An experimental therapy increased dystrophin levels to approximately 30% of normal and substantially reduced markers of muscle damage in patients with Duchenne muscular dystrophy (DMD), according to findings from a small clinical trial published in The Lancet Neurology. Whether those changes translate into improved muscle function remains unclear.
DMD causes progressive muscle weakness due to a lack of functional dystrophin, a protein that helps protect muscle cells from damage. The drug, delpacibart zotadirsen (del-zota), aims to restore some of that protein using an approach called exon 44 skipping.
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The DMD gene contains 79 exons, sections of genetic instructions used to produce dystrophin. When certain exons are missing, those instructions can become misaligned. Skipping exon 44 can bring the instructions back into alignment for patients with certain mutations, allowing their cells to produce a shorter but potentially functional version of the protein. In the trial, 62% of participants had a deletion of exon 45, one of the mutations that can be addressed through this approach.
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The EXPLORE44 trial began with 45 healthy adult men, testing the drug’s initial safety and tolerability. Researchers then enrolled 26 boys and young men with DMD, ages 7 to 26, to evaluate the treatment in patients with mutations amenable to exon 44 skipping. Of these, 19 were assigned to receive del-zota and seven to receive a placebo.
Patients who received the drug had three intravenous infusions at either 5 mg/kg every six weeks or 10 mg/kg every eight weeks. Safety was the trial’s focus, but researchers also measured changes in dystrophin levels.
The results showed substantial increases in dystrophin expression. Levels rose from 6.7% to 31.6% of normal in the lower-dose group and from 4.1% to 29.8% in the higher-dose group. These represented mean increases of 25.0 and 25.6 percentage points, respectively. Patients receiving placebo showed no meaningful change.
The researchers also observed sharp declines in creatine kinase (CK), an enzyme that enters the bloodstream when muscle cells are damaged. CK levels fell by an average of 79.3% in the lower-dose group and 86.7% in the higher-dose group. Other markers of muscle damage, such as myoglobin, also declined to near-normal levels.
The treatment also raised some safety concerns. Eighty-four percent of patients receiving del-zota and 86% of those receiving placebo reported adverse events. Most were mild or moderate, but two patients in the lower-dose group discontinued treatment because of adverse reactions. One experienced a serious anaphylactic reaction, while the other had a moderate infusion-related reaction. Both resolved.
Although some exploratory measures of muscle function and quality of life favored del-zota, researchers found no clear differences between the treatment and placebo groups in two often-used measures of walking ability: the six-minute walk test and the North Star Ambulatory Assessment.
The findings suggest that del-zota can increase dystrophin expression and reduce markers of muscle damage, but whether these changes translate into lasting clinical benefits remains unclear. Given the small sample size, differences in disease severity between groups and short follow-up, the findings “should be considered hypothesis-generating and warrant confirmation in larger, longer studies,” the researchers wrote.
