WAG, the unresolved issue is the choice of Primary Endpoint/s....

WAG, the unresolved issue is the choice of Primary Endpoint/s.

We don’t know what Neuren proposed to the FDA but there’s a good chance they wanted to use the Clinical Global Impression of Improvement (CGI-I), which rates overall improvement in each patient from baseline and is measured by a clinician. This was used in the Phase 2 trial, and a clinically and statistically significant mean score of 2.4 (p = <0.0001) was achieved, with 16 out of 18 children showing improvement.

As occurred in the trofinetide Rett syndrome trial and the Phase 2 trials of NNZ-2591 in Pitt Hopkins syndrome and Angelman syndrome, an indication specific adapted measurement scale has been developed and used. So although the CGI-I is a well-known and long-established efficacy measure, the indication-specific CGI-I endpoint used in the PMS Phase 2 trial to measure efficacy is novel.

My thinking is that the FDA is not totally convinced of the validity/robustness of this scale to measure improvement. It is probably seeking a more traditional, already validated measurement scale to be used for the primary efficacy endpoint or is perhaps demanding the addition of a well-established measure as co- primary endpoint.

This is just my speculation.