Yeah, donanemab!
https://www.alzforum.org/news/research- ... alzheimers
This came out of nowhere for me!
There is now a whole queue of amyloid lowering treatments that have efficacy in the 30% slowing range.
With dona this appears to even extend into the early moderate AD range (MMSE 20).
It is exciting that we are now seeing the scientific process firm up on certain clinical features of the trials.
For example, one of the problems with the aducan trials was that quite a number of the placebos were non-decliners even over 78 weeks and with these patients being amyloid positive. This made it a tough hill to show aducan efficacy.
"Participants had to score between 20 and 28 on the mini-mental state examination, and have
had memory loss stretching back at least six months." Requiring established memory loss is a good idea. Going somewhat later also seems like a good plan. This has been debated for almost 20 years without a clear resolution, though if you can select those deeper into the illness you have a much better sense that decline is present (though perhaps this strategy is only effective when using certain amyloid beta targets [here "recognizes Aβ(p3-42), an enzymatically modified form of Aβ adorned with pyroglutamate at its N-terminus. This form of Aβ is only found within amyloid plaques"]). Did the dona trial look at APOE epsilon 4 genotype?
It is not clear whether they did both tau and amyloid PET scans (universal?), though tau PET as inclusion is another important AD clinical trial innovation. Somewhat strange to me that they used fixed doses of 700 and 1400 mg: doesn't this mean that bigger people would receive less mg/kg? Also like the recombining of the ADCS and ADL. We need some psychometric innovation to develop a better understanding of what is happening in AD. However, it would probably still be best to report the standard ADCS and ADL values for benchmarking purposes. Using these well established instruments with a somewhat more advanced trial population than that included in the aducan also plays to the strengths of the tests. With patients around 30 MMSE in the aducan trials some of the tests might simply have not been sensitive enough to pick up on slight differences at the earliest stages of AD.
"while also validating the accuracy of home video-based cognitive assessments" This is another good one! Moving to virtual assessment makes a great deal of sense. One might be able to pick up on much more of dementia decline with essentially ongoing testing. In some way create at home immersive 24/7 testing while respecting privacy. This would probably be cheaper and yet give a near continuous measure of cognitive functioning (instead of the more typical testing every ~ 6 months).
Whoa! "Lilly referred to the second donanemab Phase 2 trial as “pivotal” "
Pivotal as in submit to FDA? Yes!
I like. I like a lot.
When (If?) there is a 343 page (or more) FDA briefing document for dona I'll do another one of these painstakingly thorough threads trying to understand what the document means. This time I hope they provide full documentation for the results of all patients and not have all the points all smushed up together. Including a summary for the cognitive results for the patients by different characteristics as I gave earlier on this thread for the aducan trials would be very much appreciated.
aducan appears to have reset the scoring for AD trials.
In addition now that we have a better idea of the efficacy range of anti-amyloid treatments ~30% companies can more efficiently progress through the clinical trial process.
They did a lot of interesting innovative things with TRAILBLAZER. It definitively feels like the scientific community is locking in on the amyloid target and developing a firm knowledge base. This could aducan's chances of approval as it is now fairly obvious that amyloid is a viable anti-AD target (shown also by BAN2401 and now dona).
One innovation I would still like to see is 18+ month trials. Everyone signs on for the 18 month trial and then the plus part is where patients would still be on trial though now those on placebo or low dose could be re-randomized up to a higher dose.
This would allow for more trial information to accumulate. This is of particular importance as we saw in the aducan trials that marginal doses are of considerable importance. Receiving the first 100 mg/kg seemed to have no real impact, yet at 150 mg/kg
a marginal 10 mg/kg made a large difference in treatment - placebo separation( ~25% relative!). Capturing this information would seem to be highly relevant from the perspective of understanding maximal clinical benefit as well as a return on invested resources.
The clinical trial would not need to be extended to accommodate the plus; the same end date could apply with earlier patients having the opportunity for more treatment.
Possibly the next big headline that we should be looking out for is a pre-AD dementia vaccine.
This has also been talked about for decades, though this would be a dramatic game-changer for all of us.
Instead of waiting until symptoms have nearly emerged (or actually have), why not step decades ahead of the problem?
This would drastically change the economics of AD.