Novartis reported that the biomarker cohort of its FORTITUDE Phase I/II study of delpacibart braxlosiran (del-brax) in facioscapulohumeral muscular dystrophy (FSHD) met its primary and key secondary biomarker endpoints, reinforcing the program’s potential as the first disease-modifying treatment for the condition. The cohort showed reductions in KHDC1L (cDUX), a DUX4-regulated circulating biomarker, and creatine kinase levels, indicating strong target engagement and decreased muscle damage in patients with FSHD, a progressive, irreversible neuromuscular disease affecting an estimated 45,000 to 87,000 people in the US and EU. Novartis said the safety profile in this cohort was consistent with prior results and that it plans to engage global regulators on the Phase I/II data, while a Phase III trial is currently enrolling.
Del-brax is an investigational antibody oligonucleotide conjugate (AOC), part of a new class of RNA therapeutics designed to address the root cause of FSHD by suppressing aberrant DUX4 expression. The AOC platform combines the tissue specificity of monoclonal antibodies with the precision of oligonucleotides, enabling targeted delivery of siRNA to hard-to-reach muscle cells in FSHD patients. Del-brax is currently the only investigational agent with disease-modifying potential for FSHD in clinical studies and has received FDA Orphan Drug and Fast Track designations, as well as EMA Orphan Drug designation.
The FORTITUDE Phase I/II trial (NCT05747924) is a randomized, double-blind, placebo-controlled study evaluating safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of del-brax in 90 adults with FSHD. Initial dose-escalation Cohorts A and B tested del-brax 2 mg/kg and 4 mg/kg versus placebo to inform dose and regimen selection; data presented at the 32nd FSHD International Research Congress in 2025 supported selection of the 2 mg/kg every-six-weeks dose for Cohort C and the Phase III program. Cohort C evaluated del-brax 2 mg/kg every six weeks versus placebo for 12 months in 51 patients aged 16–70 years, with change in plasma KHDC1L as the primary endpoint and change in creatine kinase as the key secondary endpoint.
A separate Phase III study, FORTITUDE-3 (NCT07038200), is now enrolling 200 patients with FSHD aged 16–70 to assess the efficacy and safety of del-brax using quantitative muscle testing as the primary endpoint in the US and the 10-meter walk/run test in Europe. Secondary endpoints include additional functional measures, patient-reported outcomes on FSHD signs and symptoms, and biomarker assessments. Novartis noted that the latest biomarker results replicate target engagement and downstream muscle protection seen in earlier cohorts and validate the dosing regimen used in the Phase III trial.
Del-brax is one of three late-stage, potential first-in-class disease-modifying AOC therapies Novartis added to its neuroscience pipeline through the acquisition of Avidity Biosciences completed in February 2026. The deal also brought in delpacibart-etedesiran (del-desiran), in Phase III development for myotonic dystrophy type 1, and delpacibart-zotadirsen (del-zota), in Phase II development for Duchenne muscular dystrophy, augmenting Novartis’ existing neuromuscular portfolio built around its spinal muscular atrophy expertise.
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