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Avidity Biosciences Initiates Biomarker Cohort in Phase 1/2 FORTITUDE Trial, Seeks Accelerated Approval Path for AOC 1020
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Key Takeaways
- AOC 1020 targets DUX4, the root cause of FSHD, showing significant gene expression reduction and functional improvement.
- The biomarker cohort evaluates 2 mg/kg AOC 1020 every 6 weeks, aiming for accelerated approval.
In previously reported data, AOC 1020 demonstrated a consistent reduction in double homeobox 4 regulated genes among patients with facioscapulohumeral muscular dystrophy at 4 months.
Steve Hughes, MD
(Credit: Avidity)
According to a recent company announcement, Avidity Biosciences has initiated a biomarker cohort in the phase 1/2 FORTITUDE trial (NCT05747924) assessing its investigational therapy AOC 1020, also known as delpacibart braxlosiran (del-brax), among patients living with facioscapulohumeral muscular dystrophy (FSHD). The company noted that it is pursuing a potential accelerated approval path for AOC 1020 and anticipates enrollment for the biomarker cohort to be completed in the first half of 2025.1
Since previously reported safety and tolerability outcomes were similar in participants treated with 2 mg/kg or 4 mg/kg of AOC 1020, the biomarker cohort in the study will evaluate the impact of AOC 1020 2 mg/kg every 6 weeks in patients with FSHD aged between 16 years and 70 years. The primary end points of the trial are changes in double homeobox 4 (DUX4) regulated gene expression and DUX4 regulated circulating biomarker. Avidity also announced that it remains on track to launch a functional cohort in the first half of 2025 and that enrollment of the FORTITUDE open-label extension study is ongoing.
"The initiation of the biomarker cohort marks a key step in our strategy to pursue a potential accelerated approval path for del-brax, the first potential treatment to directly target the root cause of FSHD," Steve Hughes, MD, chief medical officer at Avidity, said in a statement.1 "We are very pleased with the del-brax 2 mg/kg data which showed unprecedented and consistent reductions of DUX4-regulated genes, significant decreases in novel circulating biomarker and creatine kinase, and trends of functional improvement with favorable safety and tolerability at the four-month timepoint. We are advancing our clinical studies for del-brax as quickly as possible as we understand the urgency to bring a potential new treatment to people living with FSHD who have no treatment options."
In June 2024, the company reported initial 4-month data from the phase 1/2, randomized, double-blind, placebo-controlled FORTITUDE trial which showed that treatment with AOC 1020 resulted in pronounced reduction in DUX4 regulated genes. Presented at the 31st Annual FSHD Society International Research Congress, held June 13-14, in Denver, Colorado, investigators observed trends of functional improvement, coupled with strong safety and tolerability that further support the therapy’s development going forward.2
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The initial data included safety and tolerability in both the 2 mg/kg and 4 mg/kg groups after 4 months of treatment, approximately 39 adult participants with FSHD. 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.
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.
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.
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.
