The FDA (and other agencies like EMA) usually wants to see two phase 3 studies for the first approved indication. The phase 3's do not have to be designed identically as long as they are for the same indication (Mild to moderate AD in SAVA's case). If one trial for PTI-125 succeeds and one fails, a third study might be needed (what should have happened with Aduhelm IMO) but if both succeed at the primary endpoints they will easily satisfy the FDA's typical expectation.
The safest path for Anavex would be to have a second phase 3 going for AD. However, there are two possible pathways to get by with the results of the 2b/3 only (which should satisfy the FDA for a phase 3 pivotal study if results are good). Missling is hoping that Rett is approved (or in mid 2022 have great results for Excellence implying likelihood of approval is high). If so, then they could submit an NDA for A273 for AD with one phase 3 (as the FDA often requires only one phase 3 for a drug already approved for a different indication). This path will work if the FDA does not have a problem with the different age categories. A second path to get approval with one phase 3 is the Accelerated Approval pathway that the FDA surprised us with in the case of Aduhelm. To get this approval the FDA will need to accept the S1R mRNA data as a biomarker. This is no small feat and the second path is riskier than the first.
If everything falls into place and A273 is approved for Rett and Anavex can shortly thereafter submit the NDA after one phase 3 (or if the FDA accepts S1R mRNA as a biomarker), then Missling is a hero. If the FDA holds fast on the 2 Phase 3 requirement, then he is a zero who squandered a huge opportunity losing 3 years by not starting a second phase 3 in 2020.
