"Distressing indeed that the poster DOC, an obviously sharp medical cat and neurologist, has said a 20 percent chance of success on the read out, if I understand him, and he is very generous here with his outstanding insights and thoughts on this board, to what most here are, "laymen"...albeit interested and closely watching laymen, and so many here themselves sophisticated and knowledgeable about the area as laymen. Can anybody suggest why he might be too conservative in his assessment?"
Excellent question.
I have tried to probe his reasoning on that point, and (pending his response to you) here are my conclusions:
1. Doc does not buy the premise that 2-73 has a unique mechanism of action. After all, it is an agonist of the Sigma-1 receptor and Donepezil, the only approved drug for Alzheimer's, is also an agonist of the same receptor. Therefore, we should not expect a significantly different outcome when the two drugs agonize the same receptor, even though he grants that there are other clinical distinctions between the drugs (which for our purposes here would be considered secondary).
2. In response to my question, his position is that Anavex has not even designed its Phase 2 PDD test in a way that would result in an accelerated approval for the primary endpoint.
Doc is a neurologist, so he is a rare resource on this board. He is the expert here on trial protocols and practice. However, I read him as primarily a clinician rather than an academic or a theorist. Theorists and clinicians have different worldviews. They each have their strengths, and imagination is a strength of the theorist. You have to have imagination to believe that not everything should be evaluated according to what has been, and that not everything is being operated as it should be. You have to be much more open to questioning standard practice and beliefs.
Doc is holding to the standard belief that one drug should, at least as a default, be analogized to an existing drug. I have been looking, in particular, at the historical posts of falconer and amstocks. They support the premise of 2-73 as a unique drug. Amstocks, also clearly an expert in this field, has said directly that every Sigma-1 agonist will have a different biological effect -- i.e., it is not one size fits all. We can look at the Phase 1 AD trial and its aftermath and see support for that claim. Critically for me, Doc has not addressed their arguments and evidence.
I also do not understand why Anavex would design a Phase 2 PDD trial that was designed to favor the development of secondary endpoints over a primary endpoint. Why not just make the secondary endpoints, or some of them, primary? (I am sure there is an answer for this, but as a layman I can't see it.)
Doc has also evaded my question as to what would represent a successful Phase 2 PDD trial if the 5.5 delta threshold for the existing therapeutic is more illusory than real since Missling has stated that the existing drug is not used due to its side effects.
The short answer is that I, the layman, have the temerity to believe that Doc, the neurologist, has misread the meaning of Anavex's 2-73. So in my ignorance, or because of my imagination and openness to possibility, I am more optimistic.
