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Backgrounder On Epilepsy And Anavex Life Sciences

|Includes: Anavex Life Sciences Corp. (AVXL)

Anavex Life Science's leading drug candidate, Anavex 2-73, is now at the design stage for a pivotal phase 2/3 trial targeting Alzheimer's, but the same drug has now completed preclinical trials targeting epilepsy. As I understand it, clinical trials of A2-73 for epilepsy may have years cut off their development process due to the phase 1 and phase 2a trials already conducted for Alzheimer's, but which have determined drug safety, pharmacokinetics, and pharmacodynamics which apply to humans regardless of target diseases. Anavex will present the results of the epilepsy preclinicals on December 7, 2015 at the American Epilepsy Society's annual meeting in Philadelphia. This article is to provide some background on epilepsy to Anavex (NASDAQ:AVXL) investors.


"Epilepsy and seizures affect 3 million Americans of all ages… [and] 50 million people worldwide… Every two minutes a new case of epilepsy is diagnosed… Epilepsy is the third most common neurological disorder in the US, after Alzheimer's and stroke, according to the Epilepsy Foundation of AmericaEach year… 40,000 people will die as a result of seizures, which is the same number of people that will die as a result of breast cancer."

The following article is by Amor Mehta, M.D., an expert on epilepsy, which he posted in public and private forums and gave me permission to publish here. I added all use of bold and italic for visual relief and emphasis:

"Epilepsy is a disorder of the brain whereby one has a propensity towards recurrent, unprovoked seizures. The official criteria for epilepsy is either: Two or more unprovoked seizures (separated by at least 24 hours) occurring in a lifetime or one unprovoked seizure and a clinical situation or objective evidence suggestive that one is likely to have further unprovoked seizures in a lifetime. A seizure is a paroxysmal event characterized by the sudden onset of hypersynchronous and rhythmic/repetitive electrical discharges occurring within a portion of the brain or the whole brain itself manifesting clinically in a myriad of different ways - most people would think of the manifestation as a generalized tonic-clonic seizure (formerly called "grand mal" seizures).

"One in 10 people will experience one seizure in a lifetime and that is usually related to a provoked cause such as drug/alcohol use, massive sleep deprivation, contact injury, febrile illness, toxic/metabolic insult, etc. One in 26 people will develop epilepsy in his/her lifetime.

"Epilepsy can occur at any age and there tends to be 2 peaks in terms of the age of distribution: in the very young and in the very old. In the very young, epilepsy is usually the result of a congenital neurodevelopmental abnormality or related to an inherited/genetic disorder. In the very old, epilepsy is usually the result of an acquired brain abnormality… structural changes of the brain that can make it more susceptible to seizing.

"Epilepsy must be properly classified as treatment depends on the proper diagnosis and classification. The most revised epilepsy classification system is based on the current ILAE (International League Against Epilepsy) classification system however - the nomenclature seems to change every few years - epileptologists fight over the way we name/classify things. Basically there are two types of epilepsies (further details are impertinent to this discussion): Generalized epilepsies in which seizure onset begins throughout the brain, in both hemispheres at once, and Focal epilepsies in which seizure onset begins at one portion of the brain and may spread to other portions or the whole brain after onset.

"Generalized epilepsies are subdivided into different types depending on the clinical and/or electrographic presentation: childhood absence epilepsy, juvenile myoclonic epilepsy, tonic epilepsy, atonic epilepsy (drop attacks), etc. Focal epilepsies are subdivided based on clinical features (whether there is loss of awareness or not, dyscognitive features or not and whether the seizure starts in the frontal, temporal, parietal or occipital lobe of the brain).

"It is very important for a clinician to correctly classify the epilepsy syndrome before treatment decisions are made. Most epilepsies are treated by general neurologists however there are many types of epilepsies that are very difficult to diagnose/classify and or recognize and, if subspecialty care is available, more often are managed by dedicated epileptologists, like myself. Epileptologists are neurologists who have completed training in general neurology or pediatric neurology but have done 2 more years of further training specifically in the subspecialty of epileptology. Epileptologists are proficient at electroencephalography and management of all epilepsies and seizure disorders including the use of medications, non-medication treatments, vagal nerve stimulation, responsive neurostimulation and the planning of palliative and/or curative epilepsy neurosurgery. Epileptologists have expertise in intracorticography, intracranial electroencephalography and brain mapping and are most adept at managing the most complicated epilepsy syndromes. Epileptologists are generally double or triple-board certified - in general neurology/pediatric neurology, clinical neurophysiology and/or epilepsy however not all are.

"The best way to describe why recurrent unprovoked seizures happen is to oversimplify the brain function as falling within a spectrum whereby at one side there is excessive hyperexcitability and at the other side there is excessive inhibition. Normal brain function usually falls within the center of this spectrum - there is a good balance between brain inhibitory function and excitatory function. A brain capable of seizing is one that falls within the hyperexcitable side of the spectrum.

