Experimental drug del-brax curbs signs of muscle damage in FSHD: Study
Phase 3 trial currently recruiting people with form of muscular dystrophy
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The experimental medication delpacibart braxlosiran (del-brax) reduced biological markers of facioscapulohumeral muscular dystrophy (FSHD) disease activity in a Phase 1/2 clinical trial, meeting the study’s goals, according to developer Novartis.
Based on results from earlier parts of the trial, FORTITUDE (NCT05747924), investigators selected a dosage for this group of participants, dubbed the biomarker cohort. Intravenous (into-the-vein) infusions at this dose reduced blood markers of the abnormal protein production that leads to FSHD symptoms. Novartis is implementing the same dosing plan in an ongoing Phase 3 trial of del-brax 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,” Nazem Atassi, global head of neuroscience and gene therapy development at Novartis, said in a company press release. “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.”
FORTITUDE-3 (NCT07038200), the Phase 3 study, is currently recruiting people with FSHD ages 16 to 70. The trial has sites in the U.S. and internationally.
Data showed significant decrease in levels of protein biomarker
In FSHD, a form of muscular dystrophy, alterations in chromosome 4 cause abnormal production of the DUX4 protein, which is toxic to muscle cells. This leads to muscle weakness mainly in the face, shoulders, and upper arms.
Del-brax aims to counteract the effects of FSHD-causing mutations by turning off DUX4 production. The medication contains two components — an antibody to target a protein receptor in muscle cells and a small piece of RNA meant to reduce the activity of the DUX4 gene.
The FORTITUDE Phase 1/2 study, now complete, included 90 people with FSHD aged 16 to 70. Eligible participants could walk but had weakness in both their upper and lower body.
In the first part of the study, investigators tested two dose strengths of del-brax versus a placebo for one year (nine-month treatment and three-month follow-up). The therapy showed signs of helping improve muscle function and strength. Based on the results, the 2 mg/kg dose, given by intravenous infusion every six weeks, was selected for further testing.
Participants in the biomarker cohort again received del-brax or a placebo, with a total study duration of nearly one year. Throughout that time, the trial team performed blood tests for a protein biomarker called KHDC1L. Because DUX4 regulates KHDC1L, lower levels of blood KHDC1L may indicate less abnormal DUX4 production.
Biomarker data showed a significant decrease in KHDC1L levels in the del-brax treatment group, meeting the primary goal of the trial. Additionally, levels of creatine kinase, a marker of muscle damage, also decreased during treatment.
Safety results were consistent with previous results, according to Novartis. In earlier portions of the trial, the most common side effects included fatigue and low levels of hemoglobin, a protein that helps red blood cells transport oxygen throughout the body.
FORTITUDE results could support applications to regulatory authorities
Novartis plans to continue analyzing FORTITUDE data to support further development of del-brax.
“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,” Atassi said.
FORTITUDE-3 aims to expand on these results in a larger group of approximately 200 FSHD participants. They will receive del-brax or a placebo every six weeks for 72 weeks (slightly under 1.5 years). The primary goal in the U.S. part of the trial is to measure changes in muscle strength, as tested with the Quantitative Muscle Testing score. Investigators will also continue collecting biomarker data, and assess measures of physical function and patient-reported outcomes relevant to FSHD.
In addition to FORTITUDE-3, Novartis is sponsoring the ongoing Phase 2 FORTITUDE-OLE study (NCT06547216), open to individuals who completed the Phase 1/2 trial. Participants in this long-term extension will receive del-brax for up to 46 months, or nearly four years.
If successful, the combined FORTITUDE results could support applications to regulatory authorities for approval of del-brax. The U.S. Food and Drug Administration previously granted del-brax fast track and orphan drug designations, statuses that incentivize development of promising experimental therapies. Novartis is developing the therapy after its acquisition of Avidity Biosciences.
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