Results from a Phase I Proof-of-Mechanism Study with a Vasopressin 1a Receptor Antagonist in ASD

Background:  The hypothalamic neuropeptide vasopressin (anti-diuretic hormone) is involved in higher brain functions, including learning and memory, emotional control, social behavior and interaction. In particular, animal and human studies have implicated this neuropeptide in the modulation of both core and associated symptoms of autism spectrum disorders (ASD).  Specific alleles of the arginine vasopressin 1a receptor (AVPR1A) gene have been associated with a higher risk for ASD. V1a receptor antagonism may offer therapeutic benefits in ASD. In this proof-of-mechanism (PoM) study the effects of the V1a receptor antagonist RG7713 on behavioral and physiological biomarkers of social communication were investigated to establish early evidence of potential therapeutic effects.

Objectives:  To investigate the effects of the V1a receptor antagonist RG7713 on behavioral and physiological biomarkers of social communication.

Methods:  19 high-functioning adults with ASD (mean age=23.4 ± 5.16 (SD) years (range: 18-40), full scale IQ (FSIQ)=99.95 ± 14 (78-136), Vineland Adaptive Behavior Composite (VABS) score= 62 ± 12.9 (29-77), ABC-full Total score = 27±19.9 (7-94) and ADOS Total score 12±4.8 (4‑23)) participated in randomized, double-blind, placebo-controlled, cross-over study. A single dose of the V1a receptor antagonist RG7713 or placebo was administered intravenously to each subject on two different days separated by one week wash-out. Effects on measures of eye-tracking in established paradigms (gender and gaze discrimination, activity monitoring, detection of biomotion), affective speech recognition (ASR), the “reading the mind in the eye” test (RMET) and olfactory recognition were evaluated. A composite score for all eye-tracking measures was calculated.

Results:  Administration of RG7713 was associated with a slight improvement on the eye-tracking composite score (effect size = 0.2) and in orienting for biological motion (ES=0.8), smell recognition (correct recognition after RG7713: 79%; after placebo administration 76%; ES = 0.2) and the RMET (correct answers after RG7713 administration: 64%, after placebo administration 61%; ES=0.2), but a small decrement in ASR total performance (correct answers after RG7713 administration 54%, after placebo administration 57%; ES=-0.1). This effect of RG7713 on overall ASR performance was largely driven by a decreased ability to detect the emotion ‘lust’ and ‘fear’ (ES = -0.7 for both), consistent with a potential anxiolytic effect of a V1a receptor antagonist bringing the performance closer to levels observed in healthy volunteers.  The ability to detect the emotions ‘happy’ and ‘surprise’ was increased following RG7713 dosing (ES = 0.2 for both). None of the reported differences reached levels of nominal statistical significance. 

Conclusions:  After a single administration of the V1a receptor antagonist RG7713 some evidence of an ameliorating effect on physiological and behavioral measures of social communication was observed in high functioning ASD adults. The results of this small PoM study support the further clinical exploration of V1a receptor antagonism as a therapeutic approach in ASD.