EPI-743 for Metabolism or Mitochondrial Disorders

The clinical manifestations of disorders of energy metabolism and defects in
oxidation/reduction are similar because the basic defect involves the inability to transfer
electrons. The same is true for many mitochondrial diseases. Affected patients exhibit a wide
variety of signs and symptoms, but the most frequent and earliest dysfunctions occur in the
muscle and brain, where energy requirements are high. The diagnosis of this type of defect is
problematic because of the nonspecific and protean clinical manifestations of these
disorders. Treatment is equally challenging, since the exact locus of the primary defect
generally remains enigmatic. As a consequence, physicians rely upon generic cocktails of
vitamin co-factors or endogenous intermediates intended to enhance mitochondrial electron
transport, diminish the damage of reactive oxygen species, and promote energy production. The
field is such a morass that, in general, it calls for trial-and-error treatment based upon
empiric data. Edison Pharmaceuticals, Inc, has developed an in vitro assay that utilizes
patient fibroblasts to model the innate susceptibility to oxidative stress caused by the
disorders of energy metabolism and oxidation/reduction. The assay system also determines if
the cells respond with increased viability to an IND drug called EPI-743. We propose a
clinical trial that enrolls 20 children who meet three criteria. First, they must have a
disorder that, based upon studies performed in a clinical protocol such as 76-HG-0238
("Diagnosis and Treatment of Patients with Inborn Errors of Metabolism and Other Genetic
Disorders"), is consistent with a defect in energy metabolism or oxidation/reduction. Second,
their cultured fibroblasts must exhibit a defect in the ability to withstand oxidant stress.
Third, their fibroblasts must respond to EPI-743 in vitro by showing improved viability under
conditions of oxidative stress. This protocol is a double-blind, placebo-controlled crossover
study with 6-month periods of treatment and a two-month washout period. Patients will be
admitted to the NIH Clinical Center for 2-5 days every 3 months. The primary outcome measure
will be quality of life based upon the Newcastle Paediatric Mitochondrial Disease Scale
(NPMDS) for ages 2-11 years; parts IIII

will be evaluated separately from part IV. Secondary outcome measures will be tailored to
each patient's laboratory, imaging, and clinical abnormalities. Results while receiving
EPI-743 will be compared to results while receiving placebo; both repeated measures analyses
and Student's t test will be employed.

- INCLUSION CRITERIA:

Inclusion criteria involve enrollment in protocol 76-HG-0238, Diagnosis and Treatment of
Patients with Inborn Errors of Metabolism and Other Genetic Disorders . In addition,
patients must:

- Be 2-11 years of age

- Manifest clinical findings of a neuromuscular disease with a component of impaired
energy or oxidation/reduction. Typical symptoms would include hypotonia, dystonia, or
seizures.

- Have a disorder that is untreatable or poorly treatable.

- Have cultured fibroblasts that exhibit reduced viability under conditions of oxidative
stress, compared to age matched control fibroblasts.

- Have cultured fibroblasts that achieve at least 80% viability rescue with EPI-743 at
1micromolar upon exposure to oxidative stress and that have a half maximal effective
concentration of EPI-743 of less than or equal to 50 nanomolar.

- Be willing to abstain from initiating the use of dietary supplements and nonprescribed
medications, foods or beverages or bars fortified with coenzyme Q(10), vitamin E,
super fortified functional foods or beverages, and idebenone.

- Be able to travel to the Clinical Center for at least 8 visits.

EXCLUSION CRITERIA:

- Age < 2 years or >11 years

- Diagnosis of mitochondrial diseases benefiting from treatment and at risk from being
moved to placebo

- Allergy to EPI-743 or sesame oil

- Hepatic insufficiency with liver function tests greater than 3-times the upper limit
of normal

- Renal insufficiency requiring dialysis

- Significant malabsorption of fats precluding drug absorption

- Allergy to vitamin E

- Significant coagulation abnormalities as evidenced by abnormal PT/PTT tests

- Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in
lactic acidosis

- Ventilator-dependence

- Chronic pancreatitis

- Clinical history of bleeding requiring ongoing medical management

- Abnormal red cell parameters requiring ongoing medical management besides iron
supplementation

- A platelet disorder

- Neutrophils less than 500 mm3