I agree. I guarantee the current share price has affected some...

I agree. I guarantee the current share price has affected some shareholders interpretation of the FDA meeting update.

If they don't believe me, I would encourage them to consider these points:

• This situation is different to our experience with Trof (Daybue) because Trof had a larger Phase 2B trial that had far higher patient numbers and was a blinded placebo control with already established Rett Specific Endpoints (RSBQ) validated and accepted by the FDA in Phase 2. The decision to go with smaller patient numbers and non-placebo controlled is consistent with Management taking the view of expediting the process because the clinical data is so much stronger - it is harder to show statistically significant efficacy improvement with smaller patient numbers. This is a calculated risk that has paid off (so far). This Phase 3 will skip the requirement and investment of the 2B trial that was needed for Trof and paves the way for thefirst proposed Phase 3 trial for Phelan McDermid Syndrome If there was already an existing protocol the company didn't adhere to, there would be more of a claim that 'management dropped the ball' as suggested by other posters, but in this case that argument doesn't hold water.
• The Phase 2 results (whilst smaller numbers) are improved from both a safety and efficacy perspective compared to Daybue which was ultimately approved.
• The Phase 2 results included a number of 'other measures' to potential be used in a Phase 3 study (Such as Bayley-4), so management were clearly ready for this discussion. The CGI-I will likely be a primary endpoint, but the question are the subdomains and the use of the other endpoints. Presumably the Global Impression of Improvement vs the Global Impression of Severity

AS Clinical Global Impression of Improvement (CGI-I)
11 out of 13 children showed improvement measured by the AS Clinical Global Impression of
Improvement (CGI-I), an assessment by the clinician of the child’s overall status compared with baseline.
The mean CGI-I score was 3.0 (p=0.0010). Two children received a score of 2 (“much improved”). In the
3-12 years age group all 8 children showed improvement, with a mean score of 2.8 (p=0.0078).

AS Caregiver Overall Impression of Change (CIC)
8 out of 121 children showed improvement measured by the AS Caregiver Overall Impression of Change
(CIC), an assessment by the caregiver of the child’s overall status compared with baseline. The mean CIC
score was 3.2 (p=0.0273). Three children received a score of 2 (“much improved”). In the 3-12 years age
group all 8 children showed improvement, with a mean score of 2.8 (p=0.0078).

AS Clinical Global Impression of Severity (CGI-S)
Four children showed improvement measured by the AS Clinical Global Impression of Severity (CGI-S), an
assessment by the clinician of the child’s overall severity of illness, compared with the assessment at
baseline.


Not I am not a medical professional, but the primary difference in the results here is that data seems to be strongest for impression of change over impression of Severity whether it be assessed from a clinician or a caregiver. My assumption (and I could be wrong) is that measuring the improvement is much easier over smaller time periods such as 13 weeks compared to change of severity of the underlying syndrome itself.

CIC gives insight from a caregiver’s perspective on the overall perceived improvement or decline.
CGI-S provides a clinical view of how severe the illness is at a given time.
CGI-I focuses on the clinical improvement or worsening over a specific period, typically following an intervention or treatment.

The Lavendar trial used CGI-I as the primary endpoint, but it was a 40-week trial rather than what is being proposed, a 12-week trial. On that basis I would imagine Neuren has a fair case to use those endpoints for NNZ-2591 program, rather than opting for CGI-I and perhaps risking weaker results, or needing to have a longer trial to give the most chance of a meaningful improvement against Placebo (which was core issue with Daybue/Trof leading into Phase 3).