[ADDENDUM May 03, 2023: Although this blog piece was just posted yesterday, about imaging data presented last week, this morning the company has a press release that claims donanemab “significantly slowed….decline,” with data to be presented at a meeting in July].
Donanemab, an anti-amyloid IV infusion, may be better than its rival, aducanumab, in “clearing” Alzheimer subjects’ brain PET scans of amyloid. It also has some previously published positive clinical impact. Unlike aducanumab (Aduhelm TM), it remains unapproved by the FDA, denied again this year. Huh?
PET scan response data was presented last month at the Am Acad of Neurology meetings, in a dementia /Alzheimer Disease (AD) therapeutic abstract on 04.25.23. The abstract reported a “head to head” (pun I guess?) comparison of the two anti-beta amyloid therapies, featuring a matched randomization with ~ 70 subjects in each group.
Using PET scans at 6 months, 37.9% of donanemab subjects had substantial “clearing” of the beta amyloid signal, vs. 1.6% of the Aduhelm subjects. If donanemab isn’t somehow blocking the PET scan agent (one guesses that folks think the imaging is valid), this might be a > 20-fold improvement in the imaging criteria that FDA mentioned in approving Aduhelm.
Aduhelm’s FDA approval was controversial in part because of the unconventional interpretation of clinical effect for patients. FDA recently approved lecanemab (Leqembi TM) which improves amyloid PET scans somewhat, but had skeptics also raising the question of tangible clinical improvements.
So, is this magnitude of PET imaging improvement a “proof of concept?” Despite all the creative hard work of the scientists who produced these anti-amyloid agents, and BACE inhibitors too (along the beta-amyloid/”secretase” pathway in the figure below), an editorial in 2019 calls the amyloid reductions “informative failures,” specifically referring to BACE agents, while also mentioning the lack of success of the anti-amyloid monoclonals.
What patients and families want to know from this donanemab news: was there a real clinical effect, not just better looking PET scans? The abstract is brief and focused, and coyly doesn’t even hint at differences in clinical effects. However, the company is optimistic enough to press forward.
Donanemab’s Phase 2 trial results were published in 2021, NEJM, and discussed on this blog. There seemed to be a positive clinical effect, although it failed the study’s own predetermined effectiveness endpoint. Subsequent NEJM correspondence raised the issue of the positive clinical effect, and called out brain atrophy findings from the study.
Some researchers from the company behind donanemab had a viewpoint paper published last month (April) that the agent delays progression, given the measure they used, which might be clinically meaningful. Some of the same authors also published this month (May), a proposal to use “time saved” (one way to measure delay in progression) as a measure of meaningfulness.
Wattmo in Sweden (2018) in a parallel way published that response to conventional cholinesterase inhibitors (donepezil, etc) could delay nursing home admission for some months in a longitudinal observational study with national data in Sweden. The magnitude of delay seems similar. The previous post on clinical meaningfulness is linked in this sentence with the underlining.
More to the point in a big picture way, two well known AD researchers try to approach the “unsolved mystery” of why these anti-amyloid agents don’t really improve patients. They pose their own questions and formulate their own answers with a review perspective paper last year:
[spoiler: they claim that previous failures do not prove that the amyloid hypothesis itself is a failure (seems I’ve heard a Harvard geneticist say that on a TV interview before). They do address issues with aducanumab, lecanemab and donanemab, but seem to leave the “thorny question of clinical meaningfulness” aside. They end up saying, like others have, that perhaps we need to treat brain healthy people (“presymptomatic”) with these agents for decades to see if there might be a difference. Not quite like a Sherlock Holmes paper, Dr. Watson, especially for people now affected the most.]
They include a very nice waterfall picture written over with a version of the “amyloid cascade hypothesis” [or are they teasing us with answers in the crytpic code rock carvings that seem hidden behind the water? Is it the Reichenbach Falls motif for hero Sherlock Holmes and his nemesis “Amyloid” Moriarty from “The Final Solution”?]
As tantalizing as the donanemab abstract is, one wonders if it will prove to be a breakthrough, or just another mind & heartbreaker.
Apologies for the lyric revision, but here’s how Tom Petty and his Heartbreakers might have responded:
Don’t come around here no more
Whatever you’re looking for
Hey! Don’t come around here no more
I’ve given up, stop
I’ve given up, stop
Ah, ah, ah, ooh-ooh
I’ve given up, stop, on waiting any longer
I’ve given up, on this [AD monoclonal therapy] getting stronger
