Review: The Unique Anavex Mechanism of Action
The future of Anavex Life Sciences Corp depends upon its ability to successfully market any of its several pipeline drugs against various central nervous system (CNS) and other diseases. For commercial marketing (and revenue generation) several matters must be resolved.
Presently, positive therapeutic outcomes, absent negating adverse events (“side effects”), must appear in any of the three, being-arranged clinical trials of the lead drug candidate, Anavex 2-73. Proper, well-constructed clinical trials of the drug against three CNS conditions are being arranged. In 2019, the drug will be tested against Rett syndrome, a debilitating nervous system condition of young girls. Tests of Anavex 2-73 in mice with Rett syndrome pathologies show very promising therapeutic results, absent any significant adverse effects. Various manifestations of Parkinson’s disease are being clinically assessed. In the largest, most lengthy clinical trial (in Australia), Anavex 2-73 will be used to treat 300 patients with Alzheimer’s disease, in two 150-patient dosage-level arms. A third arm of 150 patients will be the control (blinded with a starch pill).
Should therapeutic results be positive in any of these three CNS conditions, Anavex 2-73 will gain regulatory approval for commercial use. The successful future of the company would be assured.
But successful Anavex therapies depend upon two things: a) sufficient absence of debilitating, negating adverse events, and b) therapeutic outcomes that equal or surpass existing standard of care (SOC) drugs.
In both murine (lab rodent) tests and preliminary human clinical trials, rates and severities of adverse events have been low. No indications either in rodents or humans that Anavex 2-73 at therapeutic dosages causes side effects of any consequence. This is uncommon in neuroactive drugs.
The matter of greatest importance, of course, is therapeutic efficacy. Does Anavex 2-73 yield desirable therapeutic outcomes? That is the primary question to be resolved by the three clinical trials getting underway.
Those results will be positive only if the drug can provide a unique MOA that creates or restores normalized nerve function(s). To understand how this is likely to happen, consider Anavex 2-73's unique chemistry inside malfunctioning neurons (nerve cells).
First, understand that the majority of nerve-based diseases involve or are caused by dysfunctional mitochondria. The majority of CNS diseases involve dysfunctional mitochondria. Very simply, but very profoundly, create or restore normalized mitochondrial function and nerves will function normally. The disease state is obviated.
How, then, might Anavex 2-73 accomplish this otherwise heretofore unattainable outcome?
In fact, if mitochondria themselves fail to function, a neuron with them simply dies. Primarily and essentially, mitochondria extract energy from several intracellular molecules (primarily the simple sugar glucose) and transfer it to created adenosine triphosphate (ATP) molecules. The generated ATPs then move to other parts of the neuron, where they power virtually all of the essential chemical reactions. A phosphate ion is popped off the ATP, creating a low-energy adenosine diphosphate (ADP), and a high-energy phosphate ion. The available bond energy of that released phosphate powers all of the other energy-requiring reactions in the cell. That’s the reason mitochondria are called the “powerhouses of the cell.”
But more specifically, in the case of the unique MOA of Anavex 2-73, a second cellular structure is involved, the endoplasmic reticulum. Endoplasmic reticula (ERs) take up significant quantities of ATP from the immediately adjacent, connected mitochondria, and use the energy in the ATPs to power the precise, complicated folding of strings, polymers of amino acids to synthesize essential catalytic proteins, cellular enzymes.
These enzymes control virtually every chemical reaction within a neuron. Enzymes are like door keys, with precise architectures that either connect chemical feedstocks, or conversely, unlock or break them apart. If the proteins of essential enzymes are improperly folded, essential chemical reactions within the neuron don’t occur; disease results.
And such is the case with Alzheimer’s. With the most exceptional occurrences, Alzheimer’s doesn’t set in until middle or geriatric ages. Before, nerve enzymes are properly shaped and nerves function normally. But with age (perhaps also mediated by other factors), the chemistry of neurons fails. Normal protein wastes (such as beta-amyloids and tau tangles) are no longer efficiently cleared. Accumulation of these then disrupt the transmission and receipt of nerve impulses. The CNS no longer functions well. Memory, in particular, is impeded and disrupted.
Now, to the point, where and how the unique mechanism of action of Anavex 2-73 can effectively treat the accumulated nerve protein wastes in nerves.
Anavex 2-73 is a sigma-1 receptor agonist. Within neurons (and other cells), there are sigma-1 receptors, particular proteins on the endoplasmic reticula. Among other things, the sigma-1 receptors modulate, control the release of Ca2+ ions. Precise control of calcium ion transport between attached ERs and mitochondria is required for normal neuron function, including production of ATP.
ERs must receive adequate ATPs from the adjacent, attached mitochondria to power the precise folding of proteins into properly-functioning enzymes. Insufficient ATPs or improper concentrations of calcium ions in the endoplasmic reticula prevent the synthesis of functioning enzymes. This is pathogenic (disease-causing). Alzheimer’s or other CNS diseases appear.
Uniquely, Anavex 2-73 agonizes, promotes proper sigma-1 receptor function. With that, proper, functional enzymes are produced by the ER; normalized neuron health ensues.
All of this is “homeostatic,” creating “homeostasis” within the neuron (and nerve). A multitude of chemical and organ processes within the body involve requisite “homeostasis.” “Homeo-“ means “same.” “-stasis” means “state.” The same-state condition.
Chemicals, especially those in cells, tend toward de-energized, fully-reacted states. That’s the death state. Living bodies and cells continually work against those chemical proclivities, with a multitude of homeostatic processes. If the body gets cold, the nervous system signals to the thinking parts of the brain to put on a coat. If too hot, the opposite. Thermoregulation, in all forms, is a homeostatic process. Homeostasis — the bringing back of some otherwise varying process to a normal, “same,” unvarying state
Uniquely, and with such promise, Anavex 2-73 restores neuron homeostasis. Calcium ion transport is moderated and controlled; sufficient ATP diffuses or is transported to the ER so as to allow normalized, healthful production of properly-folded enzymes that then modulate and control healthful chemical reactions in the neuron. Beta-amyloid and tau protein wastes are enzymatically cleared before they disrupt normal nerve and brain function. Neuron homeostasis is restored. The CNS disease state is obviated.
There are no existing drugs that have this MOA, nor are able to restore neuron homeostasis.
