Firstly, I’d like to point out that this article is not new to...

Firstly, I’d like to point out that this article is not new to this forum. It was already shared here earlier last month.

I didn’t comment on the article at the time but I will now.

According to the article, experts say that current outcome measures in Rett syndrome clinical trials lack the sensitivity to measure nuanced changes.

It states that research is underway in animal and human models to validate new Rett syndrome biomarkers and endpoints.

This is unremarkable. Researchers are always casting a critical eye over what exists and are always looking for ways to improve on things like treatments and measurements.

Respected Rett researcher, Dr Alan Percy, is quoted in the article. He says that, while RSBQ is a validated endpoint, in his opinion, it doesn’t place enough focus on Rett’s physical manifestations, including walking and hand use.

While that may be Dr Percy’s opinion, note that he clearly states that the RSBQ is validated. Also, it’s important to remember that, prior to the pivotal trial of trofinetide in Rett syndrome, the RSBQ was agreed upon by the FDA as a co-primary endpoint. In addition, be careful not to conclude that the RSBQ lacks any measurement of physical manifestations of Rett syndrome. The RSBQ measures 45 items, grouped into 8 subscales: General Mood, Breathing Abnormalities, Hand Behaviours, Repetitive Face Movements, Body Rocking and Expressionless Face, Night-time Behaviour, Fear/Anxiety and Walking/Standing. Note, 5 of the 8 subscales measure physical manifestations of the disease with just 3 being related to emotional behaviours. Yet Dr Percy thinks that the RSBQ doesn’t place enough focus on Rett’s physical manifestations?

The author, William Newton, then writes

In open-label trials so far, neither asset (trofinetide, ANAVEX2-73) has shown any apparent improvement in these physical outcomes, he (Percy) says.

I’m going to give Dr.Percy the benefit of the doubt and conclude that it is William Newton who has dropped the clanger here. As shareholders of Neuren are well aware, until the recent Lilac trial, all clinical trials of trofinetide have used the gold-standard trial design – randomized, double-blind and placebo-contolled. Furthermore, Dr Percy would be well aware of this, as he was an Investigator for both the adult and paediatric Phase 2 trofinetide in Rett trials and co-authored papers following both trials. Below is the conclusion from one of those papers.

A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome

Conclusion: Trofinetide was well tolerated in adolescent and adult females with Rett syndrome. Although this study had a relatively short duration in a small number of subjects with an advanced stage of disease, consistent efficacy trends at the higher dose were observed in several outcome measures that assess important dimensions of Rett syndrome. These results represented clinically meaningful improvement from the perspective of the clinicians as well as the caregivers.

https://pubmed.ncbi.nlm.nih.gov/28964591/

I’ll also point out that this article was published last month, prior to the trofinetide Phase 3 results being released. The results in Phase 3 were even better that those of the two Phase 2 trials. Therefore I'd assume that, as Dr. Percy deemed that Phase 2 trofinetide results represented "clinically meaningful improvement from the perspective of the clinicians as well as the caregivers", he would be even more impressed by the Phase 3 results.

Finally, for anyone who might be concerned that the trial results didn’t capture improvements in the physical manifestations of Rett, I provide the RSBQ subscores treatment difference full analysis set from the trial below.