Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-κB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy

Abstract

Background: Edasalonexent is an orally administered small molecule designed to inhibit NF- κ B, which is activated from infancy in Duchenne muscular dystrophy and is central to causing muscle damage and preventing muscle regeneration. Objective: Evaluate the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of three doses of edasalonexent in ambulatory males ≥4 to <8 years of age with genetically confirmed Duchenne muscular dystrophy. Methods: This was a 1-week, open-label, multiple-dose study with 3 sequential ascending doses (33, 67 and 100 mg/kg/day) of edasalonexent administered under different dietary conditions to 17 males with a mean age of 5.5 years. Results: All doses of edasalonexent were well tolerated, with no serious adverse events, no drug discontinuations and no dose reductions. The majority of adverse events were mild, and the most common adverse events were gastrointestinal (primarily diarrhea). Edasalonexent was rapidly absorbed with peak levels observed 2–6 hours after dosing and exposures appeared to increase nearly proportionally to dose for the 2 lower and all 3 doses under low-fat and high-fat meal conditions, respectively. Only minor plasma accumulation of edasalonexent was observed with 7 days of dosing. After treatment with edasalonexent for 7 days, levels of NF- κ B-regulated genes and serum proteins were decreased. Conclusions: This first report of edasalonexent oral administration for one week in male pediatric patients with Duchenne muscular dystrophy showed that treatment was well tolerated and inhibited NF-kB pathways.

Glucocorticoids counteract hypertrophic effects of myostatin inhibition in dystrophic muscle

“…As the identification of effective small molecule therapeutics to combat inflammation, fibrosis, and muscle wasting in DMD and BMD will continue to remain an unmet medical need, our findings highlight the importance of evaluating candidate therapeutic efficacy in combination with standard-of-care therapies. Additionally, these data further support the rationale to explore alternative standard-of-care regimens for dystrophinopathy patients other than chronic glucocorticoids, such as intermittent glucocorticoid dosing (12) and/or nonsteroidal NF-κB inhibitors (68,69), both of which demonstrate efficacy and safety without promoting skeletal muscle atrophy.…”

AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy

“…five patients for the AMPK activator, metformin) or the short‐term duration of the treatment (i.e. 1 week for the NF‐κB inhibitor, CAT‐1004). Trials with the utrophin up‐regulator (Ezutromid®) turned out to be disappointing and have been recently stopped (http://www.musculardystrophynews.com).…”

Targeted Treatments for Inherited Neuromuscular Diseases of Childhood

“…Chronic activation of nuclear factor (NF) kB drives muscle degeneration and suppresses muscle regeneration in DMD. 27 Edasalonexent inhibits NF-kB-dependent inflammatory responses and downstream proinflammatory genes, and therefore it may play a role in replacing steroids for these patients. A phase 1/2 study showed it was well tolerated and inhibited the NF-kB pathways, 27 and a phase 3 study is currently underway (NCT03703882).…”

“…27 Edasalonexent inhibits NF-kB-dependent inflammatory responses and downstream proinflammatory genes, and therefore it may play a role in replacing steroids for these patients. A phase 1/2 study showed it was well tolerated and inhibited the NF-kB pathways, 27 and a phase 3 study is currently underway (NCT03703882). In August 2018, the development of domagrozumab, a monoclonal antibody inhibitor of myostatin, was terminated after the drug did not meet the primary efficacy end point in a phase 2 clinical trial.…”