A hand reaches from above to add a pill to a stack that is resting against the x-axis of a graph.
Illustration by Laurène Boglio
Illustration by Laurène Boglio

Going on Trial: Arbaclofen reboot; cell implants; psilocybin microdoses

Going on Trial rounds up new developments in autism-related drug trials. This month we’re revisiting decade-old data from a trial of arbaclofen for fragile X syndrome and looking into a new implant-based approach to quelling seizures, among other treatment strategies.

Welcome to the first edition of Going on Trial, a monthly newsletter rounding up the latest developments in autism-related drug trials. In this issue, we recap new developments about arbaclofen, an experimental cell implant therapy, psilocybin, ketamine and oxytocin.

This newsletter is in its safety and dose-finding phase, so email me at [email protected] with your tips, questions or feedback on how to improve it. And don’t forget to subscribe to receive this newsletter in your inbox every month.

 A fragile X treatment, revisited:

Almost half of 38 children with fragile X syndrome who took a high dose of the drug arbaclofen showed clinically meaningful improvements in irritability, social avoidance and social responsiveness, compared with 4 percent of the 44 who got a placebo. The results, presented last year by Allos Pharma at the National Fragile X Foundation International Fragile X Conference in San Diego, California, yielded a p-value of 0.00003 (values of less than 0.001 are typically considered highly statistically significant).

The data came from a trial of 5- to 11-year-olds that wrapped up in 2013. The original results showed no significant benefit over placebo, but Allos re-analyzed the data after it licensed the rights to develop the drug for fragile X syndrome in 2020, Fragile X News Today reported last August. The researchers applied new thresholds for improvement to subscales of the Aberrant Behavior Checklist, which is filled out by parents and served as the trial’s outcome measure.

This re-analysis of the drug, which dampens inhibitory signaling via gamma-aminobutyric acid (GABA) receptors, is “very exciting,” says Joseph Piven, professor of psychiatry and pediatrics at the University of North Carolina at Chapel Hill, who was not involved in the study or the re-analysis. But the small number of participants means that the results require replication, he adds.

Placebo issues are also a concern, says Allan Reiss, professor of psychiatry and behavioral sciences at Stanford University in California, who was not involved in the original trial or the re-analysis.

“One of the big issues to consider in these studies is whether the active medication group was truly blinded, since arbaclofen is known to have adverse effects,” he says.  “On the other hand, it is possible that some of these effects” — mild sedation, for instance — “could have accounted for the ‘therapeutic response’ in a proportion of participants in the active arm.”

Having participants complete a learning test that assesses how much they improve in specific cognitive abilities could paint a clearer picture of the drug’s benefits, Reiss says. “I am cautious about clinical trial results that utilize drug versus placebo-only designs in children with long-standing neurodevelopmental problems like fragile X syndrome.”

 Seizure relief from cell therapy:

Two people with drug-resistant epilepsy experienced significant relief from their seizures after doctors implanted a single dose of inhibitory neurons into the hyperexcitable parts of their brains, according to preliminary results presented at the American Epilepsy Society meeting in December. One of the trial participants went from having more than 30 seizures per month to just 4 seizures over three months after receiving the treatment, dubbed NRTX-1001 and created by Neurona Therapeutics in San Francisco, California. That participant has also experienced no serious adverse events, according to the December presentation. The other participant went from having 14 seizures per month to only 1 in the month following treatment.

“It’s exciting work to address an important problem,” says Paul Knoepfler, professor of cell biology and human anatomy at the University of California, Davis, who is not working on the ongoing trial. “Overall, the clinical work seems off to a good start.”

Long-term monitoring of the trial participants will be key to understanding how the treatment works — and to assessing possible safety issues, Knoepfler says. “For example, in some participants the new inhibitory neurons might exhibit unexpected activity. There’s also the possibility of transplanted cells proliferating or migrating to areas where you don’t want them.”

Another fascinating question, he adds, is how long the transplanted neurons remain effective.

Drug samples:

  • Children with Dravet syndrome or Lennox-Gastaut syndrome, severe forms of epilepsy linked to autism, saw their seizures drop by an average of 50 and 17 percent, respectively, while taking the anti-seizure drug soticlestat, according to the results of a phase 2 trial.
  • In mice modeling Phelan-McDermid syndrome, treatment with an investigational drug derived from insulin-like growth factor-binding protein 2 (IGFBP2) rescues synapse and circuit dysfunctions, as well as several behavioral deficits, according to a preclinical study targeting synaptic plasticity.
  • On 12 March, the U.S. Food and Drug Administration (FDA) plans to announce its decision on whether to approve the investigational drug trofinetide to treat the core traits of Rett syndrome.
  • A gene therapy for Angelman syndrome boosts the expression of the protein UBE3A in the brains of wildtype monkeys, suggesting that it could do the same in people with the condition, who lack UBE3A.
  • A trial of another gene therapy for Angelman has restarted after serious adverse events caused it to be put on hold in 2020.
  • Children with a rare form of autism called ADNP syndrome showed improvement across multiple domains after low doses of ketamine, a new open-label study with 10 participants shows. And the children’s electrophysiological data proved effective for tracking their responses to the treatment, the study also shows. Ketamine has shown mixed results in clinical trials for autism and related conditions, but clinicians and multiple teams of researchers are continuing to pursue it, Spectrum reported in June.
  • A phase 2 clinical trial of the drug alogabat is recruiting 15- to 45-year-old participants with autism. The drug acts on the inhibitory neurotransmitter GABA, and sponsor Hoffmann-La Roche has identified adaptive behavior as the trial’s primary outcome measure. A second trial of alogabat, seeking children and teenagers with Angelman syndrome, has been posted but is not yet recruiting as of this newsletter’s publication.
  • Ten people with fragile X syndrome are set to receive microdoses of psilocybin after Vancouver-based biotech company Nova Mentis gained approval from Health Canada to start a phase 2A open-label trial in partnership with KGK Science. Miniscule doses of psilocybin rescue a cognitive deficit in rats modeling fragile X syndrome, according to a December study from a team including Nova Mentis scientists.
  • A group of 21 autistic men who received oxytocin showed several changes in amygdala activity compared with 17 who received placebo, according to a double-blind, randomized brain-imaging study. But these changes did not differ significantly between men who got a single dose and those who took 28 daily doses.
  • Children with 22q11.2 deletion syndrome who received the transdermal cannabidiol gel Zygel showed significant improvement on multiple measures, including anxiety and aberrant behaviors, according to a phase 2 trial completed last year. As a result, in November the European Commission granted drugmaker Zynerba Pharmaceuticals orphan drug designation for Zygel, which fast-tracks the drug’s approval process and gives the company exclusive marketing rights if it is approved. Zynerba is also pursuing Zygel as a treatment for fragile X syndrome.

And that’s it for our first edition of Going on Trial! Be sure to subscribe so you can receive this newsletter in your inbox every month.