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

Hammers, David W.; Sleeper, Margaret M.; Forbes, Sean C.; Coker, Cora C.; Jirousek, Michael R.; Zimmer, Michael; Walter, Glenn A.; Sweeney, H. Lee

doi:10.1172/jci.insight.90341

Cited by 48 publications

(60 citation statements)

References 33 publications

(34 reference statements)

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“…The edasalonexent doses used in the phase 1 studies included those that will be tested on a weight‐adjusted basis in the DMD pediatric patient population. Of note, the exposures following these single and multiple doses were greater than those found to be pharmacologically active in mouse and dog models of DMD, in which edasalonexent or analogues demonstrated disease‐modifying activity . The level of NF‐κB inhibition necessary for clinical benefit in DMD patients is not known.…”

Section: Discussionmentioning

confidence: 98%

“…Long‐term administration of edasalonexent, or the related analogue CAT‐1041 in which DHA is replaced by eicosapentaenoic acid to maintain equivalent pharmacology, demonstrated several disease‐modifying characteristics. Reduction of fatigue in skeletal muscle following repeated eccentric contractions and increases in skeletal muscle mass were observed . In addition, reduction of inflammation and fibrosis resulted in increased exercise endurance in mdx mice and improved diaphragm function in both the mouse and dog DMD models …”

mentioning

confidence: 93%

“…Reduction of fatigue in skeletal muscle following repeated eccentric contractions and increases in skeletal muscle mass were observed . In addition, reduction of inflammation and fibrosis resulted in increased exercise endurance in mdx mice and improved diaphragm function in both the mouse and dog DMD models …”

mentioning

confidence: 93%

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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

Donovan

Zimmer

Offman

et al. 2017

The Journal of Clinical Pharma

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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.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 93%

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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

Donovan

Zimmer

Offman

et al. 2017

The Journal of Clinical Pharma

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“…In more recent studies of mdx mice receiving once‐weekly glucocorticoid treatment, sarcolemmal repair improved, and limited muscle atrophy was encountered, whereas daily treatment led to activation of atrophic pathways . The mechanism of action of GC may be via downregulation of nuclear factor‐κB pathways, which are known to be upregulated in boys with DMD …”

Section: Discussionmentioning

confidence: 99%

Twice‐weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy

et al. 2019

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Introduction: Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). Methods: This is a multisite, 1‐year, open‐label trial of twice‐weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4–2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley‐III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty‐three of 25 participants completed the study. Results: Treated boys gained an average of 0.5 points on the Bayley‐III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. Discussion: This study provides evidence that twice‐weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow‐up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve 59:650–657, 2019

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“…Daily GC therapy has also been observed to delay the onset of scoliosis . Although the precise mechanism by which GC exert their therapeutic effect in DMD is not known, it is presumed to be multifactorial, with increasing evidence pointing to the downregulation of the nuclear factor‐kappa light‐chain enhancer of activated B cells (NF‐κB) pathway as a predominant mechanism of action …”

mentioning

confidence: 99%

Intermittent glucocorticoid regimes for younger boys with duchenne muscular dystrophy: Balancing efficacy with side effects

McMillan

2019

Muscle and Nerve

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

Cited by 48 publications

References 33 publications

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

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

Twice‐weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy

Intermittent glucocorticoid regimes for younger boys with duchenne muscular dystrophy: Balancing efficacy with side effects

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