Targeting Vasopressin May Improve Social Deficits in Autism

Batya Swift Yasgur, MA, LSW

May 20, 2019

Modulation of the vasopressin pathway may be a promising new target for improving social and communication deficits in patients with autism spectrum disorder (ASD), new research suggests.

Results from two recent trials showed that modulating vasopressin's biological pathways safely enhanced social functioning in adults and children with ASD.

The 12-week phase 2 Vasopressin Antagonist to Improve Social Communication in Autism (VANILLA) trial compared three doses of balovaptan, an investigational oral vasopressin (V1a) receptor antagonist, to placebo in 223 adult men with autism.

Participants who received balovaptan showed dose-dependent and meaningful improvements in socialization and communication scores. There were no adverse events.

"Balovaptan was safe and well tolerated, with no imbalances in adverse events between placebo and balovaptan, and there were no specific serious adverse event reports of concern," Kevin Sanders, MD, global development lead of the Balovaptan Program at Roche Pharmaceuticals, told Medscape Medical News.

Although the primary efficacy endpoint, improvement on the Social Responsiveness Scale (SRS-2) at week 12, was not met, a treatment effect was observed on a key secondary endpoint: the communication and socialization scores of the Vineland-II Adaptive Behavior Scales, Sanders noted.

A second study compared the maximum daily target dose of intranasal vasopressin (Vasostrict, Par Sterile Products) with placebo in 30 children with ASD. Among the patients who received the active drug, social abilities were enhanced, anxiety symptoms diminished, and some repetitive behaviors diminished. The drug was well tolerated, and there were minimal side effects.

The findings of both studies were published online May 1 in Science Translational Medicine.

High, Unmet Need

"Using three different lines of analysis enabled us to show convergent, independent evidence to support the statistically significant finding that vasopressin enhanced social abilities, relative to kids treated with placebo," Karen J. Parker, PhD, associate professor and director of the Social Neurosciences Research Program, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California, who was the lead author for the second study, told Medscape Medical News.

"What was also exciting was that we saw convergent support from blinded clinical evaluation of these kids, and they were performing better on these social cognitive tasks," she said.

Sanders noted that "ASD is deeply personal and can cause significant strain on the individual as well as family, friends, and caregivers. But despite its prevalence, no pharmacological therapies for core symptoms exist, and there is a high, unmet need."

"The neuropeptide vasopressin has been implicated in modulation of brain circuits regulating social behavior," the VANILLA trial investigators note.

Vasopressin acts on the G protein–coupled vasopressin receptors V1a and V1b, with V1a as the dominant receptor subtype in the brain.

"Alteration of vasopressin expression or expression of its receptors affects social behaviors, such as social anxiety, pair bonding, and aggression," the researchers write.

Modulates Cooperativity, Memory

Several studies have suggested that administration of vasopressin can modulate cooperativity, memory, and perception of facial expressions. Moreover, studies have reported potential linkage between social behaviors and microsatellite DNA in the gene encoding the V1a receptor.

Balovaptan is an orally administered selective V1a receptor competitive antagonist. In phase 1 clinical trials of balovaptan, no safety or tolerability concerns arose.

The VANILLA trial was designed to evaluate over a 12-week period three doses of balovaptan in comparison with placebo in adult men with moderate to severe ASD. The patients had an IQ of at least 70.

The 223 participants (median age, 22 – 26 years; median IQ, 95.5 – 98.5) were randomly assigned to receive either placebo (n = 75) or balovaptan at 1.5 mg (n = 32), 4 mg (n = 77), or 10 mg (n = 39).

The primary efficacy outcome was change from baseline at week 12 in ASD symptoms, as measured by caregiver-rated SRS-2 total T score.

The secondary efficacy outcome was change from baseline on the Vineland-II Adaptive Behavior Scales, which assesses adaptive behaviors and skills in communication, socialization, and daily living.

"The VANILLA study focused on the core symptoms of ASD, including difficulties with communication and social interaction," Sanders said.

VANILLA Findings

All groups, including the patients who received placebo, showed a mean improvement in symptoms on the SRS-2 from baseline to week 12.

