Use of Nonclinical and Expanded Access Clinical Study data to Guide Development Programs Targeting Mitochondrial Diseases of Lipid Peroxidation

Background: Many diseases of neurodegeneration associated with mitochondrial Lipid Peroxidation have poorly predictive animal models and present unique challenges for clinical trial design. RT001 is a dideuterated isotopomer of linoleic acid that inhibits Lipid Peroxidation. To correlate non clinical models with clinical response, we reviewed the effects of RT001 in disease models and clinical indications associated with Lipid Peroxidation.

Methods: We identified 10 specific target diseases known to be associated with Lipid Peroxidation. We evaluated the effects of RT001 in cellular models, animal models, and expanded access clinical study of these Lipid Peroxidation associated diseases.

Results: Significant beneficial effects were seen in 7 disorders. Clinical efficacy was seen in 6, no benefits were seen in 3, and data was inconclusive in 1. Inconsistencies between nonclinical and clinical experiences were seen; in vitro and animal models often demonstrate a lack of consistency with clinical response.

Conclusion: The response to RT001 in nonclinical models often demonstrated little concordance with the clinical effects in patients with the corresponding disease. The best predictor of RT001’s beneficial effects in patients remains clinical exposure. Thus, because RT001 has efficacy in some diseases and not others, there is no substitute for performing definitive clinical trials disease by disease in order to determine clinical benefit.

Keywords: Expanded access; Mitochondrial disorder; Lipid Peroxidation; Neurodegeneration; RT001