The media has been hyping donanemab as a major advance against Alzheimer’s disease…again. Over a year ago Time’s headline read: “Eli Lilly’s Alzheimer’s Drug Shows Greatest Benefit Yet.” On June 10, 2024 the New York Times headline read: “Advisory Panel of Experts Endorses F.D.A. Approval of New Alzheimer’s Drug.” And Forbes noted that “Eli Lilly shares jumped more than 2% in after-hours trading after closing Monday at $865, continuing a steep jump in price that began last Thursday.” But what readers of The People’s Pharmacy really want to know is how helpful donanemab for Alzheimer’s disease will be when it comes to things people really care about?
The Quick Overview of Donanemab:
This is what the New York Times (June 10, 2024) said about donanemab:
“It modestly slowed cognitive decline in patients in the early stages of the disease but also had significant safety risks, including swelling and bleeding in the brain.”
Reuters (June 10, 2024) offered this summary:
“In Lilly’s large clinical trial, donanemab, given by infusion once a month, slowed progression of memory and thinking problems by 29% overall, roughly comparable to the 27% slowing seen with Leqembi.“Brain swelling and bleeding – a known risk for this class of drugs – occurred in 24% and 31%, respectively for those taking donanemab and three patients died.”
The Psychiatric Times (June 10, 2024) quotes Dr. Howard Fillit, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF):
“Today’s vote offers hope that donanemab will be approved in the coming months, but it’s important to look at this milestone in the larger treatment landscape for Alzheimer’s, which will entail a combination therapy and precision medicine approach.”
Dr. Fillit describes donanemab as a “milestone.” We will let you judge that for yourself.
The Summary on Donanemab:
This drug appears to slow the decline of Alzheimer’s disease (AD) a little bit. What it won’t do is restore memories. Someone who has forgotten friends and relatives will not suddenly recognize these people. A person who can’t balance a checkbook or drive will not suddenly regain these skills.
What Does the Drug Actually Do?
This person wants to know how well donanemab really works.
Q. Can you comment on the new findings about donanemab? I read that in a Phase 3 clinical trial, “Donanemab slowed clinical decline by 35% compared to placebo on the primary outcome measure and resulted in 40% less decline in the ability to perform activities of daily living.” What exactly does that mean?
A. Eli Lilly created headlines with its study of the drug donanemab for Alzheimer’s disease (AD). All of the participants in the trial performed worse on cognitive tests as the study progressed. However, those on donanemab declined somewhat more slowly. Whether this will keep such patients out of nursing homes remains to be determined. That’s just one aspect of AD that people really care about!
What Do Patients and Families Want from AD Drugs?
Let’s be clear, dementia is devastating. It not only robs patients of their memories, it takes away their ability to function. AD makes it impossible for people to continue working. When this mind-slayer hits people in mid life, it has ruinous effects on finances.
Older retired people are also in trouble. Nursing homes can be unbelievably expensive, if they will even take someone with dementia. The annual cost can exceed $100,000 per year. If a person with AD has not been admitted to a long-term care facility, they can be refused entrance if they depend upon Medicaid.
Then there are the practicalities. People with advanced AD may not be able to care for themselves. Getting dressed may seem like an insurmountable challenge. Brushing teeth, getting to a doctor’s appointment or just interacting with friends and family can be overwhelming.
Will Donanemab for Alzheimer’s Disease Reverse the Brain Decline?
Donanemab may show the “Greatest Benefit Yet,” but that is a very low bar. None of our previous drugs have been able to meaningfully slow or stop the inevitable decline of AD.
When Eli Lilly states that donanemab for Alzheimer’s disease “showed 35% slowing of decline,” that does not mean the drug will keep patients out of nursing homes. It does not mean it will enable people with AD to recognize their grandchildren. We have seen no evidence that it will allow people to keep working or driving once the disease has progressed.
Will Donanemab Prevent the Inevitable Downward Spiral of AD?
