Alzheimer’s: Do We Have The Wonder Drug?

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Since Alzheimer’s Disease (AD) was discovered over a century ago, hundreds of drugs have been tried but only three approved; two of them in the last two years.  Do we finally have a cure?  

A mountain of failure including #1

AD accounts for 70% of dementia cases. That’s why, in the USA, Alzheimer’s Disease is the umbrella term, and is the focus for most drug research. There’s a mountain of research going on; the US Alzheimer’s Association alone sponsors nearly 1,000 projects in 48 countries.

Yet, after all this effort, drug candidates have seen almost 100% failure  A study of 413 clinical trials of Alzheimer’s drugs over a 10-year period found that the success rate was a tiny 0.4%. That is, 99.6% of the drugs studied in clinical trials failed.

That study was completed after the FDA approved the first Alzheimer’s Disease (AD) drug, Tacrine in 1993, which was later withdrawn due to side effects. Tacrine, it seems was definitely not the wonder drug.

#2 didn’t fare much better

alzheimers do we have wonder drug-aduhelm
Aduhelm from Eisai & Biogen

It was  a full 18 years before the FDA approved the second dementia drug, Aduhelm – made by Eisai and marketed by Biogen under generic name Aducanemab – to great fanfare.

This approval is a victory for people living with Alzheimer’s and their families‘ said the CEO of the Alzheimer’s Association in 2021. This drug, like its predecessor, was approved on trials using a ‘marker’, a lab measurement which mimics a natural process. With Aduhelm, the marker was ‘amyloid-beta’, a protein in the brain said to indicate cognitive decline.  

This distinction was possible due to the FDA’s Acccelerated Approval, given for drugs ‘that treat serious conditions, and fill an unmet medical need, based on a surrogate endpoint‘ (another name for a marker). Aduhelm met all these criteria, and was given wide enough approval to be prescribed for every AD sufferer in the USA.

This approval (Aduhelm) is a victory for people living with Alzheimer’s and their families.

Alzheimer’s Association 2021

In Europe, authorities were less captivated.

Less than a year later, marketing approval for Aduhelm was withdrawn. The summary said: ‘The European Medicines Agency noted that although Aduhelm reduces amyloid-beta in the brain, the link between this effect and clinical improvement had not been established.’

In other words, the drug changed something but not brain function. The agency also raised concerns about serious side effects, including brain bleeding and swelling, which occurred in 40% of patients.  

although Aduhelm reduces amyloid-beta in the brain, the link between this effect and clinical improvement had not been established.

European Medicines Agency 2022

In 2022, Biogen made news again, more than once.

In July it wrote down the value of its Aduhelm inventory, declaring it ‘de minimis’ or functionally worthless. In other words, the drug had no future.

Two months later, Biogen and Eisai announced promising clinical trial results for their new drug ‘Leqembi’, (generic name lecanemab).

Third time lucky?

alzheimers do we have wonder drug-leqembi
Leqembi from Eisai & Biogen

Leqembi gained also FDA Accelerated Approval, in January of 2023.

Like Aduhelm, Leqembi measures amyloid beta. We’ve been told for decades that more plaque means more dementia yet, six months after granting limited approval for Leqembi, the FDA was more muted:

In its confirmation of Leqembi’s clinical benefit in June 2023, the FDA calls amyloid plaque: ‘a marker of Alzheimer’s disease that’s believed to be associated with improved outcomes.’  Even on this basis, full FDA approval will almost certainly occur in coming months.

So, what does Leqembi do? In earlier trials, the drug apparently did reduce amyloid-beta, did slow down cognitive decline and did show about half the rate of brain-swelling and brain-bleeding compared to Aduhelm. A first for an AD drug.

A reduction in the reduction

The slow down of 27%  does sound  impressive, yet the real world adds some context: Leqembi is only effective on very early-stage AD and only 1-2% of people with dementia are tested to find out. In everyone else, there would likely be little or no benefit.

By the makers’ own admission, the trial was designed to include only sufferers in the earliest stages of AD; that is, those most likely to respond. The reality for others may be quite different.

