Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Abstract

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-< 8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T 2 relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.

A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial

“…While the functional status of those with DMD in the age range from 4 to 7 on steroids is generally acknowledged to be stable or improved as assessed by the NSAA [ 25, 34 ], patients in this trial generally declined over the 52 weeks, consistent with observations in the off-treatment period in the Phase 2 study of edasalonexent in steroid-naïve patients [ 22 ]. To our knowledge, the placebo group in the current study represents the largest observational study of the NSAA in patients aged 4 to 7 not on steroids.…”

“…In a multipart phase 1/2 trial in patients 4 to 8 years of age with DMD not on steroids (MoveDMD, NCT02439216), edasalonexent inhibited NF-κB dependent target genes after one week of dosing [ 21 ]. Statistically significant changes in MRI T2 measures known to correlate with disease progression were observed after 12 weeks and multiple subsequent time points, compared with a pretreatment period [ 22 ]. In this study there appeared to be clinically meaningful slowing of disease progression during edasalonexent treatment compared to a prior untreated observation period, with improvements in biomarkers of muscle health and inflammation [ 22 ].…”

“…Statistically significant changes in MRI T2 measures known to correlate with disease progression were observed after 12 weeks and multiple subsequent time points, compared with a pretreatment period [ 22 ]. In this study there appeared to be clinically meaningful slowing of disease progression during edasalonexent treatment compared to a prior untreated observation period, with improvements in biomarkers of muscle health and inflammation [ 22 ]. The MoveDMD study informed the design and dose selection for this phase 3 trial.…”

Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration

“…Upregulation of IL-6 promotes inflammation and reduces the muscle satellite cell populations required for muscle regeneration in DMD [23][24][25]. Therefore, multiple NF-κB inhibitors including Edasalonexent (CAT-1004) and Flavocoxid have been used to reduce inflammation in DMD and are currently in Phase 2 and Phase 3 clinical trials, respectively [26,27]. Furthermore, transient administration of a STAT3 inhibitor in mdx mice improved the overall regenerative capacity of the muscle [28].…”

Two decades of advances in muscle imaging in children: from pattern recognition of muscle diseases to quantification and machine learning approaches

“…In this disorder, we have enough data to sustain that muscle MRI is a source for valid prognostic and monitoring biomarkers [65][66][67][68] . Muscle MRI is now incorporated to several clinical trials in Duchenne muscular dystrophy [69][70][71] demonstrating a large potential of muscle MRI in clinical development of new drugs and approaches for neuromuscular imaging.…”