A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects

Abstract

In Duchenne muscular dystrophy (DMD), NF‐κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT‐1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF‐κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF‐κB upon intracellular cleavage to these bioactive components. Preclinical data demonstrate disease‐modifying activity in DMD animal models. Three placebo‐controlled studies in adult subjects assessed the safety, pharmacokinetics, and pharmacodynamics of single or multiple edasalonexent doses up to 6000 mg. Seventy‐nine adult subjects received edasalonexent, and 25 received placebo. Pharmacokinetic results were consistent with the intracellular cleavage of edasalonexent to its active components. Food increased plasma exposures of edasalonexent and salicyluric acid, an intracellularly formed metabolite of salicylic acid. The NF‐κB pathway and proteosome gene expression profiles in peripheral mononuclear cells were significantly decreased (P = .02 and P = .002, respectively) after 2 weeks of edasalonexent treatment. NF‐κB activity was inhibited following a single dose of edasalonexent but not by equimolar doses of salicylic acid and DHA. Edasalonexent was well tolerated, and the most common adverse events were mild diarrhea and headache. In first‐in‐human studies, edasalonexent was safe, well tolerated, and inhibited activated NF‐κB pathways, suggesting potential therapeutic utility in DMD regardless of the causative dystrophin mutation, as well as other NF‐κB–mediated diseases.

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

“…Our data further provide a novel understanding of E 2induced apoptosis through extensive interactions of ERa with inflammation-and stress-associated transcription factors, such as NF-kB and PPARg (15,16,27), which facilitates apoptosisassociated inflammation and stress after long-term E 2 deficiency. Importantly, these transcription factors are also therapeutic targets for different diseases (51)(52)(53). Together, this study not only supports the deployment of antiglucocorticoids to enhance sex steroid-induced apoptosis in cancer therapy, but also provides an insight into the mechanism of MPA with glucocorticoid activity to increase breast cancer incidence in the WHI.…”

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

“…The 24-hour plasma exposures at this dosage were 450 and 270 ng hr/ml for edasalonexent and CAT-1041, respectively. These values are at the lower end of clinical exposures observed in phase 1 studies in adults and boys with DMD (30), suggesting that efficacy is obtained in the mdx mouse at clinically relevant exposures. Moreover, the exposure of edasalonexent was 7.2-fold greater in the gastrocnemius muscle compared with plasma and 4.0-fold higher in muscle than plasma for CAT-1041, demonstrating that both molecules are able to effectively reach and accumulate in skeletal muscle.…”

“…An attractive feature of the compounds used in the current study is that they are orally bioavailable small molecules with low risk of toxicity that exhibit substantial NF-κB inhibitory effects and demonstrate the capacity to improve the dystrophic muscle phenotype in 2 animal models, with no signs of adverse events. In fact, a recently completed phase 1 trial with edasalonexent demonstrated high safety profiles in subjects after 2 weeks of administration (30), with plasma exposure levels that exceeded those observed in mice.…”

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice

“…17,18 Regulatory T cells have been shown to block and/or ameliorate dystrophic symptoms in mouse and canine DMD models. 7,17,[19][20][21][22][23][24][25][26] The nuclear pore functions as a key regulator of intracellular molecules such as proteins, RNA molecules, and ions. 27,28 The nuclear pore consists of various regulatory proteins called nucleoporins that together form the nuclear pore complex (NPC).…”