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Aducanumab versus GV-971 (from brown algae)
Lane Simonian
Posted: Sunday, November 17, 2019 10:04 AM
Joined: 12/12/2011
Posts: 4751


Biogen's and Eisai's aducanumab and Shanghai Green Valley Pharmeceuticals both claim they have reached a major breakthrough against Alzheimer's disease.  Biogen is seeking FDA approval for their drug and Green Valley Pharmeceuticals have been granted conditional approval for their drug in China.

I don't remember two more controversial resuts being released for Alzheimer's disease before.  The data for aducanumab does not support FDA approval and the data for GV-971 is for too short of time to have won conditional approval.

Biogen ran two nearly identifical trials (Emerge and Engage).  At 24 and 78 weeks the results for each drug group were nearly identical.  At 48 weeks though there was a discrepancy between the two groups with the Emerge group declining more rapidly (which I cannot explain).  At 78 weeks, the placebo group in the Emerge trial had declined more rapidly than the placebo group in the Engage trial.  My guess is that the Emerge placebo group had more APOE4 carriers who decline more rapidly during the early stages of Alzheimer's disease.  The results of these two variations is that the Emerge group appears to be progressing at a steady rate (albeit slightly less rapidly that those on the placebo) whereas in the Emerge group the drug appears to be stabilizing the disease.  The first is true (steady decline) whereas the later is a chimera.

https://investors.biogen.com/static-files/40565136-b61f-4473-9e58-9be769bbac6c (page 22).

Anti-amyloid antibody drugs such as aducanumab appear to have little effect on those without the APOE4 gene (in Biogen and Eisai's trial for BAN2401 for instance, the drug removed 93 percent of the amyloid but only reduced disease progression by seven percent).  Those with the APOE4 gene (or genes) both have more oxidative stress and more amyloid oligomers than those without the gene (or genes) so removing one of the triggers for oxidative stress (amyloid oligomers) has more of an effect on carriers than non-carriers early in the disease.  Their rate of decline slows down near the level of non-carriers.  This slow down is marginally significant from both a statistical and a clinical perspective.  Based on this, the FDA should never approve aducanumab for non-carriers and should probably not approve it for APOE4 carriers.

GV-971 on the other hand appears to stabilize Alzheimer's disease for 36 weeks.  The makers of the drug have been casting around to find a mechanism to explain the results.  They have latched upon a recently popular analysis: the drug inhibits inflammation in the gut which then reduce inflammation in the brain. 

https://www.nature.com/articles/s41422-019-0216-x

 Amyloid oligomers and activated microglia (which are initially the results of oxidative stress) contribute to inflammation and oxidation in the brain but they are far from the only source of this inflammation and oxidation.

In the brain, alginate oligossacharides (GV-971 is a depolymerized alginate oligosaccharide) have three main effects.  First they reduce levels of amyloid oligomers and activated microglia which further reduces brain inflammation and oxidation early in Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584357/

Second, they reduce levels of hydrogen peroxide which harms neurons during the early stages of Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pubmed/21543116

http://www.jbc.org/content/280/43/35789.abstract

Third they inhibit the formation of peroxynitrite which also kills neurons.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571823/

Herbal treatments that have the same mechanism of action have largely stablized Alzheimer's disease for up to two years, so that is what might be expected for GV-971 as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

http://www.imedpub.com/articles/botanical-mixture-stabilizes-cognitive-function-in-patients-with-mild-and-moderate-alzheimers-disease.php?aid=23217