MoveDMD (NCT02439216) is a three-part, ongoing clinical trial investigating an oral drug — edasalonexent (CAT-1004) — as a potential therapy in boys, ages 4 to 7, with Duchenne muscular dystrophy (DMD).
The drug targets NF-kB, a protein activated in DMD and shown to promote the disease by driving inflammation, muscle degeneration, and preventing muscle regeneration. Two distinct doses of the drug — 67 mg per kg of body weight a day (mg/kg/day), and 100 mg/kg/day — were tested over a 12-week period.
Results from Part A and Part B (both completed) showed that, while all the drug doses were well-tolerated with no major safety signals reported, the treatment led to no statistical improvement in lower leg muscle function by magnetic resonance imaging (MRI) after 12 weeks. That was the trial’s primary efficacy endpoint.
We asked Dr. Jill C. Milne, PhD, co-founder and chief executive officer of Catabasis Pharmaceuticals, how these results affected the study goals.
“While the MRI T2 primary endpoint, an exploratory early biomarker, was not met, improvements were seen across the functional assessments,” Milne said in the email interview. “In the placebo-controlled analysis, the combined edasalonexent groups vs. placebo were numerically better for 5 of the 6 function-associated endpoints, all not statistically significant.”
Milne added that researchers “used MRI T2 as the primary endpoint to serve as an early biomarker for demonstrating a benefit on muscle composition that potentially would allow us to see an effect of edasalonexent at 12 weeks of treatment, as has been seen by others with corticosteroids.”
The trial included as secondary endpoints other functional parameters: the 10-meter walk/run, a four-stair climb, the time it takes boys to stand, North Star Ambulatory Assessment (NSAA) scores; muscle strength, and MRI fat fraction. Additionally, researchers analyzed Pediatrics Outcomes Data Collection Instrument (PODCI).
“The NSAA is a clinician‑reported outcome instrument designed to measure gross motor function. During this assessment, patients are asked to perform 17 different functional activities, including a 10‑meter walk/run, rising from sit to stand, standing on one leg, climbing and descending a step, rising from the floor, lifting the head, standing on heels, and jumping. The PODCI is parent-reported assessment of function containing 86 questions. Muscle strength was assessed through measurement of knee extension and plantar flexion,” Milne said.
In fact, the researchers observed a tendency for improvements across many of the secondary endpoints, but “the trial was not powered for changes in these secondary endpoints, and statistically significant changes were not generally seen in these measures.”
Researchers are, however, optimistic about these results, Milne said, explaining, “We believe the data to-date are compelling — showing consistent improvements across functional assessments in boys after 12 weeks of treatment with edasalonexent using two different prespecified analyses and we are excited about these results.”
One important point was related to the number of NF-kB target genes whose activity was affected by edasalonexent. The researchers observed that, “a set of 200 NF-kB genes were evaluated and were significantly inhibited in the 67 and 100 mg/kg/day dose groups in Part A of the MoveDMD trial.” Most importantly, “a dose-proportional decrease in NF-kB activity was seen,” Milne said.
Part C is ongoing, and will evaluate edasalonexent’s long-term safety and efficacy. First set up to last 36 weeks, it was later extended, and participants are now being treated for 60 weeks beyond the study’s 12-week placebo-controlled evaluation in Part B. This new period will allow all participants to continue to received the drug. As Milne explained, “the boys participating in Part C did not all start at the same time. We extended Part C of the MoveDMD trial for an additional 24 weeks beyond the original 36 week open-label extension so that the first boys that started the open-label extension in July last year could to continue to receive edasalonexent treatment.”
Interim Part C results are expected in the third quarter of 2017, reporting data after 24 weeks of treatment, but Milne noted that “the trial’s third phase was not designed to provide statistical significances.” Rather, she said, results will allow researchers to “gain information on key functional assessments as well as on longer-term safety and tolerability.”
Current DMD therapeutic research has many investigation angles, one of which is using a strategy, called oligonucleotide-based exon skipping, to restore dystrophin expression. When asked about the potential of combining this approach with a drug therapy such as with edasalonexent, Milne said the possibility is being explored with another pharmaceutical company, Sarepta. In fact, their joint work already demonstrated that combining an exon-skipping approach with edasalonexent increased dystrophin protein expression in a mouse model of DMD.
“External researchers have previously reported that activated NF-kB can suppress dystrophin expression via the regulation of microRNAs [molecules that regulate gene expression] in muscle cells,” Milne added, “and this could be the mechanism by which edasalonexent was observed to increase dystrophin expression when combined with a dystrophin exon-skipping agent. Therefore, edasalonexent may have the ability to increase dystrophin expression independent of how the dystrophin is produced.”
So, “while we are currently developing edasalonexent as a monotherapy in DMD, we also believe that it has potential as part of a combination approach with therapies that target dystrophin,” she concluded.