Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The “endophenotype-associated surrogate endpoint (EASE)” concept

• This article proposed a new concept of an “endophenotype-associated surrogate endpoint”.
• The concept is a combination of “endophenotype” and “surrogate endpoint”.
• The advantages are expected in both drug development and uncovering pathogenesis.
• Significant effect is likely to be observed with smaller sample and shorter period.
• Elucidating biological mechanisms underlying novel treatments can be expected.

In this article, a new concept of an “endophenotype-associated surrogate endpoint (EASE)” is proposed. To examine effect of a novel therapeutic molecule on a target phenotype of a genotype associated with the molecule, state-dependent aspect of an endophenotype can be used as a surrogate endpoint. Desired characteristics for EASE are (1) a close relationship to the endophenotype associated with therapeutics, (2) longitudinal changes in illness severity, while the original “endophenotype” is primarily state independent, (3) a physical sign or laboratory measurement that occurs in association with a pathological process and has putative diagnostic and/or prognostic utility, and (4) serves as a substitute for a clinically meaningful endpoint. Advantages are expected for both surrogate endpoints in drug development and endophenotypes in uncovering pathogenesis. EASE are closer to molecules than clinically meaningful endpoints and can respond to administration of the molecule in a more direct manner. Therefore, a statistically significant effect is likely to be observed in clinical trials with smaller sample sizes and shorter durations. As with endophenotypes, reduced heterogeneity might be expected especially in heterogeneous syndromes such as psychiatric disorders. Potential interactions (e.g., elucidating biological mechanisms underlying novel treatments) can be further expected.