"There is still so much that isn't known about how people develop epilepsy - the details are still left to be figured out. We do know that epileptic persons tend to have generalized or focal cortical hyperexcitability - in layman's terms this suggests that there are neurons that tend to fire more electrical discharges relative to normal functioning neurons. At a molecular level, the cell membrane of these hyperexcitable neurons are unstable and there may be cellular ion channel abnormalities that contribute to this overexcited state. Each neuron has different types of ionic channels - for example sodium channels, chloride channels, potassium channels, etc. Most of the antiepileptic medications available are directed to these particular channels - sodium channel blockers tend to be the most commonly used types of antiepileptic medications used. A detailed discussion about channelopathies is inappropriate for an investors review - if interested, I suggest reading a clinical neurophysiology text.

"As we know basically why neurons are hyperexcitable, we are treating these dysfunctions - which are likely the end result of an ongoing or prior insulting process. Many times, just by treating the channelopathy, full seizure control isn't achieved. Even if full seizure control is achieved with standard of care antiepileptic drugs, there continues to be a slow progressive decline in many epileptic patients' cognitive abilities. Why does this happen if seizures are well controlled (or not well controlled)?

"This question brings into play the role of neuroinflammation that perhaps lies as the direct cause of neuronal injury that leads neurons to become epileptogenic with dysfunctional intermembrane channelopathies. I believe that current antiepileptic treatment treats the end result of the neuronal injury but does nothing about the cause of the neuronal injury. Neuronal hyperexcitability is the end result of an ongoing cascade of insults that occur in the still unknown process of neuroinflammation and the end result being epileptogenesis (i.e. the development of epilepsy).

"Neurosteroids have a wide variety of diverse functions and are mediated through different mechanisms: through ion-gated neurotransmitter receptors or directly/indirectly through the modulation of other neurotransmitter receptors. Endogenous neurosteroids activate and inhibit different cell receptors that cause neuromodulation or other processes. If there are certain exogenous drugs that mimic what some endogenous neurosteroids do, perhaps the epileptogenic process can be disrupted and reversed. (paraphrased from reference below)

"This brings into play the role of sigma-1 receptors. It appears that sigma-1 receptor ligands exert potent neuromodulation on excitatory neurotransmitter systems including glutamate and cholinergic systems and that sigma-1 receptor agonists are neuroprotective in that they can stabilize neuronal cell membranes whereby the insulting process that causes neuronal hyperexcitability may be terminated. This is likely why Anavex 2-73 shows such synergy with standard of care antiepileptic drugs.

"The current antiepileptic drugs just act on the end result of the insulting process that causes neuronal hyperexcitability. They act on the hyperexcitable neuron but do nothing about the process that caused the neuron to become hyperexcitable to begin with. Anavex 2-73 may likely act at the beginning of the cascade of the neuronal insulting process and, in essence, it may stop the epileptogenic process.

"Perhaps Anavex 2-73 alone can promote neuronal cell stabilization and allow for the brains endogenous repair mechanisms to heal damaged neurons on their own or Anavex 2-73 paired with standard of care channel blocking antiepileptic drugs can work on both ends of the cascade - it can stop the ongoing insulting process and counteract the excessive hyperexcitability by managing the channelopathy in question.

"There is a huge need for more medications to treat the generalized epilepsies and the refractory focal and generalized epilepsies. Emerging antiepileptic therapies are looking towards cell membrane stabilization not just focusing on dysfunctional ion channels. Cannabidiol may play a role in the neuro-inflammatory cascade - the man who trained and mentored me, Dr. Orrin Devinsky, is running the clinical trials for Epidolex - a pure cannabidiol antiepileptic medication for treatment of catastrophic epileptic encephalopathies (results may be promising when they are published).

"I tried to break things down to as simple as possible however I would become too neurotic if I simplified things a little further. Do your own due diligence regarding AVXL and especially the science behind Anavex 2-73. I am so excited about a possible epilepsy indication. Epilepsy is the 4th most common neurological disorder in the US and there are so many people who live with seizures that are misdiagnosed as having panic attacks or some other problem when it is likely an epileptic seizure. I will do my best to present a detailed report of the Anavex 2-73 poster presentation at the upcoming AES convention in December. This company is really onto something with its science - it is not a scam and I'm fully committed to keeping my investment long for the rest of my life (or until a buyout ;) )."

Referenced by Dr. Mehta: Mellon and Griffen - Department of Obstetrics, Gynecology and Reproductive Sciences, The Center for Reproductive Sciences, The Metabolic Research Unit, University of California, San Francisco, CA 94143, USA. Brain Research Reviews (Impact Factor: 5.93). 12/2001; 37(1-3):3-12. DOI: 10.1016/S0165-0173(01)00109-6 Source: PubMed

SheKnows Reference:

Disclosure: I am/we are long AVXL.

Additional disclosure: I have been a shareholder in AVXL since 2011, and have been tracking it longer than that. I also have Mild Cognitive Impairment (MCI), which may be a precursor to Alzheimer’s. I am emotionally invested in Anavex because A2-73 is at the top of my list as the most promising drug candidate for an effective treatment for Alzheimer’s and MCI.