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New Anavex trial
Llewis
Posted: Saturday, February 9, 2019 5:00 PM
Joined: 2/9/2019
Posts: 6


Has anyone been involved with the the new trial for the new drug Anavex? Just started a few months ago. They had really encouraging results from a small study here in Australia but that was a small test group. Whole new approach to what other drugs do. We can't participate in the study here in US but really interested in trying it. Would really be interested in any experiences you have. Thanks and bless you all.

Lane Simonian
Posted: Saturday, February 9, 2019 7:41 PM
Joined: 12/12/2011
Posts: 4565


I have not been involved in the Anavex trial (and I do not own stock in the company) but I have been following the trial and writing about it for several years.

The clinical trial results so far indeed involve a small number of people, is not placebo-controlled, and is not double-blinded.  However, the results have been positive: at 109 weeks the drug seemed to continue to stabilize cognition and activities in daily living in those who received the highest dose of the drug (see slides on page 23 and 24).

https://www.anavex.com/wp-content/uploads/2018/05/Anavex-ANAVEX2-73-CTAD-Phase-2a-November-2017.pdf

Anavex 2-73--a sigma-1 agonist--reduces the release of intracellular calcium and by doing so reduces the damage that peroxynitrite (ONOO-) does to the brain through oxidation and nitration.  

https://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

This damage includes the reduced synthesis and release of neurotransmitters needed for the retrieval of short-term memories, sleep, mood, social recognition, and alertness, decreased blood flow and the transport of glucose in the brain (which can lead to delusions), impaired neurotransmissions, inflammation, DNA damage, mitochondrial dysfunction, and the death of neurons.

Tetrahydrofuran derivatives, such as Anavex 2-73, are hydrogen donors and hydrogen donors partially reverse oxidation and nitration and thus may partially ameliorate the damage described above.  They also may increase the effects of other antioxidants.

Here is a story about the results of the drug so far:

https://www.australianageingagenda.com.au/2018/07/13/next-stage-of-national-drug-trial-underway/

Hopefully, someone on these boards from Australia has been part of the trial and can discuss their experiences and observations.

Best wishes to you.


markus8174
Posted: Sunday, February 10, 2019 5:49 AM
Joined: 1/25/2018
Posts: 535


Lane- I'm never sure whether your responses are mostly gibberish just to throw sand in our eyes, or you should be heading the Alzheimer's research department in the U.S. D.O.H., but you always give me hope and angst at the same time. If we know so much about the underlying processes of AD (and related), how can there have been no significant new treatments put forward in the last 10 years? It seems there are many branches of "new directions" in drug therapy every day, but only successes in "small trials with no double blind or placebo controls".  Any true, large scale trials seem to get dropped lone before later phases are completed. I have hope this disease will be cured, or at least controlled, but for my great grand children, not for us in the trenches today. I see current AD treatment where Diabetes treatment was 70 years ago. Porcine insulins revolutionized type 1 DM management, but true, effective treatment took until about 20 years ago. Are we looking at 50 more years of useless trials before we have a handle on this disease?
Llewis
Posted: Sunday, February 10, 2019 8:43 AM
Joined: 2/9/2019
Posts: 6


Markus; I don't know Lane but I know he's written extensively on ALZ and seems to know what he's talking about including scientific details. The articles of his that I've read are well balanced and not hype.

In my humble (and maybe wrong) opinion big pharma has been chasing their tales for years and concentrating their research on the wrong causes and treatments. After they've committed tons of money it's hard to admit they were chasing the wrong rabbit and scrap it. Some of these new drugs have greater potential because they are NOT pursueing the same ideas. Anavex has 3 trials going now and the one in Australia should give some definitive answers. They are also developing precision medicine and have identified which genetic makeup should respond to their drug. 80% of the population contain the right makeup.

Sadly in our world there are other factors affecting new drug development. Wherever there is money there is corruption. Big Pharm to me is another name for mafia and they'll do anything needed to block new drugs until they get their share. All IMO of course to protect myself legally.

Don't give up hope

 



Lane Simonian
Posted: Sunday, February 10, 2019 10:23 AM
Joined: 12/12/2011
Posts: 4565


Thank you for two wonderful responses.

I began studying Alzheimer's disease fifteen years ago when my aunt and cousin were in the late stages of Alzheimer's disease and my mother was in the early stages of Alzheimer's disease.  My aunt was an educator and began to "teach" autistic children near the end of her life.  A few times a year, we would visit my aunt in a memory care facility; my uncle would visit her every day.  While it was a well-run facility, I was saddened by all those "residents" who were all alone.  I figured if I worked hard enough I could do something to keep my mother at home (and with the help of my sister who she would live with half the year, we were able to do that).

