Edison Pharmaceuticals, a specialty pharmaceutical company, has announced the initiation of phase II clinical trial entitled, "Double-Blind, Placebo-Controlled Clinical Trial of EPI-743 in patients with Cobalamin C Defect."

The trial is a placebo-controlled study lasting 12 months, preceded by a six-month run-in phase for all patients to establish a defined clinical and metabolic baseline. The primary endpoint is improvement in visual function with secondary outcome measurements assessing neurologic and neuromuscular function, glutathione biomarkers, quality of life, as well as safety parameters.

The rationale underlying this investigation is centered on understanding whether EPI-743 – a therapeutic targeting primary defects in electron transport – might hold therapeutic benefit in disorders of intermediary metabolism that also result in redox disturbances.

"Cobalamin C deficiency represents an inherited disorder that induces perturbations in the metabolism of glutathione. Given the central role of glutathione in cellular redox balance and antioxidant defense systems, we are eager to explore whether a therapeutic that increases glutathione such as EPI-743 will provide clinical benefit," stated Professor Carlo Dionisi-Vici, Division of Metabolism, Bambino Gesu Children's Hospital– the trial's principal investigator.

Cobalamin C (Cbl-C) defect belongs to the family of diseases known as methylmalonic acidurias and is the most common inborn error of vitamin B12 metabolism. Cbl-C defect is a syndrome that results in multiorgan system disease most significantly impacting the central nervous system. While the clinical presentation can be heterogeneous, the onset of symptoms typically arises within the first year of life and includes seizures, hypotonia, hydrocephalus, developmental delay, and failure to thrive. Visual impairment results from retinal atrophy and oculomotor defects. Cardiovascular disease, hemolytic uremic syndrome, and gastrointestinal involvement may also occur. A smaller subset of patients may present later in childhood or early adulthood and typically have a milder phenotype with neurological and vascular manifestations.

Cbl-C defect is an autosomal recessive disorder with an estimated incidence of 1:60,000 to 1:100,000. The gene responsible for the Cbl-C defect is known as MMACHC and is located on chromosome 1p. On a biochemical level, the Cbl-C defect prevents the conversion of vitamin B12 into its most important metabolically active forms - methylcobalamin and adenosylcobalamin. This in turn leads to the accumulation of methylmalonic acid and homocysteine as well as to the reduced synthesis of methionine. It is believed that the accumulation of methylmalonic acid and homocysteine, along with reduced synthesis of methionine, results in increased cellular oxidative stress and to perturbation in glutathione metabolism — a critical and endogenous cellular antioxidant.

Despite existing vitamin replacement therapies, biochemical abnormalities never fully normalize and there is an unsatisfactory impact on the neurologic outcome.

EPI-743 is an orally bioavailable small molecule being developed by Edison Pharmaceuticals for the treatment of Friedreich's ataxia and other inherited mitochondrial diseases. EPI-743 is a member of the para-benzoquinone class of drugs. It serves as a cofactor for the novel drug target– NADPH quinone oxidase 1 (NQO1). Through a redox-based mechanism, EPI-743 augments endogenous glutathione biosynthesis– essential for the control of oxidative stress.

Edison Pharmaceuticals is dedicated to developing treatments for children and adults with orphan mitochondrial diseases.