Recent Comments: Responses and Reflections

Doc Gumshoe Follows up on Alzheimer's, Biogen, Anavex... and on evidence and causality in general

By Michael Jorrin, "Doc Gumshoe", October 23, 2019

The many welcome comments to the Alzheimer’s piece that posted a couple of weeks ago prompt me to supply answers (if I am able to do that), but also set my mind to wandering on the fringes of a number of issues that may be of interest to the Gumshoe constituency.

Anavex 2-73

At the top the list, chronologically at least, was a question about Anavex Life Sciences (AVXL) and its leading candidate Anavex 2-73.   Doc Gumshoe discussed Anavex 2-73 in a previous piece about Alzheimer’s, entitled “Alzheimer’s Wrap-Up,” which posted nearly four years ago – December 21, 2015.   At that moment, Anavex had announced, to great fanfare, the results of a small uncontrolled clinical trial in which they gave about 50 subjects their drug, following which they evaluated their cognition, using the standard tests.   Most of these 50 subjects did a little better after being treated with Anavex 2-73, but only a little better.   I find myself in total agreement with what I said then, that there is no way of knowing if that slight improvement on those tests was due to the drug.   There was no control group as a basis of comparison, and it would hardly be surprising if these 50 subjects, pleased and excited to be in a clinical trial of a supposedly promising new drug, actually did do a bit better on those tests.   That could be considered a placebo effect.   The absence of a control group increased my skepticism by at least a factor of ten, and the ballyhoo surrounding the announcement of the test results by another factor of ten.

That was four years ago.   What has happened since?   A few months ago, Anavex Life Sciences announced a Phase 2 study, to be conducted in Spain, to evaluate Anavex 2-73 as a treatment for dementia in patients with Parkinson’s disease.   

What Anavex 2-73 does is target the sigma-1 receptor, which is located in the endoplasmic reticulum in the brain.   Activation of this receptor is said to stimulate the functioning of the cellular recycling system, which gets rid of old cells and permits the growth of new cells, preventing the accumulation of toxic protein clumps, including amyloid beta and tau protein.

Anavex cites experiments in mice and worms to support their claims that their drug may be effective in improving cognition in humans.   In mice, Anavex 2-73 restored the function of damaged nerve cells and improved motor function.   In worms, deposition of amyloid beta induced paralysis, which was reversed by Anavex 2-73.

It seems pretty clear that Anavex 2-73 is a long, long way from emerging as a useful drug in the treatment of Alzheimer’s disease.   Whether one of the Big Pharma moneybags sees promising signs in the doings of Anavex and swoops in with an offer too big to refuse is anybody’s guess.   My guess is that it’s Anavex’s big hope. 

Donepezil and Memantine

Both of these drugs are among the tiny few that are actually FDA approved for the treatment of Alzheimer’s disease.   Donepezil (Aricept), from Eisai/Pfizer, was originally marketed for Parkinsonism, and has demonstrated clear benefit in preventing falls, which commonly affect Parkinson’s patients and is one of the troubling symptoms of that disease.   The effect on cognition, both in Parkinson’s and Alzheimer’s, is small – at best it slows the decline.   

Donepezil is a cholesterinase inhibitor, cholesterinase being an enzyme that degrades acetylcholine, which in turn is a neurotransmitter essential for brain activity.   So the essential mechanism of donepezil is that it slows down the agent that degrades another agent that is essential for transmission of information in the brain.

Memantine (Namenda), from Forest Pharmaceuticals, an antagonist of N-methyl-D-aspartate (hence the name Namenda), is thought to work by preventing glutamate-induced damage of neurons in Alzheimer’s disease.   As with donepezil, the effect on cognition consists at best of slowing the decline.

Donepezil and memantine are frequently prescribed together in the hope that the dual mechanisms of action will slow the decline in cognition to a greater degree than could be achieved by either drug alone.

Enbrel and Alzheimer ’s disease

Amgen, the maker of Enbrel (etanercept) has been accused of prioritizing their profit margin over the possibility that their highly successful drug might be valuable in the treatment of Alzheimer’s.   

Enbrel, as perhaps you know, is one of a handful of drugs that is highly effective in the treatment of rheumatoid arthritis.   Enbrel’s mechanism of action is that it binds to a receptor o