Del-zota for DMD awarded FDA breakthrough therapy designation
Developer on track to submit approval application by year's end
The U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation to delpacibart zotadirsen, known as del-zota, as a treatment for people with Duchenne muscular dystrophy (DMD) amenable to exon 44 skipping.
This designation is intended to speed the development and review of therapies for serious conditions when early clinical evidence is suggestive of a substantial improvement over available alternatives.
Avidity Biosciences, the company developing del-zota, said it’s planning to submit an application to the FDA seeking regulatory approval by year’s end. Indeed, preparations for a U.S. launch of del-zota — if the therapy is approved — are already underway, according to a company press release.
“Breakthrough therapy designation further underscores the FDA’s appreciation for the significant potential of del-zota to address the underlying cause of DMD44 and the urgent need to bring innovative treatment options to the DMD community,” said Steve Hughes, MD, chief medical officer at Avidity.
DMD is caused by mutations in the DMD gene, which contains instructions for cells to manufacture the protein dystrophin. Dystrophin helps protect muscles from damage, and the lack of functional protein in DMD leads to characteristic symptoms of progressive muscle weakness and wasting.
Genes, including DMD, typically contain segments called exons, which encode information about how to produce a protein. Exon-skipping therapies allow cells to mask specific exons in the DMD gene sequence using short strands of nucleic acids that bind to specific regions on the pre-mRNA molecule that is made from DNA. This results in a shorter but functional version of the targeted protein.
Del-zota is one such therapy. It uses an antibody to target muscle cells and a molecule called a phosphorodiamidate morpholino oligomer, or PMO, to skip exon 44 of the DMD gene.
Del-zota use showed benefits for DMD patients in Phase 1/2 trial
Top-line data from the Phase 1/2 EXPLORE44 trial (NCT05670730) showed favorable safety and tolerability, as well as increases in dystrophin production and a decrease in levels of a biomarker of muscle damage called creatine kinase.
In the first part of EXPLORE44, investigators administered single doses of the medication or a placebo to healthy volunteers. The second part involved males with DMD amenable to exon 44 skipping, who received three doses of del-zota or the placebo at either 5 mg/kg every six weeks, or 10 mg/kg every eight weeks. Del-zota was administered via intravenous, or into-the-vein, infusion.
Patients in the del-zota group experienced a significant increase in dystrophin production, restoring total dystrophin up to 58% of normal levels. Creatine kinase decreased by more than 80%, resulting in levels near normal, according to the company.
Del-zota also increased exon skipping by about 40%, a statistically significant change. Most treatment-emergent side effects were mild or moderate, with favorable safety seen with both doses.
With the remarkable, consistent improvements we’ve seen in multiple biomarkers including dystrophin in the Phase 1/2 EXPLORE44 trial, we are focused on bringing del-zota to people living with DMD44 as quickly as possible and remain on track for our planned [biologics license application] submission at year end 2025.
Based on these results, the company chose the lower (5 mg/kg), more frequent dosing option for future studies — and the planned biologics license application (BLA) submission to the FDA.
“With the remarkable, consistent improvements we’ve seen in multiple biomarkers including dystrophin in the Phase 1/2 EXPLORE44 trial, we are focused on bringing del-zota to people living with DMD44 as quickly as possible and remain on track for our planned BLA submission at year end 2025,” Hughes said.
Avidity also intends to release top-line results from the ongoing EXPLORE44 open-label extension study (NCT06244082) in the fourth quarter of the year. This study involves 39 participants, all treated every six weeks for nearly two years. Preliminary data showed sustained reductions in creatine kinase with up to a year of treatment.
In addition to del-zota for DMD, Avidity is developing therapies for myotonic dystrophy type 1 and facioscapulohumeral muscular dystrophy, also forms of muscular dystrophy (MD). Among all MD types, DMD is the most common.
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