Investor and frrol raised excellent questions. The company had access to these subgroup data since the 2022 CTAD, yet only released detailed results at the 2024 AAIC and CTAD conferences. Why the delay? It seems likely that none of the prespecified subgroups achieved statistical significance on both co-primary endpoints under the current SAP, which limits any claim of trial success. This implies the new data adds little to previously disclosed but challenged outcomes under the agreed SAP.
Why hasn’t the company acknowledged a trial failure per the agreed SAP and initiated a targeted Phase 3? The likely explanation is their awareness—perhaps through Dr. Kun—of the pending FDA “sole endpoint” guideline, so they opted to await its finalization.
Currently, I believe the company is waiting on three critical elements before filing:
1. EMA “sole endpoint” guidance: The FDA’s draft guideline was highlighted at AAIC 2024, and the 2024 CTAD noted an equivalent EMA version is forthcoming.
2. Interim OLE results: Even for endpoints like ADAS-Cog and CDR-SB that met significance, efficacy was only notable at week 48, so short of starting a confirmatory trial, the interim OLE results are essential to confirm sustained benefit.
3. Peer-reviewed publication: Academic validation, though not a filing prerequisite, could reinforce clinical confidence.
Items 1 and 2 are also the 2 largest remaining risk factors IMO. #3 does not need to be published but needs to be in the acceptance stage.
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