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

Abstract

Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD).

Objective: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 - < 8 years old with DMD due to any dystrophin mutation examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52 weeks.

Methods: Endpoints were changes in the North Star Ambulatory Assessment (NSAA; primary) and timed function tests (TFTs; secondary). Assessment of health-related function used the Pediatric Outcomes Data Collection tool (PODCI).

Results: One hundred thirty one patients received edasalonexent (n = 88) and placebo (n = 43). At week 52, differences between edasalonexent and placebo for NSAA total score and TFTs were not statistically significant, although there were consistently less functional declines in the edasalonexent group. A pre-specified analysis by age demonstrated that younger patients (≤6.0 years) showed more robust and statistically significant differences between edasalonexent and placebo for some assessments. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly involved the gastrointestinal system (primarily diarrhea).

Conclusions: Edasalonexent was generally well-tolerated with a manageable safety profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. (NCT03703882).

Keywords: CAT-1004; Duchenne muscular dystrophy; NF-κB; age effects; edasalonexent.

Conflict of interest statement

RSF, CMM, EF, ENK, KM, WM, JS, JN, HM, GM, CT, MR, DOR, WMF, MT, WBB, CTN, KV, JJ, HP and all additional members of the Polaris study group are principal investigators in clinical trials for Catabasis and have received research support from Catabasis. HLS, ME and KW have received research support from Catabasis. RSF, CMM, HLS, and ME are consultants for Catabasis. MM, JM, and JMD were employees/contractors of Catabasis Pharmaceuticals, Inc. at the time of the study. All authors participated in the conduct of the study as well as manuscript planning, preparation and editing. In addition, RSF, CMM, HLS, MM, JM and JMD participated in the design and analysis of the study. All authors approved the final manuscript.

Figures

Fig. 1

Study Design and Disposition of Patients. *Siblings of previously randomized patients. **Among randomized patients, four received eteplirsen and three had no post baseline NSAA, yielding a full analysis set of 119 patients, 81 in the edasalonexent group and 38 in the placebo group.

Fig. 2

NSAA Total Score (mean±SE) change from baseline overall population (A) and by age group for patients ≤6.0 years (B) and > 6.0 years (C).

Fig. 3

Timed Function Assessments. Change from baseline (mean±SE) for timed function test speed (sec–1) and the absolute times (sec) for the overall population and age groups patients ≤6.0 years and > 6.0 years. (A) Time to stand from supine speed change from baseline (B) Time to stand from supine absolute time C. 4-stair climb change from baseline D. 4-stair climb absolute time. E. 10MRWT speed change from baseline. F. 10MRWT absolute time.

Fig. 4

PODCI Scales for the Overall Population and by Age Group for Patients ≤6.0 years and > 6.0 years.

Fig. 5

Analysis of Impact of Baseline Age on NSAA Total Score. Change from baseline in total NSAA (mean±SE) at 52 weeks by age at enrollment (A), and baseline NSAA total score (mean±SD) by age at enrollment (B).