Clinical Trials Examining Rett Syndrome


David Lieberman, MD, PhD, discusses the results of the phase 3 LAVENDER trial of trofinetide and the phase 3 AVATAR trial of blarcamesine and how patients and families can learn about eligible clinical trials for possible participation.

David Lieberman, MD, PhD: The true phenotype trial by Acadia Pharmaceutical had 2 co–end points: the RSBQ (the Rett syndrome behavior questionnaire) and the CGI, a clinical global impression of improvement. This was a double-blind, placebo-controlled trial in girls and women aged 5 to 20 years old. There was an improvement in the RSBQ score that’s provided by the caregiver. There was an improvement in the CGI improvement score that was provided by the clinician. There were some [adverse] effects of vomiting and diarrhea, but many of the patients were able to complete that trial. There’s an open-label extension study that’s still ongoing for girls and women who are still on that trial. There has been also a small trial looking at girls aged 2 to 5 as an open-label trial to see how trofinetide helps them when it’s given at an earlier age than in the original trial. The improvements in the RSBQ and the CGI were small but statistically significant. Among neurodevelopmental disorders, it’s one of the first positive trials in quite some time. For example, in fragile X [syndrome], which is another neurodevelopmental disorder, they’ve had a hard time bringing things that look very promising from animal research to clinical trials, which been disappointing. To have a positive effect from a trial that’s just a matter of a few weeks in duration is encouraging, and we’ll just have to see how this plays out with the review by the FDA.

There is a trial [being conducted] by Anavex Pharmaceuticals of blarcamesine, which is a sigma-1 receptor ligand. They were also looking at RSBQ and CGI, and had other measures as well as secondary end points, including some measures of…GABA [gamma-aminobutyric acid] in the bloodstream. They also found positive effects of their compound, as well as an improvement in seizure frequency. It was a smaller trial, and they’re still collecting some data for 1 of their phase 3 studies. I think they’ll be presenting their data to the FDA in the next year or 2.

The treatment landscape with these 2 new agents being brought to clinical trials is encouraging. It suggests that we may be able to at least reduce the number of drugs that we might be administering to patients. As I said earlier, we’ve been kind of doing a 1 symptom, 1 drug or a 1 symptom, 2 drugs approach. If we find that 1 of these compounds can improve their gastrointestinal function and reduce their seizures, then we can either cut down on the number or at least cut down on the dose of co-administered medications. Because these compounds work by improving neuronal function, we have the possibility of improving some of the core features of Rett that we don’t really have adequate medications for at present. I think the Rett community is excited to see something new on the horizon and something promising that they could try.

For families that might be interested in participating in clinical trials, the International Rett Syndrome Foundation has a trial finder. This web-based tool can provide some information about what clinical trials are out there, where they’re located, and who to contact to get into those trials. is a government website that lists all federal trials going on in the US, searchable by key words. Also, it provides some contact information for the providers there. We’ve had a very good response from the families that come to our clinic to participate in clinical trials. [The families are very motivated] to try to find ways to improve the lives of their kids. There are different ways you can participate in trials. There are interventional trials that may involve pharmaceuticals, but there are also observational trials that just require the patient to participate in some measurement in a clinic setting, [such as] questionnaires that the families can complete at home. All these trials are important to help move the field forward and to bring promising compounds to market.

Transcript edited for clarity.

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