EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment

Bambino Gesù Hospital and Research Institute

Status and phase: Completed; Phase 2

Conditions: Retinopathy; Methylmalonic Aciduria and Homocystinuria,Cblc Type; Genetic Disease

Treatments: Other: Placebo supplementation; Drug: Epi-743

Study type: Interventional

Funder types: Other

Identifiers

NCT01793090

R-12-92

Details and patient eligibility

About

The aim of the research is to investigate the safety and efficacy of EPI-743 treatment in patients with Cbl-C defect and related visual and neurological impairment. Primary Endpoints will be the improvement in visual function as assessed by visual acuity and eye-hand coordination and manual dexterity. Secondary Endpoints will be the improvement in neurologic function, evaluated by a battery of age-appropriated psychophysical tests, and/or in objective electrophysiological tests such as Visual Evoked potentials (VEP) and Electroretinogram (ERG) and/or the change in serum markers of redox state.

Full description

Cobalamin C (Cbl-C) defect is the most common inborn error of cobalamin metabolism causing methylmalonic aciduria and homocystinuria. Cbl-Cdefect is due to impaired activity of MMACHC, a cobalamin trafficking protein, involved in the decyanation of cyanocobalamin as well as in the dealkylation of alkylcobalamins through a glutathione transferase activity. Despite pharmacological treatment with hydroxycobalamin, betaine, folic acid, (and carnitine), long-term outcome in early-onset patients is in most cases unsatisfactory with progression of visual and neurological impairment, mainly expressed in the form of retinal degeneration and/or maculopathy. Moreover, despite some hypotheses have been proposed, the pathophysiological mechanism causing progressive eye and brain damage still remains unclear. Recently, the contribution of oxidative stress has been hypothesized based on in vitro studies showing in Cbl-C fibroblasts a significant increase of reactive oxygen species (ROS) and in vivo studies documenting severe alteration of glutathione species, the main cellular redox buffer.

EPI-743 is a small molecule therapeutic that has demonstrated beneficial effects in diseases characterized by oxidative stress and alterations in glutathione redox balance including Leigh syndrome and other inherited respiratory chain diseases.

Based on the principle that Cbl-C defect causes both in vivo and in vitro perturbations of redox state, the aim of our study is to verify the potential beneficial effects of EPI-743 in preventing/reducing progression of neurological and visual signs, as well as in ameliorating redox abnormalities in Cbl-C patients, in combination with standard therapy.

Primary Endpoints will include the improvement in visual function as assessed by visual acuity and eye-hand coordination and manual dexterity. Secondary Endpoints will be improvement in neurologic function, evaluated by a battery of age-appropriated psychophysical tests, and/or in objective electrophysiological tests such as VEP and ERG, and/or the change in serum markers of redox state. Patient's and parental Quality of life will be regularly assessed prior of treatment start and periodically while on EPI-743.

Enrollment: 30 patients

Sex: All

Ages: 1 to 20 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• genetically confirmed Cbl-C defect;
• abstention from antioxidant medications (i.e. coenzyme Q10, idebenone, vitamin E) prior to trial initiation and throughout conduct of trial.

Exclusion criteria

• allergy to EPI-743 or sesame oil (a screening test will be performed);
• abnormal coagulation;
• hepatic insufficiency with Liver Function Tests greater than 2-times normal values;
• renal insufficiency requiring dialysis;
• fat malabsorption precluding drug absorption.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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30 participants in 2 patient groups, including a placebo group

EPI-743

Active Comparator group

Description:

EPI- 743 in capsule or formulation comprised of USP/NF (United States Pharmacopeia and The National Formulary)Sesame Oil at a potency of 100 mg EPI-743/ 1 mL total volume. Mode of Administration: Oral with meal or G-Tube infusion with food. Dose: 100mg or 200 mg tid for 12 months, to be continued if clinically effective

Treatment:

Drug: Epi-743

Placebo supplementation

Placebo Comparator group

Description:

placebo in the same formulation as the active comparator will be administered to patients, assigned to this arm in a randomized design

Treatment:

Other: Placebo supplementation