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Sunday, 01/15/2023 7:19:19 PM

Sunday, January 15, 2023 7:19:19 PM

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I have a couple of thoughts/observations to relate. This represents my own thoughts/opinions and is not intended as investment advice.

In the Avatar Rett trial, “seizure frequency via seizure diary” was one of the “other outcome measures.” The results showed that there was a 50% decrease in seizure risk.” From my reading, epilepsy has been reported in 60-80% of patients with Rett syndrome. Epilepsy continues to be a major concern in adults with Rett syndrome. 2/3 of women above thirty years of age remained with active epilepsy and 50% of them had seizures at least weekly.

To contextualize this, note that the preclinical anti-seizure efficacy of Anavex 2-73 was strongly positive. Anavex 2-73 was compared to three generations of epilepsy drugs in multiple standard seizure-inducing animal models. It was tested both alone and in combination with these three drugs, all of which are still in use. The data demonstrated significant improvement in the reduction of seizures by Anavex 2-73 relative to these three generations of epilepsy drugs, as well as significant synergy with each of them.

Regarding this, Missling stated, “Efficacy is important in an anticonvulsant drug candidate. The key, however, to the next generation of epilepsy therapies is safety since most currently used epilepsy drugs require therapeutic drug monitoring given their significant differences in individual’s therapeutic dosages. Adding Anavex 2-73 to a current epilepsy drug regimen has the potential to increase safety by means of a dose reduction, while at the same time significantly improving anti-seizure efficacy. This data also suggests that Anavex 2-73 has the potential to become a platform drug for additional indications beyond Alzheimer’s disease.”

Missling went on to say, “Another important implication is a recent finding that Alzheimer’s disease and seizures together seem to accelerate the worsening of symptoms, suggesting that the seizure disorder adds to the degenerative Alzheimer’s disease pathology to exacerbate the cognitive decline. We are encouraged to explore this additional indication.”

Alzheimer’s patients are estimated to have anywhere from a two- to six-fold increase in the risk of seizures compared to the general population. 10-26% of Alzheimer’s patients will experience seizures over the course of the disease. Having two or more seizures is classified as epilepsy.

Dr. Jacqueline French, professor of neurology at NYU, past president of the American Epilepsy Society, Chief Medical Officer of the Epilepsy Foundation, who lectures internationally on clinical trials and the use of anti epileptic drugs, and who is a member of the Anavex SAB, had this to say about Anavex 2-73: “I am extremely impressed with the positive preclinical epilepsy data for Anavex 2-73…Additionally, Anavex 2-73 was shown to be safe in a phase 1 human trial, which is critical to next generation epilepsy therapies…I look forward to collaborating with Anavex and it’s impressive team of scientific advisers as we work to further develop Anavex 2-73.”

It is known that patients with epilepsy are at significant risk for cognitive impairment and behavioral abnormalities. Also, adverse effects of anti epileptic drugs are considered by patients to be at least as important as repetitive seizures in terms of quality of life. To my knowledge, no anti-seizure medication has been shown to promote improvement in cognition. However, Anavex 2-73 has shown evidence of cognitive enhancement in three different neurodegenerative diseases, including Rett, PD, and AD. As noted above, Anavex 2-73 has been associated with a 50% decrease in seizure risk in the Avatar Rett trial. This is not a formal epilepsy trial. But it does increase my optimism about Anavex 2-73 not only as a Rett treatment but also as a platform drug for other neurodegenerative diseases. I am happy with my investment in Anavex on the basis of its two completed Rett trials alone. Additionally, with multiple other potential indications for this drug, as well as its other pipeline drugs, Anavex has multiple shots on goal.

As has been discussed on this board before, neurodegenerative diseases such as Alzheimer’s are considered complex diseases. Complex diseases, such as hypertension, usually require multiple medications that work in different ways and thereby complement each other. Hypertensive patients frequently require two, three or even four medications for adequate control. In regard to Alzheimer’s, Timo Grimmer, an investigator in the Anavex 2-73 P2/3 Alzheimer’s trial and head of the Centre for Cognitive Disorders at the University of Munich School of Medicine, and the newest member of the Anavex SAB, stated in his CTAD comments in the Roche podcast, “…we all agree that we will probably need combination therapy in the end.” I suspect the FDA realizes this as well. This is why I am (somewhat reluctantly) OK with the FDA’s approval of Lecanemab and Auhelm (I am not a Biogen investor) because anti-Alzheimer’s drugs need to be available to be used in combination. Perhaps lecanemab and Anavex 2-73 (or other AD drugs in development by other companies) will had additive or even Supra-additive effects. So, downstream drugs are now available. My view is that upstream drugs are now needed, and that Anavex 2-73 fits the bill. It has a good safety profile, is orally administered, does not cause brain swelling/bleeding, does not require.MRI follow up, and has shown impressive efficacy in multiple neurodegenerative and neurodevelopmental diseases.

Unfortunately, the wheels of science turn slowly (and by saying this I do not mean to say Missling is “off the hook” for missed timelines). My concern is that the cost of Alzheimer’s is projected to bankrupt Medicare in the not-too-distant future so there’s no time to waste. And this applies to Missling and to the FDA. Meanwhile, millions are dying or losing their memories and personalities

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