A Hit and a Miss for Novel Autism Drug

Pauline Anderson

July 18, 2022

Balovaptan, a novel drug that binds to and blocks vasopressin 1A (V1a) receptors, does not improve social communication in children and adolescents with autism spectrum disorder (ASD), new research shows.

Efficacy analysis from a phase 2 trial included more than 160 participants, making it the largest of its kind to date, investigators note.

Although the results were negative, the study does provide useful information to inform future clinical trials, study investigator Eric Hollander, MD, director of the Autism and Obsessive Compulsive Spectrum Program and professor of psychiatry and behavioral sciences at Albert Einstein College of Medicine, Bronx, New York, told Medscape Medical News.

For example, it provides clues about possible changes to study design, subject entry criteria, and outcome measures, Hollander noted.

"This study also tells us that building skills, such as communication skills, from the ground up is very different from just decreasing problem behaviors such as disruptive behaviors — and that we have to understand how we can combine this type of medication with psychosocial treatments in the future," he said.

The findings were published online July 6 in JAMA Psychiatry.

Core ASD Symptoms

Current US Food and Drug Administration–approved medications do not target core symptoms of ASD, which include restrictive or repetitive behaviors and difficulties in communication. Social interaction and communication are partly modulated by neuropeptides, including vasopressin.

Previous studies of therapies that block vasopressin receptors have shown promise. As reported by Medscape Medical News, results from the phase 2 VANILLA study in high functioning younger adults with ASD showed significant change with balovaptan on the secondary outcome measure of improved score on the Vineland Adaptive Behavior Scales.

The current phase 2 clinical trial, known as aV1ation, included children between the ages of 5 and 12 and adolescents between the ages of 13 and 17 years with ASD and an IQ ≥ 70. Enrollment occurred at 41 sites across the United States.

All participants were randomly assigned to receive the equivalent of a 10-mg adult dose of balovaptan or placebo.

The primary endpoint was change from baseline to 24 weeks on the caregiver-assessed Vineland-II two-domain composite (2DC), which combines social and communication domains.

The efficacy analysis included 167 participants (mean age, 12.1 years; 83.2% male; 79.6% White). Of these, 86 received the active treatment and 81 received placebo.

"Treatment differences between groups were estimated using least squares mean (LSM) with 90% CIs," the investigators report.

No Significant Differences

Results showed no significant differences in change on the Vineland-II 2DC score for balovaptan (LSM, 2.17) vs placebo (LSM, 2.34). The difference in adjusted LSM was -0.16 (90% CI, -2.56 to 2.23; P = .91).

There were also no significant differences in any of the secondary endpoints. Hollander noted this was the case whether the outcome was assessed by caregivers or clinicians, and this could be owing to "expectation bias."

"If there's a lot of buzz that there's a new drug that could help core symptoms like social communication, and nothing currently exists, family members or clinicians may get their expectations up and that could contribute to high placebo response," he said.

He added that another factor possibly contributing to lack of separation between the active drug and placebo was the age of the patient population. Perhaps those younger than 5 years would have fared better on the treatment, he said.

"If we can intervene at an earlier stage, we might be able to show a bigger change," said Hollander.

He noted that participants in the current study already had difficulty with social communication "and it's hard to build those skills when they don't previously exist."

Perhaps genotyping should be used to select subgroups that are more likely to respond, he added.

Less Dynamic Than Peptides?

Hollander suggested that a pharmaceutical intervention other than oral balovaptan might be more effective. "We are pretty confident this particular drug, given in this particular fashion, may not be effective," he said.

He noted that though vasopressin peptide is "pumped out in a pulsatile fashion" in response to social engagement, "this compound just binds to the receptor and stays there, so there is less of the dynamic effect we see with these peptide systems in the real world."

Administering a pharmaceutical agent in a pulsatile fashion and perhaps pairing it with social skills training might provide "a more long-lasting and bigger separation from drug and placebo," said Hollander.

It also might be necessary to develop more reliable outcome measures. "We may need to develop digital biomarkers that are closer to the underlying neurobiological dysfunction in the illness and that might be more sensitive to change than a parent or clinician measure," Hollander said.

The good news is that the treatment had "essentially, absolutely no side effects," he noted. "Kids didn't get sedated; they didn't have motor side effects; they didn't have weight gain; and there were no cognitive difficulties."

A robust placebo response, as was shown in this study, poses a significant challenge for drug development in the autism field overall, Hollander noted.

"And it becomes an even bigger problem when we are studying compounds that have no side effects," he said.

Setting the Stage

Commenting on the study for Medscape Medical News, Rachel Brown, MBBS, professor and chair of Psychiatry and Behavioral Sciences, The University of Kansas School of Medicine, Wichita, praised the study for being "well-designed" with sufficient statistical power to engender trust in the findings.

However, part of what sets this study apart is that it is negative, she noted. "We know historically that negative studies are not published," said Brown, who was not involved with the research.

"This is a great example of an initially promising intervention that had some good basis for thinking it had some benefit, but when they did a really good study, they found it doesn't help," she said.

Brown agreed with the investigators that the study sets the stage for developing better biomarkers and to carry out further research to determine whether this drug might fare better in certain subgroups, in younger children, or in those with a particular genetic makeup.

The study was funded by F. Hoffmann-La Roche Ltd. Hollander reported having received research grants from the US Department of Defense, the US Food and Drug Administration, GW Pharma, and F. Hoffmann-La Roche Ltd and editorial stipends from Elsevier. He has also served on scientific advisory boards for GW Pharma and F. Hoffmann-La Roche Ltd. Brown reported no relevant financial relationships.

JAMA Psychiatry. Published online July 6, 2022. Abstract

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