Avidity Biosciences has commenced a biomarker cohort within its Phase 1/2 FORTITUDE trial (NCT05747924), evaluating AOC 1020, also known as delpacibart braxlosiran (del-brax), in patients with facioscapulohumeral muscular dystrophy (FSHD). The company is aiming for a potential accelerated approval pathway for AOC 1020, with the biomarker cohort's enrollment anticipated to conclude in the first half of 2025.
Given the similar safety and tolerability profiles observed in participants treated with 2 mg/kg and 4 mg/kg doses of AOC 1020 in earlier stages of the study, the biomarker cohort will assess the impact of a 2 mg/kg dose administered every six weeks in FSHD patients aged 16 to 70. The trial's primary endpoints are focused on changes in double homeobox 4 (DUX4)-regulated gene expression and DUX4-regulated circulating biomarkers. Avidity also confirmed that the launch of a functional cohort remains on track for the first half of 2025, and the enrollment for the FORTITUDE open-label extension study is ongoing.
Targeting the Root Cause of FSHD
"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," stated Steve Hughes, MD, chief medical officer at Avidity. He further added, "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."
Promising Initial Data
In June 2024, Avidity reported initial four-month data from the randomized, double-blind, placebo-controlled FORTITUDE trial, demonstrating that AOC 1020 treatment led to a marked reduction in DUX4-regulated genes. The data, presented at the 31st Annual FSHD Society International Research Congress, also indicated trends of functional improvement, coupled with a strong safety and tolerability profile, further bolstering the therapy's continued development.
The initial data encompassed safety and tolerability assessments in both the 2 mg/kg and 4 mg/kg groups after four months of treatment in approximately 39 adult participants with FSHD. Data on DUX4-regulated genes, circulating biomarkers, and muscle strength and function were evaluated from 12 participants in the 2 mg/kg cohort. This subgroup showed mean reductions exceeding 50% in DUX4-regulated genes across multiple panels for DUX4-regulated gene expression in muscle.
Observed Reductions in DUX4 and Functional Improvements
In the four-month assessment, participants in the 2 mg/kg cohort received a single 1 mg/kg dose of AOC 1020, followed by two 2 mg/kg doses of AOC 1020 (siRNA dose), or placebo. Within this cohort, all participants treated with the investigational therapy exhibited reductions greater than 20% in DUX4-regulated genes. Additionally, investigators reported mean reductions of at least 25% in a novel circulating biomarker and creatine kinase.
AOC 1020-treated patients demonstrated 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. The therapy was well-tolerated, with no serious adverse events (AEs) or discontinuations reported. All AEs were considered mild or moderate in nature. Muscle function was improved in treated patients, as demonstrated through comparison analysis against placebo and the ReSolve natural history study.
Addressing Unmet Needs in FSHD
FSHD, a rare, hereditary disorder, is caused by abnormal DUX4 expression. Currently, there are no approved therapies for the condition. AOC 1020, which has received orphan drug and fast track designations from the FDA, comprises a monoclonal antibody that binds to transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DUX4 mRNA. Preclinical studies showed that a single intravenous dose of the murine version of the agent prevented the development of muscle weakness across three functional assays.
