The Relentless Focus on Amyloid Clearance for Later Stage Alzheimer's Disease is Disintegrating

In hindsight, the Alzheimer's research and development community of the past fifteen years or so has been a strange place. The vast, overwhelming majority of investment has gone towards attempts to clear amyloid-β in later stage Alzheimer's disease, largely via immunotherapies. This strategy has failed, over and again, long past the point at which it was defensible to blame that failure on the challenging nature of the underlying projects to first make immunotherapies work at all, and then to make them work in the brain. Enormous sums were spent on repeated attempts to clear amyloid-β even as the research community was settling on the consensus that aggregation of amyloid-β is a feature of early Alzheimer's. It only causes mild cognitive impairment on its own, but sets the stage for the later accumulation of hyperphosphorylated tau. It is tau aggregates and their surrounding biochemistry that cause the real harm, the severe dysfunction and death of neurons.

Where years of relentless failure did not move the leaders who determined strategy for Alzheimer's development at the large scale, the rise of plausible, much cheaper alternatives has finally produced motion. Large anti-amyloid programs are being cancelled, trial development halted. It is becoming apparent that low cost senolytics have a large effect on late stage Alzheimer's disease animal models, perhaps more so than many of the immunotherapies when they were tested in mice. Meanwhile, groups are working on drainage or filtration of cerebrospinal fluid, which should clear out a usefully large fraction of all of the protein aggregates involved in neurodegeneration, again much more cheaply than immunotherapies. Other researchers are focused on removing bacterial and viral contributions to amyloid buildup and neuroinflammation.

Ironically, just as this flourishing of alternative and potentially more cost effective development programs takes place, some of the anti-amyloid immunotherapies are finally starting to achieve their goals, to remove significant amounts of amyloid-β from the human brain. Yet they haven't moved the needle on patient outcomes. This upheaval, when taken as a whole, seems a positive development. The old industry is being disrupted by the growth of a new industry. Bad investments are being cleared out, and more productive new investments are being made. The Alzheimer's research community of the early 2020s will be a much more diverse ecosystem with a greater expectation of success.

Biogen/Eisai Halt Phase 3 Aducanumab Trials

Today, Biogen and Eisai announced they would terminate the Phase 3 ENGAGE and EMERGE trials of aducanumab for early Alzheimer's disease. A futility analysis run by an independent data-monitoring committee concluded that that trials would not reach their primary endpoint, the slowing of cognitive decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Aducanumab is a monoclonal antibody that helps clear amyloid-β (Aβ) from the brain. The trials had recruited more than 3,200 patients around the world.

"This tells us that removal of amyloid in people with disease is too late. Amyloid is a disease trigger. Once the neurodegenerative disease process is up and running, it is up and running. Even though this trial was in the early symptomatic phase of AD, it is still in the phase when Aβ is no longer likely to be the driving process but where tau and inflammation probably are. I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD, before tau and inflammation have started driving the disease. I think this solidifies the opinion that amyloid-targeted therapies do not have a clinical effect at the symptomatic stages of the disease process. Might anti-amyloid therapies work prior to the development of symptoms? Maybe, but with no symptomatic signal, it is risky to continue in that space. We clearly need other targets, and tau is the leading candidate for now."

Alzheimer's Drug Failure Leaves Scientists Seeking New Direction

The brain has been a black box for drug developers, but focusing on beta amyloid has long been viewed as the best hope for treating the mysterious ailment that affects millions of Americans and their families. For many, the hypothesis became an article of faith, motivating billions of dollars in research spending and putting thousands of patients through clinical trials. "It's not science anymore. It has turned into a religion."

Biogen and Eisai will discontinue two late-stage trials designed to evaluate the efficacy and safety of the drug, aducanumab, which has cost the partners more than $830 million over the past three years. The results showed that the drug was unlikely to help patients, the companies said in a statement, and the discontinuation wasn't related to safety concerns. The latest failure, following the unraveling of similar experimental beta amyloid drugs from Eli Lilly & Co., and Pfizer Inc. in large-scale trials, has scientists questioning whether the persistent focus on targeting the compound has prevented investment in testing drugs against other possible Alzheimer's targets. Even so, researchers had thought that perhaps the Biogen compound might be different from previous failures.

Comments

Not everyone gets the message - even after wiping away $18 billion in investor wealth -

https://www.cnbc.com/2019/03/22/eisai-starts-phase-3-trials-for-second-alzheimers-drug-after-firsts-failure.html?fbclid=IwAR1EzcpCnat5bvP1OVWbu9h31To5Sfey9BO3vHdQz5KPblZr_HlHLbCSRkk

"We still believe that amyloid beta hypothesis is potentially the right approach for the treatment of Alzheimer's disease," an Eisai spokesman told Reuters

Pharma is like a super-tanker - takes a long time to stop and change direction

Posted by: Ira S. Pastor at March 25th, 2019 3:33 PM

The science is amazing. There was a plausible hypothesis that somehow got proved in the animal model (no surprise, since they are quite poor replication of what happens in the human brain after decades of damage accumulation). Then there was a really advanced treatment, which didn't help with the outcomes. Therefore, the theory is disproven. I am still surprised that there was no measurable benefit. Even if the tau aggregation is the main culprit , removing the amyloid should help, if only by merely clearing the pro-tau forming environment. So there are quite a few unknowns here. On top of that, having the know-how to selectively clean compounds using the immune system or antibodies might be useful somewhere else

Posted by: cuberat at March 25th, 2019 3:59 PM

@Ira S. Pastor
Hmm, good to know what to avoid as investment.

On the other hand, they might still be lucky and the cleanup of the amyloid might be required but not sufficient condition to reverse or slow AD. We shell see. However, those 18 $B could have been spent better...

Posted by: cuberat at March 25th, 2019 4:02 PM

It's the perenial problem in biology, a problem perturbs a whole host of biochemichal factors, some elevates, some depress, we take a single observation that X or Y is elevated or depressed in that disease and therefore must cause it!

It was a fair shot though based on the etiology of the familial form, but we desperately need new approaches. It's untenable now not to know that dementia's etiology is multifactorial, amyloid is a unspecific respons and is not evolved to harm you. A way forward is to focus on inflammation-causing processes in the brain, from viruses to heavy metals to metabolic derangement.

Posted by: Johannes H at March 26th, 2019 5:06 AM

I agree that canceling this uselles research is good thing for the rejuvenating biotechonogy. Many people are whinning that this is a catastrophe . Of course, no -- this is just a cleaning .

Posted by: Ariel at March 27th, 2019 7:20 PM

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