Eli Lilly released a little bit of clinical trial data on its new Alzheimer’s drug donanemab in a press release. At a glance, it appears to be slightly more effective than previous anti-amyloids, with higher risks. Without the full data, it’s still hard to say.
After almost two decades of stagnation, two new drugs for Alzheimer’s have hit the market in the last three years. The approval of Biogen and Eisai’s Aduhelm and Leqembi leaned into the theory clearing amyloid plaques could slow the disease. Enter Eli Lilly’s experimental Alzheimer’s drug donanemab. Currently wrapping its Phase 3 clinical trials and making its way toward the FDA approval process, it’s the new kid on the block.
Earlier this year, the FDA denied Eli Lilly’s application for accelerated review. Now, the drugmaker has announced in a press release that donanemab has slowed cognitive decline “by 35 and 37 percent” (according to two different types of cognitive tests). They report that seven in 10 people who received donanemab cleared the majority of toxic beta-amyloid brain plaques within 12 months.
What does that really mean for patients? A few notes on donanemab’s efficacy in treating cognitive decline:
- The drug did not stop cognitive decline in the treatment nor placebo group.
- The percentages refer to the fraction-of-a-point differences in cognitive decline between the placebo and control groups. While both groups progressed over the course of 18 months, donanemab did appear to slow down the process of cognitive decline a little bit.
- What is more telling is the absolute changes in the cognitive scores. In this case, those changes are actually quite small — the difference between of 1.2 (taking a placebo)* and 1.9 (taking the actual drug) cognitive test score points on an 18-point scale. In percentages, that difference is a nearly 37-percent one. *Being Patient’s estimate based on the limited data provided
A few notes on donanemab’s safety for Alzheimer’s patients:
- One in four patients taking the actual drug developed brain-swelling (ARIA-E)
- More than three in 10 taking the drug experience bleeding (ARIA-H)
Three out of 868 patients who took donanemab died. Two deaths were linked directly to a drug side effect, ARIA, and the other one occurred after a severe case of ARIA. (There were also three deaths reported during the lecanemab, now Leqembi, trial, but that trial had more participants.)
How is Eli Lilly measuring donanemab’s results?
Alzheimer’s drug trials measure the rate of cognitive decline over the course of 18 months using the Clinical Dementia Rating–Sum of Boxes (CDR-SB) 18-point scale. This is a validated measure of cognitive decline, where larger numbers indicate more impairment. Points are scored based on what patients can and can’t do (such as cooking food or their ability to finish a Sudoku). A loved one or caregiver is also involved in these interviews to make sure these scores are accurate.
According to the preliminary data available as of the press release, in the Phase 3 trial, participants in the placebo group declined by approximately 1.9 points while those receiving donanemab appeared to decline by an estimated 1.2 points, over 18 months. If we’re talking percentages, that’s a 36+ percent improvement. But looking at the actual numbers, this appears to be a difference of just under 0.7 points, which is below the threshold that some clinicians believe to be noticeable to a patient.
Being Patient estimated the donanemab decline based on the data provided. Neurologist Matthew Schrag reached a similar conclusion on Twitter, where he posted his back-of-the-envelope calculations to attempt to determine the impact of the new drug, also sharing the sentiment: “Topline results from EliLillyandCo’s anti-amyloid Alzheimer’s treatment, donanemab. Need to wait for full data release to draw final conclusions. Preliminarily, this is a statistically strong effect, but probably marginal clinical importance. Safety issues may outweigh benefit.”
Being Patient reached out to Eli Lilly for clarification about the data, asking for clarification on this absolute change in the CDR-SB cognitive test scores in the patients who received the drug versus those who received the placebo. The drugmaker declined to provide further information at this time.
How does donanemab compare to the Alzheimer’s treatments that are already out there?
All this said, this is a larger positive difference for patients than in the Leqembi and Aduhelm trials, where data showed the drugs slowed decline by 0.45 points and 0.39 points respectively, compared to the new drug’s 0.7.
Donanemab also outperforms the effectiveness of cholinesterase inhibitors like donepezil (Aricept). It is estimated that people taking the drug compared to a placebo group may slow their cognitive decline by 0.6 points over the course of 12 months.