However, none of the differences between the balovaptan group and the placebo group were statistically significant for all evaluated doses. The estimated treatment difference and the effect size (ES) vs placebo for the 1.5-mg dose were 0.15 and .02, respectively (P = .96); for the 4-mg dose, 0.56 and .07 (P = .74); and for 10-mg dose, −2.93 and −0.31 (P = .25).

All balovaptan groups showed improvements on the Vineland-II composite score compared with the patients who received placebo. The magnitude of the treatment effect increased with dose.

Unlike the SRS-2, the changes observed from baseline on the Vineland-II composite and domain scores were, on average, minimal in the placebo group and were small to moderate on other scales.

On individual Vineland-II domain scores, improvement with balovaptan vs placebo was observed in the socialization and communication domain standard scores.

On the daily living skills domain score, an improvement in comparison with placebo was observed only for the balovaptan 4-mg dose, not the other two doses.

A higher proportion of participants in the balovaptan 4- and 10-mg treatment groups vs the placebo group showed an improvement of at least 4 points on the Vineland-II composite score from baseline, which is regarded as a "clinically meaningful" improvement.

The researchers also assessed health-related quality of life using the Pediatric Quality of Life Inventory Generic Core Scale, the Cognitive Functioning Scale, and the Family Impact Module.

In all three measures, the investigators found improvements from baseline at week 12 in the balovaptan groups compared with the placebo group.

The proportion of participants who reported any adverse events (AEs) was similar across study cohorts. AEs were reported in 64.0% of the placebo group and in 78.1%, 66.2%, and 66.7% of the balovaptan 1.5-mg, 4-mg, and 10-mg groups, respectively.

"The VANILLA study demonstrated the potential of balovaptan to improve the core symptoms of social interaction and communication in adults with ASD, which warrants further investigation," Sanders said.

Autism Biomarker

Parker noted that a decade of work, "especially in rodents," has shown that vasopressin has prosocial effects.

She and her colleagues used a primate model of spontaneously, naturally occurring social impairments "to ask whether similar biology in either autism or other neurogenetic syndromes with high penetrance for autism or mammalian social functioning might offer a clue to a biomarker of low social functioning in these monkeys. They found that vasopressin was a biomarker that was a key driver," she said.

Her group found that levels of vasopressin in the cerebrospinal fluid (CSF) could suggest whether a monkey was or was not engaging in social behavior.

"We wanted to know if we could translate those findings to human patients," she said.

In the previous study of vasopressin in spinal fluid of children, 13 of 14 participants were correctly identified as having autism. Another study compared 36 children who had autism to 36 nonautistic children and found that those with the lowest CSF levels of vasopressin had symptoms of the highest severity.

"This suggested we could administer vasopressin and enhance social abilities in autism, which was the rational for the current study," Parker said.

The double-blind, randomized, placebo-controlled study tested the efficacy and tolerability of daily treatment with intranasal vasopressin over a 4-week period in 30 children with ASD.

All children (25 boys) received the maximum daily target dose of vasopressin for their age group. Participants aged 6 to 9.5 years received 24 international units (IU); participants aged 9.6 to 12.9 years received 32 IU.

The primary outcome measure was change from baseline total score in the parent-rated SRS-2.

Secondary outcome measures included change from baseline in social communication and social cognition abilities, as assessed by clinician evaluation and child performance on laboratory-based tests.

Both tasks focused on the capacity of the child to identify or understand emotion in another person.

Promising but Preliminary

Children who received intranasal vasopressin for 4 weeks showed greater improvement in their social abilities, as assessed by the primary outcome measure, compared with those who received placebo (F 1,20 = 9.853; P = .0052; ηp 2 = 33.0%; equivalent Cohen's d, 1.40).

This effect was dependent on pretreatment vasopressin concentrations in blood. Higher pretreatment vasopressin concentrations in blood predicted a greater treatment response in vasopressin-treated participants.

The treatment effect of vasopressin was even more pronounced with respect to scores on the Social Communication and Interaction subscale of the SRS-2.

