A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder

Abstract

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18–45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=−0.8, p=0.03) and fear (ES=−0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=−0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278

In Search of Biomarkers for Autism Spectrum Disorder

“…The data for this report are derived from two studies conducted at the same three academic centers in the United States: (a) A multicenter, observational study (http://clinicaltrials.gov: NCT01669889); and (b) an interventional study [http://clinicaltrials.gov: NCT01474278; Umbricht et al, ], for which the data included in this analysis were collected at baseline, prior to any drug administration. In both studies, identical exploratory assessments were administered in the same order.…”

Adaptive behavior in autism: Minimal clinically important differences on the Vineland‐II

“…A recent Autism Speaks sponsored working group panel recommended the Vineland‐II as suitable (having adequate reliability, validity, and responsiveness) to quantify social communication deficits in clinical trials of ASD [Anagnostou et al, ; see also McConachie et al, ]. The Vineland‐II is also increasingly used in randomized trials targeting core ASD symptoms and/or adaptive behavior more broadly [e.g., Chugani et al, ; Dawson et al, ; Hardan et al, ; Scahill et al, ; Umbricht et al, ; Veenstra‐VanderWeele et al, ; Ventola et al, ], in part due to the relative lack of other reliable measures of change in these behaviors [Anagnostou et al, ]. This increasing use may also reflect the relatively broader scope of adaptive behaviors assessed by Vineland‐II, relative to the more circumscribed set of core ASD symptoms (McDougall et al, in press).…”

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

“…The predicted pharmacokinetics and pharmacodynamics of V1a antagonists were suitable for humans, however not for rodents. Trials in humans with social deficits associated with autism have shown promising results …”

“…The 2017 Frontiers in Medicinal Chemistry (FiMC) conference, organizedj ointly by the GermanC hemical Society (GDCh;K arl-Heinz Baringhaus), the German Pharmaceutical Society( DPhG; Christa E. Müller), and the Division of Medicinal Chemistry and Chemical Biology of the Swiss Chemical Society (SCG;Y ves Auberson,J ean-Louis Reymond), was held at the Department of Chemistry and Biochemistry of the University of Bern, February [12][13][14][15]2017. While this conference has taken place every year since 2004 in ad ifferent city in Germany,t his year it was held in Switzerlandf or the first time.…”

“…Trials in humans with social deficits associated with autism have shown promising results. [15] The session comprised three furthert alks on Wednesday, startingw ith Dr.M arcus Koppitz (Bayer) presenting his work on Mps1 kinase inhibitors, where the kinase is linked to the SAC protein, playing ar ole in mitosis. This protein inhibition might lead to apoptosis and could be the basis of an ovel anticancer strategy.T hey identified two candidates for clinical trials after aS AR study of compounds based on this work.…”