I started by looking at all the major hypotheses for Alzheimer's disease: amyloid, tau, diabetes of the brain, cholesterol, etc., but what I realized is that none explained every case of Alzheimer's disease so they could contribute to Alzheimer's disease but they could not be the cause.  What was true in every case of Alzheimer's disease was calcium dysregulation.  So I began to trace what caused calcium dysregulation and what was the result of calcium dysregulation.  Over the years of reading articles that made little to no sense and rarely being able to see any connection between them, a picture began to emerge (I had some background in biology which eventually helped me).  When that picture did emerge, it was very similar to the one found in this link.

https://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

After about three years of research, I came across an obscure reference to peroxynitrite (ONOO-).  I began looking for something that might combat peroxynitrite in the brain and found this article:

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

These results demonstrated that the memory protective effects of RA in the neurotoxicity of Abeta(25-35) is due to its scavenging of ONOO(-), and that daily consumption of RA may protect against memory impairments observed in AD.

So I began to give my mother rosemary essential oil to smell every day.  After about a month she asked why are you giving me this to smell every day for a month.  That was the first indication that it was doing some good.  Over time with the addition of some other essential oils such as bay laurel, thyme, oregano, and orange, she was able to recognize her home again, remember her name, stopped having delusions, stopped fearing the shower, could count numbers and recite the alphabet, and was much more alert and aware.  Her ability to remember previous events was limited and she sometimes could not communicate in a lucid fashion, but the disease did not progress further for the last four years of her life (and improved in some areas).

I will address the science in a separate post.


Lane Simonian
Posted: Sunday, February 10, 2019 10:47 AM
Joined: 12/12/2011
Posts: 4565



Why has so little progress been made against Alzheimer's disease?  Part of it is that so much attention in larger trials have been focused against misfolded amyloid and tau proteins.  Amyloid oligomers are one of several causes of Alzheimer's disease.  The best amyloid oligomer drug comes from Biogen and it only slowed the progression of the disease by 7 percent in non-ApoE4 carriers (better in ApoE4 carriers but with added risks).  Misfolded tau proteins are a problem because they inhibit neurotransmissions, but they are not likely responsible for the rest of the disease.

Very few large-scale studies have been done with antioxidants in Alzheimer's disease in part because these come from natural products (the synthetic ones generally have not done as well).  The largest antioxidant study used Vitamin C which early in Alzheimer's disease may be a pro-oxidant and may have included the wrong form of Vitamin E and a less well-absorbed form of alpha-lipoic acid.  And yet so many people jumped on the study as evidence that anti-oxidants cannot be used to treat Alzheimer's disease.

This remains my favorite quote about Alzheimer's disease.

[Clinical trials with over-the-counter supplements have concentrated either on
items which suppress inflammation, or on antioxidants which scavenge oxygen
derived free radicals. Most of these items have proved to be worthless in the
treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s
disease do little to slow the deterioration, but instead offer a mild temporary
symptom relief. However, evidence has been accumulating that the primary driver
of Alzheimer’s disease is a nitrogen derived free radical called peroxynitrite,
which may mediate both amyloid and tau accumulation as well as their toxicity.
Excellent results have been obtained with peroxynitrite scavengers, with
reversals of Alzheimer’s disease in human clinical trials being repeatedly
demonstrated. IMHO, the only thing which may be preventing the abolition of
Alzheimer’s disease is the mental inertia of scientists, as well as the
bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money
into repeatedly testing discredited interventions, while ignoring successful
ones. Common sense is anything but…]

But certainly without larger trials this goes nowhere.

The largest trial currently underway to test a peroxynitrite scavenger for the treatment of Alzheimer's disease involves ferulic acid in rice bran oil and Angelica archangelica.

https://clinicaltrials.gov/ProvidedDocs/60/NCT03451760/Prot_SAP_000.pdf

From my perspective the key to preventing and treating Alzheimer's disease is the following:

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite.

Anavex 2-73 does the first (limits peroxynitrite formation) and may do the second (scavenge peroxynitrite) and the third (repair the damage done by peroxynitrite).  That is why of all the drugs currently being tested for Alzheimer's disease, I believe it has the best chance.

I have hope that Alzheimer's disease can be effectively treated and that some treatment may emerge in the next few years.  Some day the barrier will be broken, I just don't know how soon.