Objective: To evaluate the effects of EPI-743 in subjects with Parkinson’s disease (PD).

Background: Oxidative stress and energetic disturbances are thought to contribute to the pathogenesis of PD. EPI-743 (alpha-tocotrienol quinone) is an investigational drug targeting oxidoreductase enzymes essential for redox control of metabolism. In preclinical tests on primary cells from sporadic and mito-PD variants, EPI-743 provides protection against oxidative stress secondary to glutathione depletion.

Methods: This was a 6-month open label trial comparing 2 dose levels of orally administered EPI-743 (200 mg or 400 mg TID). Study outcomes included changes from baseline in UPDRS II and III “ON” scores, and brain metabolite levels as measured by 3T magnetic resonance spectroscopy (MRS). Wilcoxon signed rank sum tests were used in the statistical analysis.

Results: Ten subjects were enrolled in the trial (mean Hoehn and Yahr 1.5); 3 patients discontinued the study after 3 months for reasons unrelated to drug. Six of 7 patients with follow up MRS studies demonstrated a decrease in glutamine/glutamate levels in the basal ganglia opposite the side most severely affected by PD (mean decrease of 1.18 ppm to 0.74 ppm, p=0.002), signifying CNS target engagement. Clinically, subjects demonstrated an improvement in UPDRS Parts II/III, with a mean decrease from 8.1 to 6.7 (p=0.19) in UPDRS Part II and a mean decrease from 16.6 to 13.3 (p=0.17) in UPDRS Part III (n=10). EPI-743 was well tolerated with no dose-limiting toxicities or serious adverse events.

Conclusions: EPI-743 resulted in a significant decrease in CNS glutamine/glutamate levels in PD patients as well as improvements in UPDRS combined parts II and III scores, and UPDRS part III scores alone, that approached statistical significance. Treatment with EPI-743 improved an objective CNS marker of oxidative stress that correlated with clinical improvement. These positive data provide the foundation for further development of EPI-743 for PD.