A new medication aiming to improve the quality of life of people with autism spectrum disorder (ASD) is well tolerated by adolescents and significantly reduces irritability and anxiety, according to the results of a Phase I clinical trial. The drug, AB-2004, binds to and removes certain gut bacteria metabolites in the intestines, but produces no systemic effects as it is not absorbed into the bloodstream. The link between autism and gut bacteria is not fully established, although a growing body of research hints at a connection between ASD and the microbiome. In the journal Nature Medicine, the study authors explain that many people with autism also present with gastrointestinal [GI] issues and that some gut bacteria metabolites appear to be associated with certain behavioral traits. For example, one particular metabolite called 4-ethylphenyl sulfate (4EPS) has been shown to induce anxiety and other behavioral symptoms when injected into rodents, and is often dysregulated in the feces and blood plasma of individuals with ASD. At present, there are no effective pharmacological treatments for the core symptoms of autism, although anti-psychotic drugs are sometimes used to alleviate irritability. Unfortunately, these medications are associated with a range of negative side effects, highlighting a need for alternative therapies that do not produce any deleterious systemic effects. The study authors explain how “taken orally, [AB-2004] binds and sequesters related aromatic metabolites as it passes through the GI tract without being absorbed and is ultimately excreted, effectively lowering systemic metabolite exposure.” After administering the drug to 30 young people with both ASD and GI complications in Australia and New Zealand, the researchers observed no serious drug-related adverse events. “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,” they write. Among the metabolites that were reduced by the drug were 4EPS and a number of other compounds associated with autism. “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,” explain the researchers. While the improvements in anxiety persisted for several weeks after treatment ended, reductions in irritability soon returned to baseline. Nevertheless, the researchers are highly encouraged by their findings, and explain that “to our knowledge, this is the first interventional study linking phenolic metabolites in the gut with clinical features of ASD.” Though the alterations in symptomology observed during this trial are encouraging, the main objective of the study was to determine the drug’s safety profile. Confirming that it produces no apparent systemic effects, the authors say that AB-2004 could offer a preferable alternative to current treatments, revealing that they have already begun a placebo-controlled Phase II trial involving 195 young people with ASD. Robert L. Hendren, the principal investigator of the Phase II study, explained in a statement that “the lack of safe and effective treatment options for co-occurring conditions associated with ASD, such as irritability and anxiety, exacerbate the daily challenges faced by children and their families.” “A gut-targeted therapeutic approach that safely mitigates the role of bacterial metabolites on traits associated with autism would be an ideal option for addressing the significant unmet treatment need.” Future trials will reveal just how effective AB-2004 is at producing the desired therapeutic effects, although results so far certainly provide cause for optimism. Source
