Biogen (NASDAQ:BIIB) and Eisai (OTCPK:ESALF) are doing their best to get FDA approval for their Alzheimer's drug aducanumab. However, a closer look at the numbers demonstrates the limited effectiveness of the drug. These numbers further suggest that the current flurry of excitement over aducanumab should be tempered and that investors would be wise to reduce their holdings in the stock.
A little longer exposure to the highest dose of aducanumab for those with the APOE4 gene apparently slowed down the rate of decline from 2% to 25% versus placebo as measured by ADAS-cog (Alzheimer's Disease Assessment Scale - cognitive subscale) (Biogen report, pp. 18-19). Since there was nearly no change in the number of non-APOE4 carriers in the highest dose group, one can reasonably conclude that the drug has almost no impact on non-carriers with Alzheimer's disease. If this is true, then, the Food and Drug Administration would not approve aducanumab for this group.
The lack of effectiveness of aducanumab for non-APOE4 carriers is supported by other anti-amyloid drug results. In Biogen and Eisai's trial for BAN2401, non-APOE4 carriers at the highest dose declined at a 7% slower rate than non-carriers receiving the placebo, despite the fact that the drug reduced amyloid levels by 93 percent (Alzforum). Another anti-amyloid drug Tramiprosate produced similar results:
Results: Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID [twice daily], showing statistically significant effects on ADAS-cog and positive trends in CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit (source of quote).
Drugs that greatly reduce amyloid levels in Alzheimer's disease, thus, have nearly no effect on cognitive decline in non-APOE4 carriers. This strongly suggests that amyloid is not a major factor in disease onset and progression in these individuals. Indeed, it is possible to have Alzheimer's disease with little or no amyloid. It is not then that anti-amyloid drugs are given too late after too much damage has already been done to the brain, it is that amyloid itself contributes little to this damage in non-APOE4 carriers.
The story appears to be somewhat different for APOE4 carriers. The insults to the brain, which include amyloid oligomers, are amplified in these individuals. To simplify, factors which contribute to Alzheimer's disease produce more oxidative and nitrostative stress and more misfolded amyloid and tau proteins in individuals with the APOE4 gene, and higher levels of misfolded amyloid and tau proteins then increase this stress even more. This leads to a more rapid progression in the early stages of Alzheimer's disease for APOE4 carriers as captured by the following charts (taken from two earlier large-scale Alzheimer's trials) (source of charts).
Anti-amyloid drugs (such as Alzheon's tramiprosate and ProMIS PMN 310) that are particularly effective at removing amyloid oligomers may reduce the progression rate for APOE4 carriers in early Alzheimer's disease close to the rate of progression for non-carriers. These drugs may therefore early on slow down the progression of the disease better than aducanumab in APOE4 carriers with fewer side effects (ProMIS). This conclusion is partially supported by the following charts for tramiprosate (Alzheon is now working on a prodrug for tramiprosate) and placebo for APOE4 carriers (source of charts):
There are multiple studies with drugs and natural products that indicate that those with high antioxidant potential can produce better results than anti-amyloid drugs: stabilizing certain aspects of the disease, slowing down others, and leading to improvements in still others, regardless of APOE4 status (Anavex 2-73, Korean red ginseng, heat processed ginseng, Feru-guard, herbal formulation, Chinese herbs plus conventional therapy, aromatherapy).
Biogen and other companies continue to push forward with anti-amyloid strategies are on the clock. They have to convince the FDA that they are the only disease modifying treatments available (much in the same way that the current drugs for Alzheimer's disease won approval). But they are not. And for that reason alone, they are not worth the investment risk.
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