The investigational treatment edasalonexent was well-tolerated, led to no safety issues, and blocked a crucial muscle disease protein in boys with Duchenne muscular dystrophy(DMD), according to part 1 results of a Phase 1/2 trial.
The study, “Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-κB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy,” was published in the Journal of Neuromuscular Diseases.
Edasalonexent is an oral small molecule being developed by Catabasis Pharmaceuticalsfor all DMD patients, regardless of mutation in the DMD gene. It blocks the NF-κB protein, a transcription factor that regulates gene expression (protein production). Chronic activation of NF-κB drives muscle degeneration and suppression of muscle regeneration in DMD, and links the characteristic loss of the protein dystrophin to disease progression.
Edasalonexent contains salicylic acid and the omega-3 fatty acid docosahexaenoic acid, two active substances bound to produce a unique molecule. Both block NF-kB independently, but their combination is much more potent than either molecule alone, according to Catabasis.
In part 1 of the Catabasis-sponsored MoveDMD Phase 1/2 study (NCT02439216), 17 boys (mean age of 5.5 years, ranging from 4–7 years) who had never taken steroids were given 17, 33, or 67 mg/kg/day of the therapy on days 1 and 7, and 33, 67, or 100 mg/kg/day on days 2 to 6. At the start of the study, the boys showed reduced walking ability, endurance, and quality of life compared with healthy controls.
All doses were well-tolerated with no serious side effects, dosing interruptions, reductions, or treatment discontinuations due to side effects. Twelve patients reported treatment-emergent side effects, mostly mild gastrointestinal complaints.
One-week treatment with the two higher doses (67 and 100 mg/kg/day) significantly lowered the expression of NF-κB-regulated genes, as measured by whole-blood sequencing of messenger RNA — generated from DNA in protein production. Edasalonexent also decreased the levels of serum proteins that originate from damaged muscles.
The data further revealed that exposure to edasalonexent was greater with a high-fat versus a low-fat meal, which was in line with data from healthy adults, the scientists noted.
“In addition to being well tolerated in pediatric patients with DMD, our Phase 1 data demonstrated that edasalonexent (CAT-1004) inhibited NF-κB,” Joanne Donovan, MD, PhD, Catabasis’ CEO, said in a press release. “This would mean that edasalonexent has the potential to limit disease progression for all patients affected by DMD.”
“This shows that with short-term dosing, edasalonexent can directly reduce the levels of elevated NF-κB in circulating DMD mononuclear cells prior to any changes observable in muscles,” Donovan added. Peripheral blood mononuclear cells include lymphocytes and monocytes.
“These results support further clinical development of edasalonexent,” the study stated.
Erika Finanger, MD, the principal investigator for MoveDMD and a professor of pediatrics at the School of Medicine at Oregon Health & Science University, said: “The data from the Phase 1 MoveDMD clinical trial reinforce the good tolerability and safety profile of edasalonexent that we have now also observed in the Phase 2 trial and open-label extension.”
Results from part 2 and the extension of the study revealed that boys receiving edasalonexent grew normally, and showed both preserved muscle function and slowed disease progression. Over 72 weeks of treatment, the boys’ overall body mass index reduced from the 70th to the 55th percentile, closer to the average body mass index of healthy boys in the same age range.
Previous findings from MoveDMD showed reduced inflammation and muscle fat accumulation with edasalonexent treatment.
According to Donovan, the therapy’s potential for all types of DMD suggests it could also be used in combination with other treatments, including gene therapy approaches being developed. Blockage of NF-κB may also have disease-modifying effects, she added.
Finanger is also the principal investigator for the PolarisDMD trial (NCT03703882), a global Phase 3 study of edasalonexent in boys with DMD, which is currently recruiting participants at 17 sites across the U.S., Canada, and Australia. Information on study locations, including those yet to open, and contacts is available here.
PolarisDMD is intended to support an application for edasalonexent’s commercial registration. Its primary goal is to measure changes in the North Star Ambulatory Assessment score of muscle function after 12 months of treatment. Secondary objectives include other tests of muscle function, and measures of growth, and cardiac and bone health. After a placebo-controlled period of one year, the participants will enter an extension study where all will receive edasalonexent.
“I am pleased to continue to evaluate edasalonexent as a potential novel therapy for those affected by Duchenne, and I am excited to participate in the Phase 3 Polaris DMD study,” Finanger said.
Of note, six of the MoveDMD study’s authors are employees of Catabasis. Two are principal investigators in clinical trials, received financial support for the study, and served as advisory board members for the company. Three others received financial support from Catabasis, and another author is a consultant and has served as an advisory board member for the company.