Ann: Phase 2 trial shows significant improvements in Angelman, page-84

For those who think the NNZ-2591 trial results have been weak, I suggest that the NNZ-2591 Phase 2 results be compared against the Phase 3 results for trofinetide in Rett Syndrome (the Lavender main trial and the Lilac extension trial), which were the results which led to FDA approval.

A couple of points to note:

As we know, the three NNZ-2591 Phase 2 trials to date have been small and were not placebo-controlled.

I have chosen the CGI-I scale (which is clinician-assessed) for comparison as it has been reported in each of the trials, albeit the CGI-I scale for each syndrome is anchored specifically to symptoms of the particular syndrome. The Clinical Global Impression – Improvement scale (CGI-I) is a 7-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. A score of 4 represents no change, 3 minimally improved, 2 much improved and 1 very much improved. The  lower the CGI-I mean score, the better. A change in score of 1 or more is considered to be clinically significant.

Please note that in the trofinetide Phase 3 trial, participants received full dose for 12 weeks and the Lilac extension trial results followed a year of dosing (12 wks + 40 wks). As can be seen in the CGI-I mean scores and graphs provided below, continued improvement was seen over time.

In the three NNZ-2591 Phase 2 trials, patients were titrated upwards for 6 weeks and then continued at full dose for 7 weeks. The trofinetide results suggest that the NNZ-2591 scores would improve even further over a longer time frame.

The NNZ-2591 Phase 2 trials have been conducted in different indications, at different centres, using different investigators. Hence, seeing improvement consistently across all three of the NNZ-2591 trials provides greater confidence in the reliability of the results.

Rett Syndrome Lavender Phase 3 trial - Trofinetide

12 weeks at full dose

CGI-I mean score of 3.5 (vs. 3.8 placebo) (p=0.003)




Rett Syndrome LILAC Phase 3 Extension Trial – Trofinetide

40 weeks following 12 week Lavender Trial

CGI-I mean score of 3.1




Phelan McDermid Syndrome Phase 2 Trial – NNZ-2591

6 weeks up titration and 7 weeks at full dose

CGI-I mean score of 2.4 (p= 0.0001)





Pitt-Hopkins Syndrome Phase 2 Trial – NNZ-2591

6 weeks up titration and 7 weeks at full dose

CGI-I mean score of 2.6 (p= 0.0039) (N=11 completed); (p=0.0205) (N=15 including discontinued participants)






Angelman Syndrome Phase 2 Trial – NNZ-2591

6 weeks up titration and 7 weeks at full dose

CGI-I mean score of 3.0 (p= 0.0010)
CGI-I Mean Score of 2.8 (p=0.0078) for 8 children in 3-12 age group