A Novartis RNA therapy reduced blood levels of a protein that’s a biological indicator of a particular form of muscular dystrophy, clinical trial results that could support an application seeking a speedy regulatory approval of potentially the first treatment for this rare, inherited muscle disorder.
The disease, facioscapulohumeral muscular dystrophy (FSHD), stems from genetic mutations that lead to activation of the DUX4 gene, which produces proteins that damage muscle. The standard of care is symptom management for the progressively worsening muscle weakness that for many patients means eventually requiring the use a wheelchair.
Novartis’s experimental FSHD therapy, delpacibart braxlosiran (del-brax), is part of an emerging class of RNA therapies called antibody oligonucleotide conjugates (AOCs). These treatments leverage the targeting ability of an antibody to deliver to cells an oligonucleotide that modifies RNA function. Del-brax is designed to reduce expression of DUX4 messenger RNA in order to tamp down the DUX4 gene’s expression of muscle-damaging proteins.
Without reporting specific figures, Novartis said Thursday that del-brax led to reductions in blood levels of cDUX, meeting the main goal of the biomarker cohort in the placebo-controlled Phase 1/2 study, named FORTITUDE. The cDUX protein is a biomarker of FSHD. Avidity Biosciences, the company that originally developed del-brax, had previously reached agreement with the FDA that cDUX reduction could serve as a surrogate endpoint to support an application seeking accelerated regulatory approval. Novartis also said the latest results show reduction in levels of creatine kinase, a protein that’s a biomarker of muscle damage, meeting a key secondary trial goal.
Avidity had previously reported Phase 1/2 results showing del-brax reduced DUX4 expression. These initial results also showed signs of improving muscle function. Last year, Avidity started a placebo-controlled Phase 3 clinical trial that could serve as del-brax’s confirmatory study, if the therapy receives regulatory approval. In addition to testing for reduction of cDUX, the key measures for this study include assessments of functional mobility and muscle strength. All trial participants have the option to enroll in an open-label extension study during which everyone will receive the study drug.
In Thursday’s announcement, Novartis’s Nazem Atassi, global head, neuroscience and gene therapy development, said the company is evaluating the totality of the del-brax data to date as it prepares to discuss them with regulatory authorities around the world.
“The FORTITUDE biomarker cohort data importantly replicate the target engagement and downstream muscle protection seen with del-brax in earlier dose-escalation cohorts,” Atassi said. “These results validate the dosing regimen implemented in our Phase 3 trial and lend further evidence of the potential for del-brax to have a significant impact for people with FSHD.”
Neuroscience is one of Novartis’s core therapeutic areas, but it’s the smallest measured by revenue. The pharma company has turned to business development to grow its neuroscience pipeline and portfolio. Last fall, Novartis agreed to pay $12 billion to buy Avidity.
In addition to del-brax, the Avidity acquisition brought two other clinical-stage AOCs for muscle diseases: delpacibart zotadirsen for Duchenne muscular dystrophy and delpacibart etedesiran for myotonic dystrophy type 1 (DM1). At the time of the deal, Novartis CEO Vas Narasimhan said all three are expected to launch by 2030, with the FSHD and DM1 therapies expected to become blockbuster products.
Photo: Sebastien Bozon/AFP, via Getty Images