This data isn’t yet published in a peer-reviewed journal. Eli Lilly is set to present it at the upcoming Alzheimer’s Association International Conference in July and August. Peer review and data sharing means that scientists outside the trial have not been privy to the data, which helps validate the results.
Also of note, looking at anti-amyloids overall and their side effects, which can sometimes prove very serious and even fatal, not all researchers are convinced that the risks outweigh potential benefits.
Is donanemab safe for patients with Alzheimer’s?
In the last few months, some researchers have raised concerns about the safety profile of Leqembi. Anti-amyloid drugs like Aduhelm and Leqembi cause a condition called amyloid-related imaging abnormalities (ARIA) which can cause brain swelling (ARIA-E) and bleeding (ARIA-H). While it may be asymptomatic, the long-term consequences of ARIA are unknown.
In the Aduhelm trials leading up to Aduhelm’s FDA approval for Alzheimer’s treatment in the summer of 2021, ARIA occurred in more than one third of patients receiving the high dose of the drug. One in five people who received Leqembi experienced ARIA. Among these cases — only 3.5 percent were symptomatic.
One in four patients who received donanemab developed ARIA-E while more than three in ten experienced ARIA-H. Around 1.6 percent of cases of ARIA were considered severe. Three deaths occurred during the trial with two attributed to ARIA and another occurring after a severe ARIA.
“Safety is a problem,” Schrag added in his Twitter thread. “Three patients with severe ‘ARIA’ died in this trial, that’s 0.35 percent or around 3,450 deaths if a million patients are treated. And this estimate is almost certainly low. Patients in clinical trials are healthier and more closely monitored than in most clinics.”
At the end of the day, people living with Alzheimer’s need access more treatment options, and every patient and family needs to make an informed decision with their doctor about the cost-benefit analysis of taking an anti-amyloid.
What’s next for donanemab?
The drug is being tested across other Phase 3 clinical trials which are expected to finish by 2027. These results will bolster an application for traditional FDA approval in the meantime. Advocates are also hopeful that despite the adverse effect profile, the CMS will opt to cover the costs of the drug. Currently, the CMS only covers anti-amyloid drugs like Aduhelm and Leqembi for patients in clinical trials.
“These are the strongest phase 3 data for an Alzheimer’s treatment to date. The progress we’ve seen in this class of treatments, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease,” said Maria C. Carrillo, PhD., Alzheimer’s Association chief science officer. “Yet, Medicare stubbornly continues to block access for the people who could benefit.”
Alzheimer’s Drug Discovery Foundation Co-Founder and Chief Science Officer Howard Fillit, MD said today’s press release of of positive topline results marked another milestone in Alzheimer’s treatment.
“The results are encouraging news for the millions of patients and families suffering from Alzheimer’s disease,” Fillit said. “However, we know amyloid and other misfolded proteins are only one aspect of the biology of aging. We will need multiple drugs aimed at all the causes of Alzheimer’s […] that can be used in combination with one another, as well as with new biomarkers, for a precision medicine approach to conquer this disease.”
Meanwhile, Eli Lilly also remains encouraged.
“Donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer’s disease, and allow them to continue to participate in activities that are meaningful to them,” said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience, adding the company believe these results warrant coverage from the Centers for Medicare & Medicaid Services (CMS). “People with early Alzheimer’s disease need and deserve full coverage and access for approved therapies.”
“We note that these results suggest that people in the early pathological stage of disease could be the most responsive to therapeutics targeting amyloid,” said Dr. Mark Mintun, group vice president of neuroscience research and development at Lilly, and president of Avid Radiopharmaceuticals. “We thank the participants in the clinical trial and their loved ones for their time and commitment to finding solutions for this disease.”
Based on these results, Lilly plans to submit the drug for FDA approval by the end of June.
UPDATE, 4 May 2023, 10:15 A.M. ET: This article was updated to include further information about the estimates made by Being Patient editorial team members and expert neurologists in the field, and to include the drugmaker’s response to inquiries for further details.