Anavex Life Sciences Corp (AVXL)

[Doc328]

Question: if PDD does not meet primary endpoints but shows significant improvement in motor function, does our stock price get beaten down? Or do we rise being we will then run a ph3 for general PD with motor function as our primary endpoint?

IMO, A273 will not help the motor symptoms of PD much if at all. Hopefully, it will help cognition and attention. A273 is an M1-M4 agonist and S1R agonist. In PD, there is a selective loss of dopaminergic neurons, especially in the substatia nigra (pars compacta). These neurons project to the basal ganglia. DA and M4 receptors co-localize in many neurons in the BG. DA is inhibitory and ACh )acting through M4) is excitatory. Tremor is caused by the imbalance of these input signals. Hence, M4 activation is unlikely to help tremor and actually may worsen the imbalance of the inhibitory / excitatory inputs to the BG. Indeed, in the large 500+ rivastigmine PDD study, a drug that increases synaptic ACh (hence activating M1-M5), helped cognition but worsened tremor.

We occasionally use anticholinergic (i.e antagonists at M1-M4) to treat refractory tremors in PD patients and the risk is that it worsens confusion while helping tremors.

Of course A273 is also a S1R agonist and that may have a positive effect for the motor function. Will this positive effect outweigh the negative muscarinic effect?

If A273 does not help PDD cognitive endpoints, I expect SP drop and will be concerned that AD will miss as well. Rett is in a different category and PDD failkure will not imply a miss (though does not imply positive outcomes either).