Blinded parent ratings of treatment-related improvements in social behavior were significantly correlated with blinded clinician evaluations on the Clinical Global Impression–Improvement scores in the drug-treated group (r = 0.8753, P < .0001).

Moreover, parent ratings were corroborated by clinician evaluations and child performance on laboratory tests, in that vasopressin-treated participants showed greater clinician-evaluated improvement in social communication abilities after 4 weeks of treatment compared with placebo-treated participants (F 1,20 = 7.098; P = .0145; ηp 2 = 25.3%; equivalent Cohen's d, 1.16).

This finding was likewise more pronounced in vasopressin-treated participants who had higher pretreatment vasopressin blood concentrations.

Compared with participants who received placebo, those who received vasopressin showed superior performance on both laboratory tasks of enhanced theory of mind abilities, as assessed by the Reading the Mind in the Eyes Test, and increased facial emotion recognition abilities, as assessed by the Facial Emotion Recognition Test.

These effects were independent of pretreatment blood vasopressin concentrations.

Vasopressin treatment additionally reduced anxiety symptoms and some repetitive behaviors.

Vasopressin was also "well-tolerated, with minimal side effects," the investigators note.

Moreover, no participants dropped out during the study, and there were no significant differences between AEs in the treatment group and the placebo group.

"I think there are no drugs approved by the FDA that target social features of autism, so this was the first trial in that type of treatment with promising although preliminary evidence that vasopressin could be treatment for [deficits in] social functioning," Parker said.

"One limitation is that this was a small pilot trial, similar to a phase 2a. The drug was well tolerated with minimal side effects, but in a very curated population of kids," she added. "We would like to see these findings replicated and extended in a larger trial that we are currently conducting, which would be a phase 2b."

Cautious Optimism

Commenting on the findings for Medscape Medical News, Katherine Stavropoulos, PhD, assistant professor, University of California, Riverside, and assistant director of the UC Riverside SEARCH Center, said that both studies were "carefully designed and well executed."

"Taken together, [these studies] point to vasopressin as a potential target for clinical trial studies in ASD," said Stavropoulos, who was not involved with the research.

Nevertheless, she raised some concerns.

"For me, the overall take-home is 'cautious optimism,' and I certainly don't want parents or other stakeholders in the autism community to read these studies and think that we have found 'the treatment' for ASD," she said.

Stavropoulos described herself as "highly skeptical that we will ever find 'the' treatment/intervention for ASD, because it is such a highly complex and variable diagnosis."

It's more likely that "we will find interventions that work for certain people with a specific set of symptoms/specific characteristics, but I doubt there will be a one-size-fits-all," she said.

Also commenting for Medscape Medical News, Gianluca Esposito, PhD, assistant professor, Nanyang Technological University, Singapore, and associate professor, University of Trento, Italy, agreed that although the findings were very interesting, "both studies are still very preliminary, as it is not clear how and why the treatments are really working."

In addition, said Esposito, "We really do not know the ideal length of the intervention, chemical concentration of [the] pharmacological substance, as well as whether the results are stable over a long period of time." Esposito was not involved with the research.

Parker noted that if the next phase of their study successfully replicates the current findings, her group will "move into a phase 3 trial, where we would do a multisite approach to investigating vasopressin efficacy and safety in ASD."

The VANILLA trial was funded by F. Hoffmann–La Roche AG. Sanders and all of the study authors are employees of F. Hoffmann–La Roche. The trial by Parker and colleagues was supported through grants to various investigators by the National Institutes of Health, an Autism Speaks Meixner Postdoctoral Fellowship in Translational Research, the Mosbacher Family Fund for Autism Research, the Teresa and Charles Michael Endowed Fund for Autism Research and Education, the Child Health Research Institute, the Yani Calmidis Memorial Fund for Autism Research, and Stanford University's Department of Psychiatry. Parker has reported no relevant financial relationships. The other authors' disclosures are listed in the original article. Stavropoulos and Esposito have reported no relevant financial relationships.

Sci Transl Med. Published online May 1, 2019. Study 1 abstract; Study 2 abstract

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