EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
Condition: Methylmalonic Aciduria and Homocystinuria,Cblc Type; Genetic Disease; Retinopathy
MeSH terms: Homocystinuria; Genetic Diseases, Inborn
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed 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.
    

Intervention name(s): Epi-743; Placebo supplementation
Intervention type(s): Drug; Other
Intervention description(s): EPI- 743 in capsule or formulation comprised of USP/NF 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.; Placebo will be administered in the same formulation as the active comparator
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Cobalamin C defect; methylmalonic aciduria with homocystinuria; Visual function; VEP; ERG; antioxidant drugs