A Mixed-Method Study Exploring Patient-Experienced and Caregiver-Reported Benefits and Side Effects of Corticosteroid Use in Duchenne Muscular Dystrophy.

Background: Corticosteroids are recommended to all people with Duchenne as standard of care; patient experience data is important to guide corticosteroid decision making and as a comparator for new treatment options.

Objective: This study assesses patient and caregiver-reported benefits and side effects from corticosteroids to treat Duchenne muscular dystrophy, their importance, and satisfaction.

Methods: Using one-on-one interviews (n = 28) and an online survey (n = 236), parents and adults with Duchenne reported corticosteroid benefits and side effects rated as both experienced and important.

Assessing the ability of boys with Duchenne muscular dystrophy age 4-7 years to swallow softgel capsules: Clinical trial experience with edasalonexent.

What Is Known And Objective: There is limited information on acceptability of solid dosage forms by young patients with neuromuscular disorders such as Duchenne muscular dystrophy (DMD). Capsule size selection and ability to swallow the NF-κB inhibitor edasalonexent were assessed in males 4-7 years of age with DMD enrolled in clinical trials for a new therapeutic.

Methods: The Phase 3 PolarisDMD randomized, double-blind, placebo-controlled trial enrolled 131 patients from 8 countries.

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

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).

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial.

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control.

Variability and trends in corticosteroid use by male United States participants with Duchenne muscular dystrophy in the Duchenne Registry.

Background: Treatment options for Duchenne muscular dystrophy remain limited, although consensus treatment guidelines recommend corticosteroid use.

Methods: This retrospective analysis assessed corticosteroid use in ambulatory and nonambulatory US males with Duchenne, age 35 and under, or Becker muscular dystrophy, who enrolled in The Duchenne Registry from 2007 to 2016 (formerly DuchenneConnect).

Results: The mean (SD) age of corticosteroid use initiation was 5.

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

Background: Edasalonexent is an orally administered small molecule designed to inhibit NF-κB, 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.

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.

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.

Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia.

Background: Because of variability in lipoprotein cholesterol content, low-density lipoprotein (LDL) cholesterol frequently underrepresents or overrepresents the number of LDL particles. Mipomersen is an antisense oligonucleotide that reduces hepatic production of apolipoprotein B-100, the sole apolipoprotein of LDL.

Objective: To characterize the effects of mipomersen on lipoprotein particle numbers as well as subclass distribution using nuclear magnetic resonance (NMR) spectroscopy.

Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease.

Background: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease.

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.

Aims: A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD).

Methods And Results: Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28.

A 50-week extension study on the safety and efficacy of colesevelam in adults with primary hypercholesterolemia.

Background: Colesevelam is a bile acid sequestrant that differs structurally from traditional bile acid sequestrants, allowing it to bind bile acids with greater affinity. Studies have shown that colesevelam significantly reduces low-density lipoprotein cholesterol (LDL-C) levels and, in some cases, significantly increases high-density lipoprotein cholesterol (HDL-C) levels in adults with primary hypercholesterolemia.

Objective: To investigate the safety and efficacy of colesevelam in adults with primary hypercholesterolemia.

Colesevelam HCl improves fasting plasma glucose and lipid levels in patients with prediabetes.

Although colesevelam hydrochloride (HCl) is indicated to reduce low-density lipoprotein cholesterol (LDL-C) in patients with hyperlipidemia and improve glycemic control in patients with type 2 diabetes, its effects on glucose and lipids in patients with prediabetes have not been previously studied. To evaluate the effects of colesevelam HCl in patients with prediabetes, a post-hoc analysis was conducted on data from a 24-week lipid-lowering study. Using baseline laboratory safety data for fasting plasma glucose (FPG), 88 patients were identified as having prediabetes according to American Diabetes Association criteria.

Preclinical and clinical development of deferitrin, a novel, orally available iron chelator.

Deferitrin, a novel, orally available iron chelator, is in the early stage of clinical development for the treatment of chronic iron overload due to transfusional therapy. Preclinical pharmacology studies demonstrate iron excretion largely by the fecal route. Initial clinical studies have shown deferitrin to be well absorbed.

Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers.

Background & Aims: In humans, cholesterol absorbed from the intestine contributes appreciably to serum cholesterol levels. We hypothesized that cholesterol thermodynamic activity (A(t)) would predict bioavailability of cholesterol monomers in intestinal content, and that natural dietary phospholipids exhibiting high affinity for cholesterol would reduce its absorption.

Methods: Cholesterol A(t) was determined by measuring partitioning of monomeric cholesterol from aqueous solutions of taurocholate, cholesterol, and either milk sphingomyelin (MSM), dipalmitoyl phosphatidylcholine (DPPC), or egg yolk phosphatidylcholine (EYPC) into wafers of polymerized silicone.

Absorption of colesevelam hydrochloride in healthy volunteers.

Objective: To assess whether colesevelam hydrochloride is absorbed in healthy volunteers.

Methods: A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.

Effect of colesevelam on lovastatin pharmacokinetics.

Objective: To assess potential interactions of colesevelam hydrochloride and lovastatin in healthy volunteers when lovastatin alone was administered with dinner, both lovastatin and colesevelam were administered with dinner, and colesevelam was administered with dinner and lovastatin was administered 4 hours later with a snack.

Methods: A single-center, open-label, 3-period, crossover drug interaction study was performed with 22 healthy volunteers. Blood samples were collected at specified intervals before and after dosing, and plasma concentrations of lovastatin and lovastatin hydroxyacid were measured using a liquid chromatography/mass spectroscopy/mass spectroscopy method.