1- My current take on whether anti-amyloid therapies are likely to have meaningful impact on cognition, functioning & quality of life of people living w/ #dementia due to #Alzheimers disease:
Not likely.
For details, based on my recent Grand Rounds at Penn St, read on.
2- History:
After finding that active immunization with Abeta42 in mice that overexpressed APP resulted in virtual elimination of amyloid deposits, there was great enthusiasm for anti-amyloid therapies - and for the amyloid hypothesis.
pubmed.ncbi.nlm.nih.gov/10408445/
3- More history:
Unfortunately, active immunization with Abeta42 in humans resulted in unacceptable side effects.
Passive immunization with various anti-amyloid monoclonal antibodies failed in multiple studies.
It seemed like this was the end of the line, until ...
4- Despite an advisory panel voting against approval, @US_FDA granted accelerated approval for aducanumab.
What did they base this on?
5- Aducanumab is extremely good at clearing amyloid.
As are many of the other anti-amyloid monoclonal antibodies.
Which should not be surprising because that is exactly what they are designed to do.
jpreventionalzheimer.com/5919-two-rando…
6- But aducanumab had very little effect on cognition.
In ENGAGE, no sign of benefit relative to placebo.
There was slight benefit w/ high-dose aducanumab in EMERGE, though as @LonSchneiderMD pointed out, this could be due to cognition worsening more in placebo group.
7- There is reason to be skeptical of the hypothesis that reducing amyloid results in improved cognition.
To wit, this systematic review & meta-analysis found very weak correlation between amyloid reduction & improved cognition across 17 MAB studies:
pubmed.ncbi.nlm.nih.gov/33831607/
7b - Take another look at this scatter plot. If you throw out the apparent outlier in the bottom left, do you think there would be any correlation between amyloid reduction & cognitive improvement?
8- Back to aducanumab studies.
How representative were the 3000+ subjects wrt race & ethnicity?
Not at all.
That's both a scientific problem (how generalizable are these results or, for that matter, the amyloid hypothesis?) and a problem of health equity (how did this happen?)
9- Then there are side effects, esp amyloid-related imaging abnormalities (ARIA).
31% of aducanumab subjects got ARIA-E (edema), more if higher dose or if apoE e4+.
It's usually mild & reverses w/ discontinuation. But, still, it's brain edema. And it requires MRI monitoring.
9b - 18% of aducanumab subjects got ARIA-H (hemorrhage), with significant overlap with ARIA-E.
Usually asymptomatic. But, again, we will increase the risk of brain bleeding.
We will need to be very mindful of contraindications: being on blood thinner, h/o CNS bleed or stroke.
10- Of course, there's the cost. The drug itself will be $28,000 per year.
But a recent analysis found that aducanumab would need to be < $3000/y to be cost effective.
jamanetwork.com/journals/jaman…
11- And there will be a lot of other expenses:
- biomarker to establish amyloid positivity
- baseline & surveillance MRIs
- apo E testing & genetic counseling
- infusion center
Plus expertise to interpret amyloid PET (for dx) and to identify & assess severity of ARIA.
12- What does the future hold for monoclonal antibodies?
We are waiting for results of studies of
- donanemab
- lecanemab
- gantenerumab
- solanezumab (A4)
Biogen is required to complete another aducanumab study as part of FDA accelerated approval.
13- Many other types of agents in the pipeline.
Perhaps not surprisingly, since neurofibrillary tangles are within neurons, anti-tau antibody therapies have failed.
14- Conclusion, part 1
1. I think it's unlikely that anti-amyloid antibodies will have an impact on the care of people with #Alzheimers disease.
2. Blood-based biomarkers are coming soon and could result in a major change in how we diagnose AD.
15- Conclusion, part 2
Treatment of dementia requires a holistic approach:
- eliminating medications/substances that worsen cognition
- educating/supporting families & caregivers
- socializing, cognitive stimulation, exercise, diet
- supporting functioning
- addressing BPSD
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