The news from Eli Lilly about its experimental Alzheimer’s drug donanemab was upbeat. Some might say the headlines were downright euphoric:
The company’s headline on May 3, 2023 stated:
“Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease”
Lilly went on to state that:
“Nearly half (47%) of the participants on donanemab (compared to 29% on placebo) had no clinical progression at 1 year (defined as no decline in CDR-SB)”
Other headlines were equally enthusiastic:
“Eli Lilly says its new Alzheimer’s drug can stop the disease’s progression”
“New Alzheimer’s drug slows disease by a third”
One website (Seeking Alpha) that analyzes the stock market used the B word:
“Eli Lilly’s Alzheimer’s Breakthrough: A Game Changer for Investors And Patients”
How How Do Drug Companies Measure Alzheimer’s Disease?
The first thing you need to know is how drug companies test medications to treat Alzheimer’s disease. Studies of two prior drugs for Alzheimer’s disease (aducanumab and lecanemab) used the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score. It is an 18 point scale assessing memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
A score of 0 means no cognitive impairment. A score of 3-4 is interpreted as quite mild dementia. Between 4.5 and 9 is “mild” dementia. Between 9.5 and 15.5 is moderate dementia and a score of 16-18 is really severe Alzheimer’s disease. Put another way, the lower the score the better.
The drug lecanemab (Leqembi) was recently approved by the FDA to treat early Alzheimer’s disease. It reduced clinical decline by 27%. That sounds pretty good. But if you look at the actual numbers on the CDR-SB scale, it’s not that exciting.
Remember, this is an 18-point scale. At the start of the 18-month clinical trial, the patients averaged 3.2 on the CDR-SB scale. At the end of the trial, most patients had higher scores (not a good thing). Their cognitive ability declined whether they were taking the drug or not. But the patients on lecanemab improved their score by 0.45 points compared to patients on placebo. It was statistically significant, but on an 18-point scale a 0.45 point benefit leaves a lot to be desired.
How Did Donanemab Do Against Alzheimer’s Disease?
A key metric that Lilly used in its clinical trial was the Integrated Alzheimer’s Disease Rating Scale. It is abbreviated iADRS. This is different than the CDR-SB scale. It is a scale of 0-144 instead of 0-18. I admit to being somewhat confused by iADRS, but my best understanding is that it is the opposite of CDR-SB. In other words, the lower the iADRS score, the greater the cognitive impairment.
OK, if you are not confused, you are way better than I am. These cognitive testing scales are challenging to interpret. The question is, how good is donanemab at preventing cognitive decline?
The company states in its press release:
“Donanemab treatment slowed clinical decline by 35% compared to placebo, and resulted in 40% less decline on the ability to perform activities of daily living.”
Unfortunately, those numbers represent relative risk. I really want to see the raw data before I jump to any conclusions. When the research is published in a peer reviewed journal such as JAMA or the New England Journal of Medicine I will be in a better position to interpret the relative risk reduction vs. the absolute risk reduction. Percentages can be very misleading, as you probably noticed above in the lecanemab discussion.
The closest I could come to actual numbers was from an earlier study published in the New England Journal of Medicine (May 6, 2021). In that study, the researchers found that all the volunteers had lower scores at the end of the study. But those taking the placebo had average scores on the iADRS that were 3.2 points lower than those on the drug. Remember, this scale has 144 points and people in the study started with an average score of 106.
The authors described the results as modest and admitted they did not achieve their goal.
The New York Times Tries to Explain Donanemab:
Gina Kolata is a highly regarded medical reporter for the New York Times. We have interviewed her on The People’s Pharmacy syndicated radio show.
Her article on the new Lilly drug describes the benefits this way:
“The company reported that two to three out of 10 patients taking donanemab progressed over the next 18 months as compared to the expected three to four patients who did while taking a placebo.
“With the new drug, 47 percent of patients stayed stable over the subsequent year compared with 29 percent who took the placebo.”
Is that a “breakthrough”? We will have to see more data to better understand the meaning of this clinical trial. Will the drug restore memory? Could people go back to work or stay engaged in favorite activities? Most importantly, will this anti-amyloid drug keep people out of nursing homes? Those are the things that matter to families. Is this a “modest clinical benefit” or a real breakthrough?
The Downside of Donanemab:
There is a problem with most anti-amyloid drugs. They can lead to brain swelling or bleeding in the brain. Neither are a good thing! In the case of donanemab, this affected nearly one fourth of patients. That is double the rate seen with lecanemab. Three people died in the Lilly clinical trial.
Another problem is brain shrinkage. You can read about this worrisome outcome at this link. It occurs with virtually all the anti-amyloid antibody drugs. Pharmaceutical companies do not know what to make of this unexpected complication. It is not great news.