And, the 27% reduction was in the rate of slowing not the decline itself.  In other words, patients’ brains were getting worse slightly more slowly. As neuro- psychologist Karen Sullivan put it, ‘the real-world impact of this may not be noticeable to families.’

..the real-world impact of this (slowing of rate of cognitive decline) may not be noticeable to families.

Dr Karen Sullivan, Neuro- psychologist

An unexpected paradox

An odd aspect of the Leqembi trial was this: unlike all other drugs targeting amyloid plaques, Leqembi increased soluble levels of amyloid-beta. That led researchers in the US and Sweden to turn the amyloid hypothesis completely on its head, arguing that higher levels of amyloid-beta are good, not bad. 

Confused? So was I. They found that patients with amyloid plaques in their brains were no more likely to develop dementia than the general population.

That should have thrown a spanner in the works but didn’t. Others had been saying this for years, but few were listening.  

The paradox is that so many of us accrue plaques in our brains as we age, yet the plaques remain the center of our attention …’

Dr Alberto Espay, University of Cincinatti

What’s it all about, Alfie?

In other words, there were many cases of AD without amyloid plaques, and many cases with them – but no dementia.

One who has been sceptical and about the plaque-dementia link is Dr Derek Lowe, a long-time observer and researcher in the field of AD. As he wrote Science in 2022: ‘Ever since the 1990s, researchers and clinicians have been spending uncountable hours (and uncountable dollars) trying to turn the amyloid hypothesis into a treatment for Alzheimer’s. Every single one of these interventions has failed in the clinic. Every last damn one. If you look for the best outcome of all, actual reversal of Alzheimer’s symptoms, you never see it.’

Bloomberg agrees, saying: ‘For Alzheimer’s patients, their families, researchers, and the pharmaceutical industry, the bigger question is whether drugs targeting amyloid have been a multibillion-dollar dead end.

Ever since the 1990s, researchers and clinicians have been spending uncountable hours (and uncountable dollars) trying to turn the amyloid hypothesis into a treatment for Alzheimer’s’. Every single one of these interventions has failed in the clinic. Every last damn one.

Dr Eric Lowe, former AD researcher, in Science

That’s pretty strong stuff, you might say, and enough to take a hard look at the amyloid hypothesis?

‘A robust drug pipeline’

Maybe not. Despite the doubts about amyloid-beta and the drugs based on it, many dementia support websites are still pinning their hopes on both of them.  

Alzheimer’s Weekly talks about ‘recent progress made in the Alzheimer’s robust drug pipeline.’ That’s pretty surprising, given that two out of three approved drugs have failed, and the third one slows the rate of cognitive decline so little that loved ones may not even notice. The other drugs in the pipeline are in the same league.

The new candidate in the ‘robust drug pipeline’ appears to be Donanemab from Eli Lilly. It uses the same mechanism as Leqembi (an amyloid-beta marker) but is better at slowing cognitive decline; that is, it slows the decline by 2% more (if that makes sense) in mildly-impaired patients, the same early-stage ones. So far though, Donanemab shows more serious side effects so, if it will progress from pipeline to approval is yet to be seen.  

What about the patient?

Despite the focus of drug makers on amyloid plaque, or maybe because of it, the wonder drug for dementia may be still far off. After all this time, you might be tempted to ask: ‘are they looking in the wrong place‘.

You wouldn’t be alone; many now suggest that this is more than a possibility.

Away from the world of drug targets, there are many encouraging, independent studies into how to stop the progress of AD, or reverse it in the early stages. These studies are run by independent groups, mostly universities and the clinics associated with them.

Unlike the pursuers of dementia drugs, these studies are observing cognitive improvement in real people, not changes in surrogate markers that have little discernible effect. That’s why these studies are so exciting.

You can find out more about these studies, the causes of dementia (many of which are under your control), and what you can do to avoid, prevent, delay or even reverse AD. It’s all in my comprehensive eBook, Dementia: Keep Your Marbles.  

Dementia

DEMENTIA:
KEEP YOUR MARBLES

Discover how Aussie boomers can delay or prevent Alzheimer’s Disease

Kim Brebach

Kim Brebach

Hi, I’m Kim Brebach, boomer, information researcher, technical writer and Joiner of Dots at M&M. In my spare time, I review wines and love to cook.

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