Novartis AG announced that the biomarker cohort of the FORTITUDE Phase I/II study of del-brax met its primary and key secondary endpoints, with reductions in KHDC1L (cDUX) and creatine kinase biomarker levels indicating both strong target engagement and reduction in muscle damage in patients with facioscapulohumeral muscular dystrophy (FSHD). Del-brax is an investigational antibody oligonucleotide conjugate (AOC) - a new class of RNA therapeutics - showing potential to become the first disease-modifying treatment for FSHD, a rare, irreversible neuromuscular disease marked by relentless loss of muscle function and progressive disability. Del-brax is designed to address the root cause of FSHD, the aberrant expression of DUX4.

Combining the tissue specificity of monoclonal antibodies with the precision of oligonucleotides, the AOC platform enables targeted delivery of siRNA to suppress DUX4 expression in previously hard-to-reach muscle cells of FSHD patients. Del-brax is the only investigational agent showing disease-modifying potential for FSHD in clinical studies. This investigational therapy has received FDA Orphan Drug and Fast Track designations, and EMA Orphan Drug designation, and is currently in Phase III development.

Del-brax is one of three potential first-in-class, late-stage, disease-modifying AOC therapies added to the Novartis neuroscience pipeline through the acquisition of Avidity Biosciences completed in February 2026. Beyond del-brax for FSHD, the Avidity acquisition included delpacibart-etedesiran (del-desiran) in Phase III development for myotonic dystrophy type 1 (DM1), a rare progressive neuromuscular disorder with a poor prognosis and no disease-modifying therapies; and delpacibart-zotadirsen (del-zota) in Phase II development for Duchenne muscular dystrophy (DMD), a severe, early-onset disease marked by progressive muscle damage and reduced life expectancy. The FORTITUDE Phase I/II study (NCT05747924) is a randomized, double-blind, placebo-controlled clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of del-brax in 90 patients with FSHD.

The Phase I/II trial has three dose cohorts. The first two dose escalation cohorts A & B evaluated del-brax 2 mg/kg or 4 mg/kg versus placebo and were designed to assess safety as well as inform the dose and dose regimen of del-brax. Topline results from these two initial cohorts were presented at the 32 FSHD International Research Congress in June 2025.

Based on these results, the del-brax 2 mg/kg dose every 6 weeks was selected for Cohort C and the Phase III study. Cohort C, a biomarker cohort, assessed the impact of del-brax 2 mg/kg every 6 weeks versus placebo for 12 months in 51 FSHD patients aged 16-70. The primary endpoint of the study cohort was change in plasma concentration of KHDC1L, a DUX4-regulated circulating biomarker.

The key secondary endpoint was change from baseline in the levels of creatine kinase, a marker of muscle damage. FORTITUDE-3 (NCT07038200), a randomized, double-blind, placebo-controlled Phase III study evaluating the efficacy and safety of del-brax, is currently enrolling 200 patients with FSHD aged 16-70 years. The primary endpoint is quantitative muscle testing (QMT) in the US and the 10-meter walk/run test (10MWRT) in Europe.

Secondary endpoints include additional clinical functional measures, patient-reported outcomes on signs and symptoms of FSHD, and biomarkers. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and is caused by aberrant expression of the DUX4 gene. The rare neuromuscular disease is estimated to affect between 45,000 to 87,000 people in the US and EU.

People with FSHD typically begin to experience symptoms in their teenage or early adult years, characterized by progressive muscle weakness, pain, fatigue and disability. The disease leads to a steady loss of independence, with 20% of patients becoming wheelchair dependent. There are no currently approved therapies for FSHD.