Avera Pharmaceuticals

AV965 is currently in Phase 1 development. Initial single and multiple dose safety/pharmacokinetic studies using a solution formulation have been completed. The drug was generally well tolerated, exhibited no abnormal laboratory or cardiovascular findings and the current formulation demonstrated acceptable pharmacokinetic properties for further development.

Avera has developed and manufactured a solid dosage form for further Phase 1 pharmacokinetic evaluation and proof of concept testing in for Cognitive Impairment Associated with Schizophrenia and Alzheimer’s Dementia.

AV965 for Cognitive Impairment Associated with Schizophrenia
AV965 is expected to address the cognitive-attentional deficits in sensory-gating, working and verbal memory that occur in schizophrenic patients. Over the past few years a growing body of evidence has revealed that postsynaptic 5-HT1A receptors play an important role in regulating the excitability of hippocampal and cortical pyramidal neurons. The receptor has been localized to the axon initial segments of these systems and cellular studies show that serotonin acting at the postsynaptic 5-HT1A receptor elicits a hyperpolarizing current by activation of potassium channels (GIRKs). In addition, the 5-HT1A receptor appears to act as a heteroceptor on excitatory glutamatergic and cholinergic afferents to pyramidal cells, inhibiting glutamate and acetylcholine release through inhibition of N and P/Q type voltage gated calcium channels. Thus cortical and hippocampal 5-HT1A receptors are disposed to exert a negative influence on the excitability and the output of neuronal systems known to mediate cognitive processes. Blockade of this receptor by a neutral antagonist would be expected to decrease inhibitory control of pyramidal neurons by raphe serotonergic afferents, and to enhance pyramidal neuron excitability by decreasing heteroceptor inhibitory actions on afferent cholinergic and glutamatergic inputs to these cells. In the schizophrenic brain, 5-HT1A antagonists could reduce the inhibitory tone on pyramidal neurons, and also provide glutamate to prefrontal cortical and hippocampal NMDA receptors. In addition, stimulation of acetylcholine release can increase the stimulation of m1 receptors further enhancing pyramidal neuron excitability.

AV965 for Alzheimer’s Disease
The focus of recent clinical activity in this area has been on cholinergic mechanisms. However, it has become apparent that not all patients can be characterized by deficits in this system alone, as evidenced by the moderate efficacy of acetylcholinesterase inhibitors. Research suggests that the serotonergic system may be hyperactive in the disease as a result of the enhanced turnover of serotonin, which ultimately could reduce the firing of the cortical pyramidal association pathways through stimulation of 5-HT1A receptors. This finding of enhanced serotonergic turnover leads to the hypothesis that a 5-HT1A receptor antagonist may be effective in treating cognitive loss. The hypothesis is further supported by the finding that the 5-HT1A receptor agonist tandospirone, when administered orally to healthy volunteers, dose-dependently impairs explicit verbal memory by binding to receptors in the hippocampus. Postsynaptic muscarinic receptors (M1) are also localized on pyramidal neurons along with glutamatergic and 5-HT1A receptor sites. Antagonism of the 5-HT1A receptor may compensate for the loss of cholinergic excitatory input by enhancing glutamatergic transmission through the same pathway. Muscarinic signal transduction through m1 receptors may also be facilitated by blocking the hyperpolarizing action of serotonin. Finally, there has been speculation that 5-HT1A receptor antagonists may decrease the formation of ß-amyloid peptide, which has been linked to the neuronal plaques that are pathologic hallmarks of Alzheimer’s disease.