"The market is betting on a 5% chance of success which is...

"The market is betting on a 5% chance of success which is realistic" - I think the market is implying a significantly lower probability of success than the 5% you have suggested. However, even if we were take your 5% estimate with an understanding of the developments in the AD sphere, it is evident that a number of factors suggests the likelihood of achieving a CLEAN result is substantially higher than 5% (20% to 30% is my estimate).

The factors in favour of a clean result :-

1) The safety profile is excellent and well-documented.

2) Alzheimer's disease now has a defined endpoint; with the approval of aducanumab, lecanemab, and donanemab, there exists a flawed but recognized primary endpoint that facilitates FDA approval. This recent development enables trials to be better designed or optimized to achieve this endpoint.

3) The trial is exceptionally well-designed, straightforward, with a low burden, and is poised to be one of the most accurate pivotal Alzheimer's disease trials conducted to date.

4) The trial inclusion criteria utilize a p-Tau181 BB biomarker to ensure the exclusion of low or non-responders from the trial.

5) The Cortisol mechanism of action is clearly involved in the Alzheimer's disease cascade, and there is evidence that Xanamem exhibits (at least short-term) procognitive properties in healthy older individuals.

6) There is a clear link between a midlife diagnosis of major depressive disorder and the development of Alzheimer's disease, and Xanamem has demonstrated evidence of impact on both conditions.

Another important point is that this trial focuses on patients with mild to moderate Alzheimer's disease, which we can detect and monitor with relative accuracy. However, developers of amyloid beta and tau-focused drugs have already abandoned this area due to their inability to achieve measurable or meaningful slowing of cognitive decline. These developers are now targeting mild cognitive impairment (MCI) and prodromal stages of the disease, which are extremely challenging to detect cognitively and even more difficult to assess for drug efficacy in terms of cognitive improvement.