source: Neuromuscular Disorders
R. Finkel, K. Vandenborne, H. Sweeney, E. Finanger, G. Tennekoon, P. Shieh, R. Willcocks, S. Forbes, W. Triplett, S. Yum, M. Mancini, M. Friedman, A. Fretzen, J. Donovan
NF-κB is activated from infancy in DMD, driving inflammation, muscle degeneration and inhibiting muscle regeneration. Edasalonexent (CAT-1004), an oral small molecule inhibiting NF-κB, has shown positive preclinical effects on skeletal muscle, diaphragm and heart in DMD models. After a 1-week safety/PK study (Part A), a Phase 2 randomized, double-blind, placebo-controlled 12-week trial of 67 and 100 mg/kg/day was initiated (Part B), followed by a 60-week open-label extension study (Part C). Boys aged 4–7 with DMD not on steroids were enrolled, regardless of mutation type. 31 patients, including 16 from Part A, enrolled in Part B. MRI-T2 averaged over 5 lower leg muscles was the primary endpoint at 12 weeks; also assessed were timed function tests (TFT, 10-meter-walk/run, 4-stair-climb, time-tostand), muscle strength, PODCI and North Star ambulatory assessment (NSAA). In Part B, there was no statistically significant change in MRI T2 for pooled treatment groups vs. placebo. For edasalonexent 100 mg/kg there was consistent numerical improvement vs. placebo for TFT, NSAA, muscle strength and PODCI, while the 67 mg/kg group showed numerical improvement in 5/6 measures, although, as expected, not statistically significantly. Rates of change in functional measures from Part A to Part B baseline (control period, mean duration 8 months, off-treatment except 1 week Part A dosing) were compared with the rate of change in Part B for 12 boys enrolled in both Parts and treated with edasalonexent. For MRI T2, TFT, NSAA and PODCI, rates of decline were numerically less with edasalonexent compared to the control period. Edasalonexent was well tolerated with no safety signals observed, with most common adverse events gastrointestinal, all mild. Edasalonexent, an NF-κB inhibitor, showed encouraging improvements in functional endpoints in this Phase 2 study in young boys. A 60-week open-label extension (Part C) is ongoing and will provide additional information on longer term effects.
Nemours Children’s Hospital, USA; University of Florida, USA; Shriners Hospital for Children, USA; The Children’s Hospital of Philadelphia, USA; UCLA, USA; Catabasis Pharmaceuticals, USA; Statistical Consultant, USA