Despite the impact of behavioral therapies, interventions for the core symptoms (persistent social communication/interaction deficits and restricted/repetitive behaviors) of autism spectrum disorder (ASD) remain largely unmet. Furthermore, there are limited established assessments for evaluating these core symptoms in clinical trials. The vasopressin system, implicated in modulating social behaviors, is a potential target for addressing communication and social interaction symptoms of ASD. Balovaptan, an orally available, brain-penetrant, highly-selective, competitive antagonist of the vasopressin 1a receptor is being investigated as a treatment for social and communication challenges in adults and children/adolescents. The clinical program has been planned in collaboration with the ASD community, including experts and advocates.

Objectives: To present evidence from the balovaptan development program supporting Vineland™-II Adaptive Behavior Scales (Vineland-II) as an appropriate outcome measure in ASD clinical trials, and the rationale for a socialization and communication composite score as the primary endpoint in an ongoing phase 2 study in children and adolescents (aV1ation; NCT02901431) and phase 3 study in male and female adults (VIADUCT; NCT03504917).

Methods: The first balovaptan trial (VANILLA, NCT01793441) in adult males with ASD and IQ≥70 used the caregiver-rated Social Responsiveness Scale 2 (SRS-2) as the primary endpoint based on available evidence when the study was designed. With validated psychometric properties, inter-rater reliability and age-appropriate norms (0-90 years), Vineland-II was a key secondary endpoint, among others. Vineland-II assesses adaptive behaviors in 3 domains: communication, socialization, and daily living skills and is now recognized by clinical experts, autism advocates and regulatory bodies as a suitable measure of change in social communication within ASD trials. As the socialization and communication domains of Vineland-II are both reliable, independently validated endpoints in ASD trials, the Vineland-II 2-Domain Composite (2DC) score was developed to combine both into a single score.

Results: Consistent with several reports suggesting strong susceptibilities to placebo effects with SRS-2 in multicenter trials, in VANILLA, all groups, including placebo, showed improvement on the SRS-2. However, dose-dependent, significant, and clinically meaningful improvements (exceeding minimal clinically important difference threshold) on the Vineland-II composite score, driven by improvements in socialization and communication domains, were observed for participants treated with balovaptan 4 or 10 mg versus placebo.

The psychometric properties of the Vineland-II 2DC score were further validated using VANILLA data, demonstrating test-retest reliability, validity and sensitivity to change, supporting its use as the primary outcome measure for socialization and communication core symptoms, across the age/gender spectrum, in the balovaptan development program.

Conclusions: In the development program to date, balovaptan has demonstrated dose-dependent, significant, and clinically meaningful improvements on Vineland-II in adult males. This observation supports Vineland-II as an appropriate measure of change in socialization and communication core symptoms of ASD over time. Furthermore, the Vineland-II 2DC score has been chosen as the primary outcome measure enabling comprehensive assessment of these core symptoms in ongoing phase 2 and phase 3 studies of balovaptan in ASD. Balovaptan is being studied as a potential treatment option for ASD core symptoms as an amplifier of social learning, possibly by enhancing social motivation reward systems.