites, with approximately 150 patients assigned to either AOC 1001 4 mg/kg or placebo every 8 weeks for a 54-week treatment period.

REFERENCES
1. Avidity Announces Unprecedented AOC 1020 Data from Phase 1/2 FORTITUDE™ Trial Demonstrating Greater Than 50 Percent Reduction in DUX4 Regulated Genes and Trends of Functional Improvement in People Living with Facioscapulohumeral Muscular Dystrophy. News release. Avidity Biosciences. June 12, 2024. Accessed June 13, 2024. https://www.prnewswire.com/news-releases/avidity-announces-unprecedented-aoc-1020-data-from-phase-12-fortitude-trial-demonstrating-greater-than-50-percent-reduction-in-dux4-regulated-genes-and-trends-of-functional-improvement-in-people-living-with-facioscapulohumeral-m-302170099.html
2. Avidity Biosciences announces positive AOC 1001 long-term data showing reversal of disease progression in people living with myotonic dystrophy type 1 across multiple end points; same key endpoints agreed for phase 3 HARBOR study. News release. Avidity Biosciences. March 4, 2024. Accessed June 13, 2024. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-aoc-1001-long-term-data-showing-reversal-of-disease-progression-in-people-living-with-myotonic-dystrophy-type-1-across-multiple-endpoints-same-key-endpoints-agreed-for-phase-3-harbor-trial-302078020.html