Background: Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials.

Discussion points: The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results.

Conclusion: Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

SJ has received grant support from NIH and F. Hoffmann-La Roche Ltd and has attended advisory boards for Fraser, Minnesota Independence College & Community, and F. Hoffmann-La Roche Ltd. EA has received grant support from F. Hoffmann-La Roche Ltd and SynapDx; royalties from APPI, Springer, and Wiley; has acted as a consultant for Quadrant, F. Hoffmann-La Roche Ltd, and SynapDx; has received honorarium for a webinar from AIDE; has a patent on anxiety meter; and has received a study drug and in kind supports from AMO Pharma. EH has received research grants from the Department of Defense, Food and Drug Administration, GW Pharma, and F. Hoffmann-La Roche Ltd; and editorial stipends from Elsevier; and served on scientific advisory boards for GW Pharma and F. Hoffmann-La Roche Ltd. RJ’s institution received payments for clinical trial agreements from Roche Translational & Clinical Research Center, Inc. and Genentech, Inc. NM has provided research support to F. Hoffmann-La Roche Ltd; and consulted for Shire; grant support has been received from Forest Research Institute, Genentech, Lundbeck, Pfizer, F. Hoffmann-La Roche Ltd, Shire, Sunovion, and Zynerba. LS has received funding from the National Institute of Child Health and Human Development; was paid by F. Hoffmann-La Roche Ltd as a clinical research site investigator for involvement in conducting the VANILLA and aV1ation studies; has attended an advisory board for F. Hoffmann-La Roche Ltd; and has a patent pending for new formulation of intranasal oxytocin by Duke University; part of her salary is paid by the Duke Clinical Research Institute where she is providing thought leadership for trials sponsored by Tris Pharmaceuticals. RT has received grant support from Janssen and F. Hoffmann-La Roche Ltd; and has attended advisory boards for F. Hoffmann-La Roche Ltd. DM receives funding support from the EU/EFPIA/SFARI/Autistica/AUTISM SPEAKS Innovative Medicines Initiative 2 Joint Undertaking (AIMS-2-TRIALS Grant No. 777394); has received grant support from F Hoffmann-La Roche and Shire; royalties from Springer and Wiley; and has attended advisory boards for F Hoffmann-La Roche and Servier. JM has received research support from F. Hoffmann-La Roche Ltd; has attended advisory boards for GW Pharmaceuticals and F. Hoffmann-La Roche Ltd; and was a consultant for Octopharma and TRIS Pharmaceuticals. JV-VW has received research support from NIH, the Simons Foundation, Health Canada, F. Hoffmann-La Roche Ltd, Janssen, Acadia, and Zynerba; royalties from Springer and Wiley; honoraria for lectures at the American Academy of Child and Adolescent Psychiatry, Karolinska Institute, Mount Sinai, National Institute of Neurological Disease and Stroke, Florida Atlantic University, UCLA, Stanford University, Child Mind Institute, and Pennsylvania State University; has attended advisory boards for Roche; serves on the medical and/or scientific advisory boards for Autism Speaks, the Simons Foundation Autism Research Initiative, and the Brain Behavior Research Foundation; and serves as the co-chair of the Autism and Intellectual Disability Committee for the American Academy of Child and Adolescent Psychiatry. EAs is an employee of F. Hoffmann-La Roche Ltd, and has stock options in F. Hoffmann-La Roche Ltd. CC and SC are employees of F. Hoffmann-La Roche Ltd, and have stocks in F. Hoffmann-La Roche Ltd. JS, JN, KS, and LM are employees of F. Hoffmann-La Roche Ltd and have stocks and stock options in F. Hoffmann-La Roche Ltd.

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