Avidity Biosciences has initiated a biomarker cohort within its Phase 1/2 FORTITUDE trial, evaluating delpacibart braxlosiran (del-brax/AOC 1020) in individuals with facioscapulohumeral muscular dystrophy (FSHD). This move supports a potential accelerated approval pathway for del-brax, the first investigational therapy targeting the underlying cause of FSHD by directly addressing the double homeobox 4 (DUX4) gene. Currently, there are no approved treatments for FSHD, a rare, hereditary condition characterized by progressive muscle function loss, pain, fatigue, and disability.
Targeting DUX4 in FSHD
Del-brax is designed to reduce the expression of DUX4 mRNA and protein in muscles of people with FSHD. The therapy consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1), conjugated with a siRNA targeting DUX4 mRNA.
"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," said Steve Hughes, M.D., chief medical officer at Avidity.
The biomarker cohort will evaluate the impact of del-brax 2 mg/kg administered every six weeks in FSHD patients aged 16-70. Primary endpoints include changes in DUX4-regulated gene expression and circulating biomarkers.
Promising Initial Data
Avidity reported initial positive data from the FORTITUDE trial in June, demonstrating greater than 50% reductions in DUX4-regulated genes and mean reductions of 25% or greater in novel circulating biomarker and creatine kinase. These changes correlated with trends of functional improvement and favorable safety and tolerability profiles.
FORTITUDE Trial Details
The FORTITUDE trial is a randomized, placebo-controlled, double-blind Phase 1/2 clinical trial assessing single and multiple doses of del-brax in approximately 100 participants with FSHD. The trial evaluates safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenously administered del-brax. Activity is assessed via key biomarkers, MRI measures of muscle volume and composition, mobility, muscle strength, patient-reported outcomes, and quality of life measures. Participants can enroll in the FORTITUDE-OLE, an open-label extension study, upon completion of the FORTITUDE study.
Ongoing Enrollment and Future Plans
Enrollment in the del-brax biomarker cohort is expected to be completed in the first half of 2025, with the initiation of a functional cohort planned for the same period. Enrollment in the FORTITUDE Open-label Extension study (OLE) is also ongoing. The company selected the 2 mg/kg dose of del-brax to be administered every six weeks, designed to ensure continuous suppression of DUX4 for the biomarker and functional cohorts.
About FSHD
Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive, and variable hereditary muscle-weakening condition marked by life-long, relentless loss of muscle function, significant pain, fatigue, and progressive disability. It is characterized by progressive and often asymmetric skeletal muscle loss that initially causes weakness in muscles in the face, shoulders, arms and trunk and progresses to weakness in muscles in the lower body. FSHD is an autosomal dominant disease caused by the aberrant expression of the DUX4 (double homeobox 4) gene in the skeletal muscle, which activates genes that are toxic to muscle cells and leads to a series of downstream events that result in skeletal muscle wasting and compromised muscle function. Skeletal muscle weakness results in physical limitations throughout the whole body, including an inability to lift arms for more than a few seconds, loss of ability to show facial expressions and serious speech impediments. These symptoms cause many people affected by FSHD to become dependent on the use of a wheelchair for mobility. Currently, there are no approved treatments for people living with FSHD.
