Results of a Phase 2 Randomized Double-Blind Placebo Controlled Study (VANILLA) Investigating the Efficacy and Safety of a V1a Antagonist (RG7314) in Adult Men with ASD

Background:  The neuropeptide vasopressin (AVP) acts both as an endocrine hormone in the periphery and locally in the brain where it modulates social behaviors. Several lines of evidence suggest that inhibition of the vasopressin 1a receptor (V1a) could be beneficial for the treatment of core symptoms of Autism Spectrum Disorder (ASD). In the valproic acid rat model of ASD, V1a inhibition has been shown to improve social deficits in a dose-dependent manner. In a recently conducted proof-of-mechanism study we have shown that a single i.v. dose of a V1a inhibitor (RG7713) leads to subtle improvements of biomarkers of social communication in male adults with high-functioning ASD. RG7314 is an orally available V1a competitive antagonist with high specificity for V1a over V1b, V2, and oxytocin receptors that has demonstrated a favourable safety profile and pharmacokinetic parameters in healthy volunteers.

Objectives:  The primary objectives of the VANIILA study were to evaluate: 1) the efficacy of 12-week treatment with RG7314 in treating social and communication deficits in adult men with high functioning ASD and 2) the safety and tolerability of RG7314. Secondary and exploratory objectives included the evaluation of effects of RG7314 on aberrant, adaptive, and repetitive behaviours, anxiety and mood as well as the estimation of pharmacokinetics parameters.

Methods:  A staggered parallel-group, randomized, double-blind, placebo-controlled study was conducted with three doses of RG7314 (1.5, 4 or 10 mg PO per day). The treatment duration was 12 weeks and the study proceeded sequentially through four stages. Transitions from one stage to the next were decided by an Internal Monitoring Committee and an external Scientific Oversight Committee and the decisions were based on safety data review. Stage 1 tested placebo and 1.5 mg; Stage 2 placebo and 4 mg; Stage 3 placebo and 10 mg; and Stage 4 placebo, 1.5 mg, and 10 mg. The primary outcome measure was the caregiver rated SRS-2 scale. Secondary and exploratory measurements included the Vineland Adaptive Behavior Scales, second edition (VABS-II), the Aberrant Behavior Checklist (ABC), the Repetitive Behavior Scale-Revised (RBS-R), CGI-I, the State-Trait Anxiety Inventory (STAI), and the Anxiety, Depression and Mood Scale (ADAMS), amongst others. ClinicalTrials.gov Identifier: NCT01793441.

Results: A total of 223 subjects were enrolled in the four Stages (Stage 1 = 17; Stage 2 = 111; Stage 3 = 24; and Stage 4 = 71 and the dropout rate was 16.6%. At baseline, mean age was 25 years (SD = 6.53), mean FSIQ was 98.03 (SD=16.52), mean SRS-2 t-score was 77.52 (SD=7.26), mean CGI-S was 4.39 (SD=0.55), and mean Vineland-II^TM Standard Composite Score was 60.8 (SD=13). Age, IQ, and ASD severity measures at baseline were generally well-balanced across treatment groups. Based on a blinded preliminary interim assessment, RG7314 appears to be safe and well tolerated. The final primary, secondary, and exploratory outcome measures results will be presented at the meeting.

Conclusions: The VANILLA study provides valuable data to understand the safety, pharmacokinetics, and the effects of RG7314 on social, communication and repetitive behaviours.