Eli Lilly (NYSE:LLY) made headlines this morning with an announcement that their anti-amyloid antibody donanemab hit its endpoints in a Phase III clinical trial. So this definitely needs a close look! Here’s Lilly’s press release. Ryan Cross has a good writeup on the results at Endpoints, and so do Matt Herper and Adam Feuerstein at Stat (paywall). It’s important to note that the press release is all any of us have to go on, which means that we are surely looking at the most optimistic take possible – we’ll have to wait for filing with the FDA to see more. That will happen before these results get published – Lilly says that they’re going to file for approval before the end of June, present results at a conference in July, and submit them for publication as well.
The natural comparison is with lecanemab (Leqembi), the recently approved antibody from Eisai (OTCPK:ESALF, OTCPK:ESAIY) and Biogen (BIIB). That’s tricky, though, because of differences in dosing and in patient recruitment, even where the two programs use what is supposed to be the same ratings scale. But as I did when I wrote about the lecanemab data, let’s get some of the disclaimers out of the way at the beginning. I mentioned there that no Alzheimer’s drug candidate has ever stopped the progression of the disease, and that of course means that no such candidate has ever reversed any of the damage, either. See below for more on that as it relates to donanemab, but what we’re looking for in all these cases is essentially slowing down the rate at which these patients deteriorate.
That progression of disease is measured by several different ratings scales, and over the years there have been many of these. Lecanemab’s trial used CDR-SB (Clinical Dementia Rating – Sum of Boxes), and the donanemab trial used this as well. Lilly’s clinicians also used a measure that they came up with themselves and named the “integrated Alzheimer’s Disease Rating Scale” (iADRS), which combines CDR-SB and two other ratings scales, the Alzheimer’s Disease Cooperative Study – Instrumental Activities of Daily Living scale (ADCS-iADL) and the 13-item Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog13). Lilly provided separate numbers on all these scales.
Lecanemab’s primary endpoint was the change from baseline decline in function after 18 months of treatment on the CDR-SB, dosing every two weeks. Lilly’s donanemab trial had a primary endpoint of change in that baseline decline after 18 months on their iADRS, but their antibody is dosed differently: every four weeks, but once the patients went below a certain amyloid threshold (as measured by imaging studies), the dosing stopped. Around half the participants in the trial stopped dosing by this route after one year of treatment, and by 18 months 72% had stopped. So already you can see how comparisons are going to have to be made carefully.
But here goes: lecanemab slowed decline by 27% on the CDR-SB scale, and donanemab slowed it by 29%. As you can see from my earlier writeup on the former drug, opinion was very much divided on whether the lecanemab numbers would even be noticeable in real-world use (there is no standard for clinically meaningful efficacy in CDR-SB changes). So I would have to think that the same objections apply here. We cannot be sure that this drug will actually make a difference in the real-world care of patients with Alzheimer’s – not yet, anyway. This point is completely avoided in the Lilly press release, but it is nonetheless real and we will be hearing more about it from clinicians – well, if you listen closely above all the noise, that is.
Now, there are some interesting features in the Lilly data, which they make sure to highlight. That 29% number is in the overall patient group, but in a subset of patients who had intermediate levels of the tau protein (also thought by many to be associated with Alzheimer’s, in ways that we really do not understand), the CDR-SB slowing was greater (36% versus 29%). It’s hard to know what to make of this since all we’re sure of is that tau levels seem to be associated with more severe disease (and since the lecanemab trial did not differentiate patients by tau levels). Lilly also noted that 47% of patients “had no clinical progression” on the CDR-SB after one year, which sounds quite interesting but has to be compared to 29% of the patients in the placebo group who had no progression on the scale in that time period, either. Lilly is using these numbers to cautiously broach the idea that they may have stopped the progression of the disease, but I would wait until we have more data before talking about that (and I would also want to see what the FDA’s statisticians make of that data as well). This could be good, or it could turn out to be a hard statement to support.
Finally, the topic of ARIA-E (brain swelling during treatment) and overall brain shrinkage after such treatment has to come up. I’ve written about this here before in the context of lecanemab and other attempts to target amyloid: there have been brain-imaging abnormalities associated with such treatment in virtually every clinical trial, and this latest one showed them, too. Even worse, there have been bleeding incidents (ARIA-H) and deaths associated with such amyloid removal, which apparently weakens some blood vessels in the brain that have taken on a good deal of amyloid-related scaffolding. In the lecanemab trial, the reported rates of ARIA-E and ARIA-H were 13% and 17% of the trial participants, and the rates in this new donanemab trial were noticeably higher: 24% and 31%. There may be differences in how these were measured in the two trials, but I have no information either way on that. Worse, the new trial had two deaths that were tied to ARIA-H (and one that is still being adjudicated). There were similar deaths in the lecanemab trial as well and debate about other serious side effects.
I very much look forward to a better look at more donanemab data. Until then, I cannot tell from the current press release whether the drug is truly different from lecanemab, and my opinion of that one is already not high. It is possible that it is more beneficial, and it is also possible that it has no greater benefits (such as they are) and even greater risks. We’ll have to see.
Disclosure: None.
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