French pharma companies terminate trials of bumetanide for autism | Spectrum
Limited benefit: Studies of bumetanide have not significantly reduced autism characteristics, but some researchers are unwilling to give up the drug.
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Two phase 3 clinical trials of the diuretic bumetanide were canceled by their sponsors on September 7 after preliminary data showed the drug did no better than a placebo in relieving autism symptoms.
Despite the lackluster results, researchers studying bumetanide say it is too early to give up.
“The inclusion criteria should have been a little stricter,” says co-director Yehezkel Ben-Ari, president and co-founder of the French biotech company Neurochlore, which holds the patent for bumetanide for the treatment of autism.
Neurochlore started both studies in 2018 in collaboration with the French pharmaceutical company Servier Laboratories. The two companies joined forces in 2017 after Neurochlore reported preliminary results that bumetanide alleviated autism characteristics in two different groups of children. Animal studies suggest that the drug corrects an imbalance of excitatory and inhibitory signals in the brain. It is believed that this imbalance contributes to the characteristics of autism.
After the new negative finding, however, Servier ended the partnership and left Neurochlora with no funding to continue the work.
One of the studies involved 211 autistic children aged 2 to 6 years and the other 211 autistic children and adolescents aged 7 to 17 years. At the start of both studies, participants were randomly given either 0.5 milligrams of bumetanide or a placebo twice a day for 6 months; During an open-label, six-month extension study, all participants in both groups should knowingly take the drug.
But at the end of the placebo-controlled portion of each study, participants taking bumetanide fared no differently than controls on a clinician questionnaire called the Childhood Autism Rating Scale, the study’s primary outcome measure. They also did not do better on a parenting questionnaire called the Social Responsiveness Scale, one of the study’s secondary endpoints.
There is a great temptation to blame a trial’s failure on methodological issues, but the simplest explanation would be that bumetanide isn’t helpful in autism, says Jeremy Veenstra-VanderWeele, a professor of psychiatry at Columbia University who is not involved in the trials was involved.
Separately, Ben-Ari and his colleagues re-analyze their data to see if subgroups of participants showed significant differences in autism characteristics after treatment.
A 2020 study of bumetanide for autism led by an independent team also missed its primary endpoint, which was assessed using the Social Responsiveness Scale. However, participants showed improvements in repetitive behaviors, the secondary outcome of the study, and post-hoc analysis suggested that a subset of autistic children and adolescents had improved on both interventions. Previous neurochlorine studies in 2012 and 2017 showed that bumetanide resulted in significant reductions in autism characteristics, but not necessarily in children with severe characteristics.
Anecdotal feedback from parents of participants in the stopped studies also supports this idea, says Ben-Ari.
Limiting future studies of bumetanide to those participants who are most likely to respond could help researchers spot more significant differences between treatment and placebo groups, says Hilgo Bruining, associate professor of psychiatry at Amsterdam University Medical Center in the Netherlands, who will conduct the 2020 study directed.
To this end, Bruining’s team developed a method that uses electroencephalography to identify people who could benefit from the drug due to the proposed mechanism of action. In a randomized, double-blind, placebo-controlled study involving 82 participants with autism, several brainwave markers – including the ratio of excitatory and inhibitory signals – predicted with 92 percent accuracy which participants would show greater reductions in repetitive behavior in response to Bumetanide. The researchers are conducting a post-trial study to further refine the prediction algorithm in these and other participants.
Seeking research partners in academic institutions, Ben-Ari says neurochlorine needs new funding sources to conduct further studies on bumetanide. “Right now the main problem is finances.”
Quote this article: https://doi.org/10.53053/UJIK1183