Ann: Comment on research report, page-186

We can draw no causative conclusions from FAERS but no life-threatening events have been reported. It was made clear by Acadia and Neuren that Daybue had side-effects and many community support groups offer assistance with this.

A 2023 Epidemiology report paper released in the US offers some better insights into what the average Rett patient experiences. This would have been published just prior to patients receiving Daybue. (see study here).

The authors acknowledge gaps in available data for Rett patients in the US. Highlighting a lack of understanding around the following:

· Health care resource utilization and

· Health care costs

Of the Rett patients surveyed nearly 25% had hospital admissions for lower respiratory tract infections in the previous 5 years. Roughly 12% had 2 or more admissions. Unfortunately, there were no % rates for overall hospital admissions given in the study.

It is difficult to determine then if 1 in 10 or 11 Daybue patients being hospitalised is more or less than the number of hospitalisations expected by Rett complications alone. So the quote in the Culper research report offers no particular insight as there is no context whether Daybue causes higher hospitalisation rates.

The most common clinical manifestations of Rett without Daybue treatment include:

· Neurological disorders 72.8%

· Gastrointestinal/ nutritional disorders 41.9%

· Orthopedic disorders 34.6%

The authors reported an average of 44.43 health related visits per patient per year. Feeding assistance (37.9%) was the most prevalent supportive therapy required for Rett patients. So gastro-intestinal and nutritional management is definitely part of the Rett treatment pathway whether on Daybue or not. The requirement for anti-epileptic drugs (54.8%) was also a prevalent support requirement. The conclusion of the above study was that Rett patients had a substantial disease burden. The FDA adverse events reported in the short report very much match the disease burden of a patient with Rett syndrome.