FDA Accelerated Approval Open for FSHD Agent Del-Brax, With Newly Initiated Phase 3 Study to Confirm Efficacy

Sarah Boyce

In a number of company updates, Avidity Biosciences announced the FDA’s openness for an accelerated approval for its investigational agent delpacibart braxlosiran (del-brax) as a potential treatment for facioscapulohumeral muscular dystrophy (FSHD). The company has also initiated its phase 3 FORWARD study, a confirmatory, large-scale trial further testing the agent’s efficacy and safety, that will be used as supportive evidence for a future regulatory submission.¹

FORWARD, a placebo-controlled, double-blind study lasting 18 months, is expected to include 200 patients with FSHD, aged 16-70, across 45 sites in the U.S., Canada, Europe, and Japan. Currently, quantitative muscle testing (QMT) is the listed as the study’s primary end point; however, Avidity and the FDA are also aligning on a validated surrogate end point to potentially shorten the time required prior to receiving approval.

Del-brax, an agent designed to treat the underlying cause of FSD by directly targeting the disease-causing gene, double homeobox 4 (DUX4), will be administered every 6 weeks in doses of 2 mg/kg in the study. The study will include several key FSHD-related end points that test functional mobility, such as the 10-Meter Walk-Run test and Timed Up and Go, as well as strength, using QMT total score. Investigators will also assess numerous patient-reported outcomes and decrease in KHDC1L, a novel, circulating biomarker.

"Our regulatory and clinical development progress announced today reflect our continued leadership in rare neuromuscular diseases and bring us a step closer to providing a treatment option to the FSHD community that could meaningfully impact their disease," Sarah Boyce, president and chief executive officer at Avidity, said in a statement.¹ "We have confirmed with the FDA that the accelerated approval pathway is open for del-brax. In addition, we have initiated our global confirmatory Phase 3 study intended to support our global approval strategy for del-brax."

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FORWARD also includes an open-label extension for any enrolled patients, regardless of whether they initiated with del-brax or placebo. In addition, the trial comes with a flexible design that will allow Avidity to gather additional data from the ongoing phase 1b/2a FORTITUDE biomarker cohort and elevate any of these measures to the primary end point.

FORTITUDE, a randomized, placebo-controlled study of del-brax in 90 patients with FSHD, primarily focuses on safety, tolerability, pharmacokinetics, and pharmacodynamics. The trial incorporates several biomarkers, including DUX4-regulated muscle and circulating markers, as well as MRI measures of muscle volume and composition.

Initial 4-month Data from FORTITUDE presented at the 2024 FSHD Society International Research Congress showed that treatment with del-brax led to a pronounced reduction in DUX4 regulated genes, the root cause of FSHD. In the smaller subgroup of patients in the 2 mg/kg cohort, investigators observed mean reductions of more than 50% in DUX4 regulated genes across multiple panels for DUX4 regulated gene expression in muscle. In addition, the study reported mean reductions of at least 25% in novel circulating biomarker and creatine kinase levels.²

Overall, patients treated with del-brax showed trends toward functional improvement, including increased strength in both upper and lower limb muscles, along with positive signals in patient- and clinician-reported outcomes. The therapy was well tolerated, with no serious adverse events or treatment discontinuations reported. All adverse events were mild or moderate in severity. Notably, treated patients demonstrated improved muscle function compared with both placebo and data from the ReSolve natural history study.

REFERENCES
1. Avidity Biosciences Announces the Accelerated Approval Regulatory Pathway in the U.S. is Open for Del-Brax and Initiates the Global, Confirmatory Phase 3 FORWARD™ Study in FSHD. News release. Avidity Biosciences. June 9, 2025. Accessed June 13, 2025. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-the-accelerated-approval-regulatory-pathway-in-the-us-is-open-for-del-brax-and-initiates-the-global-confirmatory-phase-3-forward-study-in-fshd-302476170.html
2. Avidity Announces Unprecedented AOC 1020 Data from Phase 1/2 FORTITUDE™ Trial Demonstrating Greater Than 50 Percent Reduction in DUX4 Regulated Genes and Trends of Functional Improvement in People Living with Facioscapulohumeral Muscular Dystrophy. News release. Avidity Biosciences. June 12, 2024. Accessed June 13, 2025. https://www.prnewswire.com/news-releases/avidity-announces-unprecedented-aoc-1020-data-from-phase-12-fortitude-trial-demonstrating-greater-than-50-percent-reduction-in-dux4-regulated-genes-and-trends-of-functional-improvement-in-people-living-with-facioscapulohumeral-m-302170099.html