Read the words from Eli Lilly carefully. The drug produced “less decline” than people taking placebos. We found an earlier study of donanemab published in the New England Journal of Medicine (May 6, 2021).
Here is what the authors reported:
“In this trial of donanemab, an amyloid plaque–specific intervention, in participants with early symptomatic Alzheimer’s disease, the primary analysis showed a smaller reduction in the iADRS score, by 3.20 points, in the donanemab group than in the placebo group. The iADRS ranges from 0 to 144. The minimal clinically important difference on this scale has not been established, but because we aimed to find a medicine that could slow Alzheimer’s disease progression by at least half, the trial was powered to show a 6-point difference (decreases from baseline of approximately 12 and 6 points for placebo and donanemab, respectively); this goal was not reached.”
What Does That Mean?
We know it can be a challenge to make sense out of medical jargon and scientific results. Let me try to explain what you read above. The iADRS score described above is the integrated Alzheimer’s Disease Rating Scale. As described, it goes from 0 to 144.
It is my understanding that 144 is a perfect score. If you were able to achieve that number during testing it would mean that you have no mental decline. As your score drops, the worse your mental state is determined to be.
Actual Numbers:
The people who participated in the study were all diagnosed with “early symptomatic Alzheimer’s disease.” Here are the results. Please pay attention to the iADRS score at the start of the study and at the end of the 76-week trial of donanemab for Alzheimer’s.
The researchers describe it like this:
“A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P=0.04). The results for most secondary outcomes showed no substantial difference.”
Did you follow that? The average score at the beginning of the study was 106. Remember, 144 is the best score possible. Zero would be the worst score possible. People on nothing (placebo) declined 10.6 points over 76 weeks. People on donanemab declined 6.86 points over 76 weeks. So…on a 144 point scale, the patients on donanemab experienced 3.2 points less decline. Not nothing. But was it meaningful? Did families find the benefits impressive? How many people dropped out of the trial?
See for Yourself:
The best way to assess the results of this study is to go to this link and scroll down until you get to Figure 2. Double click to make it readable. The top graph represents “Primary Outcome iADRS Score.” It will tell you a lot about donanemab for Alzheimer’s disease. It will only take you 30 seconds and is definitely worth that amount of time to see the results for yourself.
The TRAILBLASER-ALZ 2 Phase 3 study announced by Eli Lilly on May 3, 2023 was larger (1,736 participants) than the study cited above in the New England Journal of Medicine. The results of the randomized clinical trial were published in JAMA, Aug 8, 2023. Here is what they found:
- After 76 weeks the iADRS score in the donanemab group declined 6.02 points
- After 76 weeks the iADRS score in the placebo group declined 9.27 points.
- The difference was 3.25 points after 76 weeks.
So, the results were not very different from the earlier, smaller study published in the New England Journal of Medicine. And please remember, this “integrated Alzheimer Disease Rating Scale”(iADRS) goes from 0 (brain nonfunctional) to 144 (brain great). We leave it to you, dear reader, to determine whether a decline difference of 3.25 points on a 144 point rating scale is a “milestone.”
How many people dropped out of the trial? We always find this is a revealing metric.
“Treatment discontinuation due to adverse events was reported in 112 participants receiving donanemab and 38 participants receiving placebo.”
People often drop out of a clinical trial because of serious adverse reactions.
Final Words:
Is donanemab a breakthrough? Will it keep patients with Alzheimer’s disease out of nursing homes? What are the possible side effects and how serious are they? You can read about some adverse drug reactions at this link.
Patients with dementia did not improve their cognitive scores while taking donanemab. They got worse a little more slowly than those on placebo.
None of the anti-amyloid medications that have been tested over the last decade have actually improved cognition or activities of daily life. The best they can do is slightly slow deterioration. This has led some researchers to question the anti-amyloid approach to treating Alzheimer’s disease. You can read about that controversy at this link.
What do you think? Please add your thoughts in the comment section below. And if you think this article is worth sharing with friends and/or family, please scroll to the top of the page and click on a link to email or via social media. Thank you for supporting our work.
