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Published March 2022 | Supplemental Material
Journal Article Open

Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial

Abstract

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.

Additional Information

© 2022 Nature Publishing Group. Received 25 June 2021; Accepted 05 January 2022; Published 14 February 2022. We acknowledge the study participants and their families for their generous contributions of time and effort to this study. This work was supported by funds from Axial Therapeutics and was conducted by, and in collaboration with, the company. Data availability: Data generated or analyzed during this study are included in this published article, and individual de-identified participant data can be found in the Supplementary Information. Axial Therapeutics ('Axial'), under certain restrictions below, will provide access to at least the minimum datasets from its clinical trials that are necessary to interpret, verify and extend the research findings. Axial considers that the minimum datasets might include the study protocol (already provided as Supplementary Data) and the tables, lists and figures from the final Clinical Study Report. Such datasets will be made available only to qualified scientific researchers for legitimate scientific research purposes. Simultaneously, Axial is mandated by law and otherwise is committed to protecting the privacy and rights of all individuals who participate in its clinical trials; therefore, all data supplied will be de-identified according to applicable regulations. Data requests should be sent to the corresponding author, A. Stewart Campbell, at stewart@axialtx.com (subject line: 'AB-2004 Clinical Trial Data Request'). All data requests must be clearly described in a written proposal, including statement of research purpose, research plan and methods (including statistical analysis plan, if applicable), key research personnel and data sharing plans. All requests meeting submission requirements will be promptly considered for scientific merit by internal and external (if necessary) subject matter experts and compliance personnel, and a written response approving or denying access to the data will be provided. Approved requests will result in access to the necessary data through a secure data sharing portal, and access will be granted for a pre-specified defined period of time that is commensurate with the research plan. Under approved requests, Axial and the interested party must enter a data sharing agreement that will govern the terms and conditions for use, storage and communication of the data and terms for co-authorship resulting from any publication of the research results. It is recognized that certain regulations might apply in different countries, states or regions that might affect what data may be shared and with whom; Axial cannot guarantee access to the requested data in these circumstances. Source data are provided with this paper. Author Contributions: These authors contributed equally: A. Stewart Campbell, Brittany D. Needham, Christopher R. Meyer. Conceptualization: A.S.C., B.D.N., D.H.D. and S.K.M. Preclinical methodology: B.D.N. and S.K.M. Clinical methodology: A.S.C., C.R.M., M.C., G.M.P. and S.R. Formal analysis: B.D.N., C.R.M., G.M.P., A.C.J. and B.F. Preclinical investigation: B.D.N. Clinical investigation: A.S.C., C.R.M., J.T., G.M.P., F.B., H.H., R.G., A.G., A.C.J. and B.F. Resources: Axial Therapeutics. Writing—original draft: B.D.N. Writing—review and editing: A.S.C., B.D.N., C.R.M., F.B. and S.K.M. Visualization: B.D.N. Preclinical supervision: S.K.M. Clinical supervision: A.S.C. Project administration: B.D.N. and C.R.M. Funding acquisition: Axial Therapeutics. Competing interests: A.S.C., C.R.M., M.C., G.M.P., F.B., S.R., D.H.D. and S.K.M. have financial interests in Axial Therapeutics. J.T., A.C.J. and B.F. were paid consultants of Axial Therapeutics. H.H., R.G. and A.J.G. are investigators at clinics contracted by Axial Therapeutics. B.D.N. declares no competing interests. Peer review information: Nature Medicine thanks Ruth Luna and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jerome Staal was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Created:
August 22, 2023
Modified:
December 22, 2023