Ezutromid (SMT C1100)  is a drug therapy developed by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD), a genetic disorder characterized by progressive muscle degeneration and weakness.

DMD affects about 50,000 boys and young males worldwide and has no cure yet. It is caused by a mutation in the gene that encodes for dystrophin, a protein that plays an essential role in maintaining muscle cells. Utrophin is a naturally occurring protein with similar function and structure to that of dystrophin. It essentially is produced during the early stages of muscle fiber development, but its production stops when muscle fibers are mature. This is when dystrophin takes over. Utrophin also is produced in the early stages of the repair process after a muscle fiber is damaged.

Ezutromid is an utrophin modulator and is currently being studied as a therapy to slow or stop DMD progression.

How Ezutromid works

Ezutromid is a small molecule investigational drug to be administered orally. The drug works by modulating utrophin production, i.e., utrophin levels are maintained in order to substitute for dystrophin in mature muscle fibers. The advantage of utrophin modulation is that it has the potential to slow, or even stop, DMD progression regardless of the type of mutation causing DMD. The therapy also can be complementary to other DMD treatments.

Ezutromid studies

Two Phase 1 clinical trials testing Ezutromid in patients with DMD have been completed. One of these (NCT02056808) determined the safety and tolerability of single and multiple oral doses of Ezutromid. Patients were divided equally into three groups, each receiving different doses of the drug. Results showed that single and multiple doses of 50 mg and 100 mg of Ezutromid twice a day, or 100 mg/kg of Ezutromid three times a day, were well-tolerated (two participants required analgesia treatment for pain such as headache, ear pain, and toothache). However, Ezutromid’s plasma concentration was lower than that of similar doses administered to healthy volunteers.

Another Phase 1b study (NCT02383511) evaluated the blood plasma levels of Ezutromid in children with DMD who followed a balanced diet of fats, proteins and carbohydrates. Participants were divided randomly into three groups, receiving two different doses of the drug and a placebo, over a 14-day treatment period. There was a washout period of at least 14 days between each treatment. Results showed that the three fixed doses (250, 500 and 1,000 mg/twice a day) were safe and well-tolerated. The new Ezutromid formulation (known as F6) achieved more than six times maximum plasma levels when compared with the then-current formulation (F3) at lower doses. During this study, common side effects were pale feces due to unabsorbed Ezutromid. The drug was found to be best absorbed when taken with a small glass of full-fat milk and a balanced diet.

Following positive results from the Phase 1 studies, both formulations (F3 and F6) were considered in a Phase 2 proof-of-concept study (NCT02858362, known as PhaseOut DMD). The PhaseOut DMD is a 48-week trial with participants having the opportunity to enroll in an extension phase. The extension phase aims to gather long-term safety and efficacy data and is expected to last until Ezutromid receives marketing approval or its development is discontinued.

The Phase 2 trial will allow comparison of both F3 and F6 formulations in terms of safety and efficacy and to determine which one is to be used in future trials.

The primary endpoint of the study is the change from baseline in magnetic resonance imaging (MRI) parameters related to fat infiltration and inflammation of the leg muscles. Additional endpoints include measuring utrophin protein and muscle fiber regeneration level from muscle biopsies, safety and pharmacokinetic measures, and exploratory measures, including a six-minute walk test, North Star Ambulatory Assessment and patient-reported outcomes. The enrollment phase of PhaseOUT DMD was completed in May 2017 with the study expected to finish by mid-2018.

Ezutromid received Rare Pediatric Disease designation from the U.S. Food & Drug and Administration (FDA).

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