Roche, Biogen, And The Achilles' Heel Of Alzheimer's Drug Development

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Summary

Amyloid oligomers are only one of many contributors to Alzheimer's disease, so removing them does not help much even early in the disease.
Large pharmaceutical companies with diverse pipeline seem to be weathering Alzheimer's drug failures relatively well.
Biogen may be the exception in that it has consistently raised expectations that its anti-amyloid drugs will work.

Roche (OTCQX:RHHBY) recently announced that it has ended its phase three clinical trial for its anti-amyloid drug crenezumab because of a strong chance of futility. This result was, in essence, a double blow to the amyloid hypothesis of Alzheimer's disease as the drug targeted what is supposed to be the toxic form of amyloid (i.e. amyloid oligomers) and because it targeted those with early Alzheimer's disease when anti-amyloid drugs are conjectured to still be effective (before "it becomes too late").

The ironic aspect of this is that those trying to move the goalposts on anti-amyloid treatments may be partially right and yet still be wrong regarding the big picture. Amyloid oligomers are likely toxic because they bind copper and zinc. Zinc via its activation of a g protein-coupled receptor produces oxidative stress (zinc and Alzheimer's disease). Copper for its part contributes to the formation of the nitro-oxidant peroxynitrite early in Alzheimer's disease (copper and peroxynitrite).

Copper and zinc also participate in activating an enzyme (superoxide dismutase) that converts superoxide anions into hydrogen peroxide - an oxidant which contributes to the death of neurons. Amyloid plaques by entombing copper and zinc eliminate this particular route to brain damage. In essence, amyloid plaques are an effort by the brain to protect itself against metal ion induced toxicity (amyloid and hydrogen peroxide).

However, once superoxide anions cannot be converted into hydrogen peroxide, they combine with nitric oxide to produce peroxynitrite which causes brain damage as well.

So antibodies against amyloid oligomers should be more effective than antibodies against amyloid plaques. But the problem is that amyloid oligomers are one of several triggers that produce oxidative stress in the brain. It is the other triggers (high blood pressure due to high sodium levels, high glucose levels, air pollutants, pesticides, psychological stress, chronic bacterial, viral, and fungal infections along with many others) that usually lead to the formation of amyloid oligomers in the first place. The oligomers are an add on insult. You would have to remove all the triggers early on to prevent Alzheimer's disease and to stop its early progression. Later on removing them has very little effect because the receptors through which they operate become damaged by oxidation and nitration. So pharmaceutical companies are likely targeting the right form of amyloid and at the right stage but having almost no beneficial results to show for it.

There are still several companies working on the anti-amyloid approach (as well as the anti-tau approach). Roche, for example, is re-testing another drug - gantenerumab - at a higher dose for early stage (prodromal to mild) Alzheimer's disease. The company also continues to test crenezumab on families in Colombia with a presenilin-1 gene mutation that results in Alzheimer's disease. Indeed, some companies may have avoided significant declines in stock prices after announcing the failure of a particular drug because they still have several irons left in the Alzheimer's fire. Having other drugs in the pipeline for other conditions have also provided bigger companies with a safety net. And perhaps some investors have brushed off failures because they are no longer unexpected.

When it comes to the anti-amyloid approach, Biogen (BIIB) remains the big bull in the room (along with its partner Eisai (OTCPK:ESALY)). The company largely succeeded in refuting concerns that its drug BAN2401 performed much better than placebo because so few people with the ApoE4 gene (who probably progress more rapidly during the early stages of Alzheimer's disease) remained in the high dose group (due to adverse effects or the fear of such effects). Biogen noted a 63% slower decline in cognition in people with the gene than in placebo group. But then, the company also acknowledged that there was only a seven percent slower rate of decline in people without the gene in the highest dose drug group versus the placebo.

It is doubtful that even the 63% figure for ApoE4 carriers will hold up over time. Of the ten people left in the highest dose group with ApoE4, it is quite likely that most if not all had only one copy of the gene (since those with two copies of the gene are more likely to experience adverse effects from the drug). By contrast, several people would have had two copies of the gene in the placebo group resulting in a more rapid decline. Since ApoeE4 amplifies the triggers for Alzheimer's disease, it is quite probable that if you compare apples to apples - one copy of the gene versus one copy of the gene, two copies of the gene versus two copies of the gene in the drug versus the placebo group, BAN2401 would have slowed the progression of the disease to some degree (between 7% and 63%), but whether this is worth the risk of potentially severe side effects is a very open question.

That leaves us with Biogen's (along with Eisai's) greatest hope for Alzheimer's disease: aducanumab. The highest dose group declined about 50% percent less rapidly than placebo at 164 weeks (which is nearly the same percentage for BAN2401 albeit at a different time point and using a different cognitive test) (aducanumab charts; BAN2401 charts). Once aducanumab is subjected to the same kind of sub-analysis as BAN2401, the results should be quite similar as well. If so, this would lead credence to the contention that removing amyloid oligomers only addresses one of many causes for Alzheimer's disease and thus has only a very limited impact on disease progression, especially in non-ApoE4 carriers.

Biogen has a large pipeline, but the stock remains inflated in part because of a successful public relations campaign to convince investors and others that its drugs are more effective against Alzheimer's disease than they probably actually are. Even if there is a significant slowing down of the progression of the Alzheimer's disease, it is not the same as stopping or even partially reversing the progression of the disease. At some point, this reality will take hold and the stock should drop significantly.

This article was written by

Lane Simonian

2.41K Followers

Retired history instructor. Alzheimer's disease researcher for the past decade.My goal is to give investors solid advice based on the mechanisms of action of Alzheimer's drugs. This advice is informed by a background in biology (conservation, ecology, evolution, environmental science, and biochemistry) and seventeen years of a very in depth review of the research on Alzheimer's disease.

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