Avidity Biosciences is advancing its clinical program for delpacibart braxlosiran (del-brax), a novel therapy targeting the root cause of facioscapulohumeral muscular dystrophy (FSHD). The company has initiated a biomarker cohort within the Phase 1/2 FORTITUDE trial to evaluate the drug's impact on DUX4-regulated biomarkers. This move supports Avidity's pursuit of a potential accelerated approval pathway for del-brax, which could become the first approved treatment for this debilitating condition.
The biomarker cohort will assess the effects of del-brax at a dose of 2 mg/kg administered every six weeks in individuals aged 16-70 with FSHD. Enrollment is anticipated to be completed in the first half of 2025. The primary endpoints of this cohort are changes in the expression of DUX4-regulated genes and levels of DUX4-regulated circulating biomarkers.
Promising Initial Data
Previously reported initial data from the FORTITUDE trial demonstrated that del-brax 2 mg/kg, administered every six weeks, led to unprecedented and consistent reductions in DUX4-regulated genes. The data also showed significant decreases in a novel circulating biomarker and creatine kinase, along with trends toward functional improvement at the four-month timepoint. These findings were presented at the 31st Annual FSHD Society International Research Congress.
Steve Hughes, M.D., chief medical officer at Avidity, stated, "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."
The FORTITUDE Trial
The FORTITUDE trial is a randomized, placebo-controlled, double-blind Phase 1/2 clinical trial designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of del-brax in approximately 100 participants with FSHD. The trial assesses key biomarkers, including DUX4-regulated muscle and circulating biomarkers, as well as magnetic resonance imaging (MRI) measures of muscle volume and composition. While the trial is not statistically powered to assess functional benefit, it explores clinical activity through measures of mobility, muscle strength, patient-reported outcomes, and quality of life.
Del-brax: Targeting the Root Cause of FSHD
Del-brax (AOC 1020) is designed to address the underlying cause of FSHD, which is the abnormal expression of the double homeobox 4 (DUX4) gene. This aberrant expression leads to changes in gene expression in muscle cells, resulting in progressive muscle function loss. Del-brax aims to reduce the expression of DUX4 mRNA and protein in muscles of individuals 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.
FSHD: An Unmet Medical Need
Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive, and variable hereditary muscle-weakening condition. It is characterized by progressive and often asymmetric skeletal muscle loss, initially causing weakness in the face, shoulders, arms, and trunk, and progressing to the lower body. Currently, there are no approved treatments for FSHD, highlighting the urgent need for effective therapies like del-brax.
