Novartis' Del-Brax Hits Primary Biomarker Endpoint in Phase I/II FSHD Trial, Paving Way for First Disease-Modifying Therapy
Key Insights
The FORTITUDE Phase I/II biomarker cohort met its primary endpoint of reducing KHDC1L (search) levels and key secondary endpoint of lowering creatine kinase in FSHD patients.
Del-brax, an investigational antibody oligonucleotide conjugate (AOC), is designed to suppress aberrant DUX4 (search) expression, the root cause of FSHD.
The validated 2 mg/kg every-6-weeks dosing regimen is now being evaluated in the ongoing Phase III FORTITUDE-3 trial enrolling 200 patients.
Novartis announced on June 11, 2026 that the biomarker cohort of its FORTITUDE Phase I/II study of delpacibart braxlosiran (del-brax) met its primary and key secondary endpoints, demonstrating reductions in KHDC1L (search) (cDUX) and creatine kinase biomarker levels in patients with facioscapulohumeral muscular dystrophy (search) (FSHD). The results indicate both strong target engagement and a reduction in muscle damage, marking a significant step toward what could become the first disease-modifying treatment for this progressive and irreversible neuromuscular disease.
Del-brax is an investigational antibody oligonucleotide conjugate (AOC), a new class of RNA therapeutics that combines the tissue specificity of monoclonal antibodies with the precision of oligonucleotides. The AOC platform enables targeted delivery of siRNA to suppress DUX4 (search) expression in muscle cells that have been historically difficult to reach therapeutically. Del-brax is currently the only investigational agent in clinical studies showing disease-modifying potential for FSHD.
"The FORTITUDE biomarker cohort data importantly replicate the target engagement and downstream muscle protection seen with del-brax in earlier dose-escalation cohorts. These results validate the dosing regimen implemented in our Phase III trial and lend further evidence of the potential for del-brax to have a significant impact for people with FSHD," said Nazem Atassi, Global Head, Neuroscience and Gene Therapy Development at Novartis. "We are now evaluating the totality of the biomarker and clinical data and look forward to discussions with global regulatory agencies as we work with urgency to advance the development of del-brax for patients in need."
FORTITUDE Trial Design and Results
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 trial comprises three dose cohorts.
The first two dose-escalation cohorts, A and B, evaluated del-brax at 2 mg/kg or 4 mg/kg versus placebo to assess safety and inform dose selection. Topline results from these cohorts were presented at the 32nd FSHD International Research Congress in June 2025. Based on those findings, the 2 mg/kg dose administered every six weeks was selected for Cohort C and the Phase III program.
Cohort C, the biomarker cohort, assessed the impact of del-brax 2 mg/kg every six weeks versus placebo over 12 months in 51 FSHD patients aged 16 to 70. The primary endpoint was change in plasma concentration of KHDC1L (search), a DUX4 (search)-regulated circulating biomarker. The key secondary endpoint measured change from baseline in creatine kinase levels, a well-established marker of muscle damage. Both endpoints were met, with the safety profile remaining consistent with previous results.
Phase III Program Underway
FORTITUDE-3 (NCT07038200), a randomized, double-blind, placebo-controlled Phase III study, is currently enrolling 200 patients with FSHD aged 16 to 70 years. The primary endpoint differs by region: quantitative muscle testing (QMT) in the United States 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 biomarker assessments.
Regulatory and Pipeline Context
Del-brax has received FDA Orphan Drug and Fast Track designations, as well as EMA Orphan Drug designation. Novartis plans to engage global regulatory authorities on the Phase I/II data as the Phase III trial progresses.
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. The acquisition also included delpacibart-etedesiran (search) (del-desiran) in Phase III development for myotonic dystrophy type 1 (search) (DM1) and delpacibart-zotadirsen (search) (del-zota) in Phase II development for Duchenne muscular dystrophy (search) (DMD). Together, these programs build on Novartis' established expertise in spinal muscular atrophy, creating what the company describes as an industry-leading neuromuscular pipeline.
FSHD Disease Background
Facioscapulohumeral muscular dystrophy (search) is one of the most common forms of muscular dystrophy, caused by aberrant expression of the DUX4 (search) gene. The rare neuromuscular disease is estimated to affect between 45,000 and 87,000 people in the US and EU. Symptoms typically begin in the teenage or early adult years, characterized by progressive muscle weakness, pain, fatigue, and disability. The disease leads to a steady loss of independence, with approximately 20% of patients becoming wheelchair dependent. Currently, no approved therapies exist for FSHD.