Hot Targets for Compound Selection in ASD Trials: The NIMH FAST-ASD Network

Background: Pharmacological clinical trials in autism spectrum disorder (ASD) aiming to change core domains have yielded disappointing efficacy results. Although progress in basic science, ASD animal models, and genetics in ASD has been substantial over the past decade, the identification of compelling targets for ASD clinical trials has been a challenge and early targeted therapies have fallen short. There are several likely reasons for these failures, including inadequate integration of basic science knowledge with available, although incomplete, clinical findings, ill-defined subject selection and incomplete matching of the primary outcome measure with the chosen target (e.g., social communication).  

Objectives:  The aim of this presentation is to describe an approach to target selection driven by an effort to integrate basic and clinical findings to identify specific candidate compounds for early clinical trials in ASD.

Methods:  Based on literature review, the presentation will provide selected examples of compounds with mechanisms of action that may be relevant to ASD.

Results:  There are a number of promising targets for investigation in ASD, some with strong evidence implicating their relevance to core domains of the ASD phenotype.  After discussing the model for target selection, the presentation will describe the approach taken by the recently launched NIMH-initiated “Fast Fail Trials in Autism Spectrum Disorders (FAST-AS).”  This initiative is designed to identify and rank order promising compounds for ASD to set a course for drug development in ASD. The GABA system emerges as a compelling target with links to core and associated features of ASD.  Thus, the compound selection process will be illustrated by reviewing a highly ranked target in the GABA system.  Aspects of trial design related to this approach will also be discussed.

Conclusions:  

We are in an era of rapidly emerging findings from many sources on the pathophysiology of ASD. To make use of this accumulating information in basic science, biomarkers and clinical measurement, we need to modify our approach to drug selection, early study designs to advance drug development in ASD.