I actually think this is one of the better articles I have read on SA regarding Anavex 2-73 and Alzheimer's disease. Clear, concise and (despite the obvious writer's interest in the success of Anavex 2-73) pretty unbiased.
Many of you here will know that I have serious reservations about the efficacy data presented so far, and the data analyses generally. We could discuss that all day, but that is not what the above article is about. Instead, I'd like to address a few points regarding the basic science behind the compound, and its proposed mechanism of action.
The receptor binding profile of Anavex 2-73 is: Ki of 860 nM for sigma 1 receptor (S1R), no affinity for sigma 2 receptor (S2R), uM affinities for muscarinic M1–M4 receptors (3.3–5.2 uM), sodium channel site 2 (5.1 uM), and NMDA receptors (8.0 uM)(http://bit.ly/1OaDYD6).
In simple terms. this means that Anavex 2-73 is a weak-to-borderline muscarinic agonist. It is highly likely that Anavex 2-73 meaningfully engages muscarinic receptors at therapeutic doses or salivation would have been seen as an adverse event in the Ph2 trial (http://1.usa.gov/1HW0eft, http://bit.ly/1j5wNRo). Several companies, with different M1 drugs, have tried dosing paradigms that maintain cognitive benefits without causing salivation and related AEs, but failed. That principally leaves the S1R agonistic effects of the compound.
Anavex (via Anavex PLUS) intend to use 2-73 in combination with Donepezil. Anavex 2-73 is a weak S1R agonist (Ki of 860 nM). Donepezil on the other hand is a potent (non-selective) S1R agonist (Ki 14nM-29nM, http://bit.ly/1QCqT82, http://1.usa.gov/1PJrmED). In simple terms, about 30x more potent than Anavex 2-73. Unlike Anavex 2-73, there is clear evidence that donepezil occupies S1R at high levels at therapeutic doses (http://1.usa.gov/1Ljob0d).
One could hypothesise that, despite the high S1R occupancy by donepezil, agonism of S1R remains suboptimal, and that a higher degree of receptor agonism is required. The next move in that scenario would, however, be to apply a very potent sigma 1 agonist with better PK/PD to maximise sigma 1 receptor occupancy. Anavex 2-73 is, unfortunately, a weak agonist. It would be preferable to try a drug such as the generic SSRI fluvoxamine, which is also a potent S1R agonist (Ki 17nM, http://bit.ly/1QCqT82) with good S1R target engagement in the brain (http://1.usa.gov/1kTsNVi). Fluvoxamine is already prescribed for the depressive/anxiety symptoms of (late) Alzheimer's and may actually have utility for Alzheimer's delirium (http://bit.ly/1j0OAJD). Certainly Anavex's compound-specific US patent (https://t.co/vlHyP1E035) would not protect against this kind of off-label, generic competition.
One could alternatively (speculatively) hypothesise that Anavex 2-73 has some unusual, unspecified mechanism of agonism that is superior to donepezil (despite the fact that donepezil is 30x more potent). Given the difference in potency between the agonists, however, it is likely that donepezil would out-compete Anavex 2-73 for S1R binding in almost all paradigms. It would therefore be critical to demonstrate that Anavex 2-73 receptor binding is possible in the presence of donepezil. The first, most essential, preclinical study that should have been carried out was hence a receptor occupancy study. Note that even the potent, selective S1R ligand SA4503 (Ki 17nM: http://1.usa.gov/1kz82Po, M's Science Corporation) is out-competed by donepezil (http://1.usa.gov/1WX8I20). Without such a study there is no evidence that target engagement by Anavex 2-73 is even possible in the presence of donepezil.
To summarise this in clearer language, Anavex 2-73 is too weak a muscarinic agonist to have meaningful effects on muscarinic receptors at therapeutic doses. It is also too weak an S1R agonist to significantly increase S1R agonism in the presence of donepezil. In fact, in the presence of donepezil, it is unlikely that Anavex 2-73 can even bind S1R.
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