Age of onset in genetic prion disease and the design of preventive clinical trials (P1.1-010)

Objective: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. Background: Previous therapies tested in animal models of prion disease have been highly effective prophylactically but have shown little or no efficacy when administered at the symptomatic stage of disease, suggesting that a preventive approach may be essential in humans. Design/Methods: We assembled age of onset or death data from N=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age of onset. We used formulae and simulations to estimate statistical power for clinical trials. Results: Genetic prion disease age of onset varies over several decades for the most common mutations and is not explained by sex, parent’s age of onset, or PRNP codon 129 genotype. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Conclusions: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit. Disclosure: Dr. Minikel has nothing to disclose. Dr. Vallabh has nothing to disclose. Dr. Orseth has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bain \u0026 Co. Dr. Brandel has nothing to disclose. Dr. Haik has nothing to disclose. Dr. Laplanche has nothing to disclose. Dr. Zerr has nothing to disclose. Dr. Parchi has nothing to disclose. Dr. Capellari has nothing to disclose. Dr. Safar has nothing to disclose. Dr. Kenny has nothing to disclose. Dr. Fong has nothing to disclose. Dr. Takada has nothing to disclose. Dr. Ponto has nothing to disclose. Dr. Hermann has nothing to disclose. Dr. Knipper has nothing to disclose. Dr. Stehmann has nothing to disclose. Dr. Kitamoto has nothing to disclose. Dr. Ae has nothing to disclose. Dr. Hamaguchi has nothing to disclose. Dr. Sanjo has nothing to disclose. Dr. Tsukamoto has nothing to disclose. Dr. Mizusawa has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai Co., EA Pharma Co., Novartis Pharma Co., Sanofi Co., Tenable Mitsubishi Pharma Co., FP Parma Co., Nihon Pharma Co. Dr. Mizusawa has received personal compensation in an editorial capacity for Chugai Igaku Co., Igakushoin Co., Nankodo Co. Dr. Collins has nothing to disclose. Dr. Chiesa has nothing to disclose. Dr. Roiter has nothing to disclose. Dr. de Pedro-Cuesta has nothing to disclose. Dr. Calero has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Raman Health Technologies, SL. Dr. Calero has received personal compensation in an editorial capacity for Springer. Dr. Calero holds stock and/or stock options in Biocross SL, BIO HAPTENYC DGR SL, and Raman Health Technologies, SL which sponsored research in which Dr. Calero was involved as an investigator. Dr. Calero holds stock and/or stock options in Raman Health Technologies, SL. Dr. Calero has received research support from AMO Pharma, Ltd. Dr. Geschwind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Quest Inc., Advance Medical Inc, Guidepoint Global, Market Plus, Best Doctors, Gerson Lehrman Group, 3MCommunications, Insight Consulting, and Smith \u0026 Hennessey LLC. Dr. Geschwind has received research support from Quest Diagnostics. Dr. Yamada has nothing to disclose. Dr. Nakamura has nothing to disclose. Dr. Mead holds stock and/or stock options in GlaxoSmithKline and Ionis Pharmaceuticals. Dr. Mead has received research support from Nova Pharmaceuticals Ltd.