The Science of Anavex 2-73: Part 1
Here is a little something I am putting together to dispel some of the misinformation regarding pharmacokinetics, drug efficacy, clinical trials, and a smattering of other topics.
Let us begin with a discussion of pharmacokinetics. In English, this is the study of how a drug is processed in the human body, which is a critical factor in both safety and efficacy.
When a drug is administered, it can enter the body via multiple routes: by mouth (PO), intravenously (IV), intrathecal (IT), intramuscular (IM), intraosseous (IO), intraarterial (IA), inhalation, and a couple of others. For the sake of our discussion, let's consider PO only at the moment, as this is the route of administration of Anavex 2-73.
Oral administration of a drug is undoubtedly the most convenient (and marketable!) route for the delivery of medication, as the medication can be tailored to respond to the various environments of the gastrointestinal (GI) tract. This can facilitate rapid absorption, delayed absorption, and even alterations to the original compound by enzymes of the gastrointestinal tract and/or changes in pH.
When a compound is absorbed from the GI tract, it enters the portal venous circulation as a primary agent, which is delivered to the liver. Bioavailability determines the amount of the drug that reaches the circulation, and is important to PO medications like A2-73. The liver has a number of flexible, remarkable metabolic pathways that act to alter the chemical composition of a drug in order to prepare it for excretion. These pathways are called the Cytochrome P450 network, which has multiple subsets (I am not sure which one acts on 2-73). The primary drug undergoes transformation in these pathways and exits as a metabolite. The metabolite is a completely new drug with its own pharmacokinetic profile, ligand affinity, biologic half-life, the works.
(Of interesting note, Venlafaxine, an anti-depressant, is metabolized to desvenlafaxine, which received an additional patent protection. They just processed the original drug outside of a human body and packaged in its own pill.. cha-ching! LOL).
In the case of A2-73, both the compound itself and its metabolite are active agonists of the Sigma-1 receptor, though the biologic half-life of the metabolite is longer. So what is biologic half-life? When you take a pill, the indwelling drug will rise in serum concentration as it is absorbed and fall as it is processed. The very, very, very complex pharmacokinetic profile of a drug depends on many factors, including hydro/lipophilicity, the tendency of the compound to bind to serum albumin and other proteins, the strength of the intramolecular bonds, etc... but it simply boils down to the amount of time it takes for your body to eliminate 1/2 of the initial concentration. The implications of this are great: drug efficacy, side-effect profile, pregnancy classification, breast milk excretion, and alcohol/other drug interactions just to name a few. And it is a SIGNIFICANT REASON why Phase 1 and 2A results are critical. Establishing a good safety profile is a monumental leap from theory to clinic. Anavex has proven that 2-73 and its metabolite can exist within and be excreted by the human body with no (as of now) serious untoward effects. This SHOULD NOT be downplayed by critics/bashers. I will not sully this article with a certain notorious journalist's name, but describing these results as "meaningless" is a severe deviation from the truth.
(Of further interesting note, ethanol [booze] has a zero-order metabolic kinetic profile -- it doesn't how much or little you drink, it's eliminated at a constant rate).
With respect to efficacy, having an active compound and its metabolite in circulation seems like a bonus, assuming the primary mechanism of action is sigma-1 receptor agonism, but this too is much more complex. For a PO drug to act in the CNS, it must first cross the blood brain barrier, which is the separation of systemic circulation from the extracellular milieu that surrounds the cells of the brain. After this is completed, the compound must bind to its target receptors. Binding can be reversible, irreversible, or intermittent. Furthermore, depending on what lies downstream from the ligand/receptor interaction, binding can yield markedly different results. For example, barbiturates will bind to and potentiate GABA-A receptors, allowing the DURATION of chloride channels to remain open, whereas benzodiazepines will bind GABA-A receptors as well, and increase the FREQUENCY the channels are open. Hence, it is MUCH easier to overdose/die on barbiturates, even though the two drugs act on the same receptor!
I specifically write this to refute Mr. Shkreli's assertion on Twitter: I shorted $AVXL - i do not believe the drug *can* work given its PK and receptor pharmacology profile. This comment in itself is incredibly vague; however, even when I had a chance to discuss it with him on Twitch, he indicated that serum concentration of the ligand was not high enough (I can't quote him directly, I forgot the exact words). Regardless, that's only a tiny fraction of the puzzle. That's like saying the Germans lost World War 2 because of soldiers!
This brings us to where we are now: efficacy. If safety is the sweet words the FDA loves, efficacy is the key to "Big Pharma's" chastity belt. We'll conclude here, and I'll follow-up with a discussion on efficacy and validating such later.
** I have made every effort to be ensure accurate information of the above. If you seen any gross errors, please inform me, and I'll amend them. I am long AVXL and will continue to be unless the science/clinical results/leadership dictate otherwise.
Sources:
1. Voges O, Weigman I, Bitterlich N, Missling C, Schindler C. A Phase I Dose Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of Anavex 2-73 in Healthy Male Subjects. Poster Presentation. CNS Summit.
2. Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer's Disease: Past, present, and future. Neuropharmacology, 2014; (76). 27-50.
3. Madhura M, Banister SD, Beinat C, O'Brien-Brown J, Kassiou M. Recent Advances in the Development of Sigma-1 Receptor Ligands. Australian Journal of Chemistry, 2015; 68(4).
-Dr. H
AI
