To investors, last week’s news from Eli Lilly was clear-cut.
One of the company’s most closely watched drugs, an experimental treatment for Alzheimer’s disease, had hit every major goal of a large clinical trial evaluating whether it could slow the neurodegenerative disease. Analysts now expect these results to get the drug, named donanemab, approved, handing Lilly what could be another blockbuster product.
The company subsequently saw its market value surpass $400 billion, putting it within reach of becoming the world’s most valuable drugmaker.
But among Alzheimer’s doctors and experts, any kind of consensus around these results has yet to be reached.
Some see them as an inflection point in the fight against Alzheimer’s — proof that a long-held and, at times, controversial theory about how the disease develops is indeed correct. “This is a watershed moment in the field,” said Barry Greenberg, an associate professor of neurology at the Johns Hopkins University School of Medicine.
Others aren’t so convinced. Instead, they view Lilly’s data as further evidence drugs that work like donanemab have limited benefits.
These therapies, which include Biogen and Eisai’s marketed medicines Aduhelm and Leqembi, are the product of that prominent Alzheimer’s theory. They are designed to break up sticky collections of “amyloid beta,” a misfolded protein tied to the disease. Yet, despite decades of work and billions of research dollars, almost all amyloid-targeting treatments have failed in key clinical studies, a track record that has raised doubts about the “amyloid hypothesis” and questions over whether money would be better spent investigating different approaches.
“This is a small benefit,” Constantine Lyketsos, director of the Memory and Alzheimer's Treatment Center at Johns Hopkins, said of the donanemab results. “And if you look at the big picture of all the anti-amyloid drugs, we’re still unbalanced. Most of them bring no clear benefit.”
Drawing firm conclusions about donanemab is currently difficult for doctors because Lilly has only released high-level data from its trial, which enrolled nearly 1,750 participants who had Alzheimer’s symptoms but were still early in the course of the disease.
According to Lilly, the study found almost half of the patients given its drug had no clinical progression after one year of treatment, compared to 29% of those who received placebos.
And on the study’s main goal, which evaluated cognition and how well patients perform daily activities, donanemab was victorious. After a year and a half, the drug-treated group had declined 35% slower than its placebo comparator.
As with other amyloid-targeting therapies, there are safety concerns. Around one in four patients on donanemab developed a form of brain swelling known as ARIA-E. Roughly one in three experienced ARIA-H, or small-scale bleeding in the brain. These figures are about twice as high as what was seen in a large late-stage study of Leqembi.
Two participants in Lilly’s trial also died because of these side effects, while a third died following a serious case of ARIA. Lilly said a majority of the ARIA cases were “mild to moderate and resolved or stabilized with appropriate management.” Just 1.6% of the cases were classified as serious.
The possible side effects are “absolutely a concern, there's no doubt about it,” said Robert Vassar, director of the Mesulam Center for Cognitive Neurology and Alzheimer's Disease at Northwestern University’s Feinberg School of Medicine.
“But,” Vassar added, “if I was faced with someone telling me I have early Alzheimer's disease, and [there is] a drug that could slow down progression, but it has a small but significant risk associated with it, I would still take it. That's my own personal opinion.”
There remain many unanswered questions surrounding donanemab and other anti-amyloid medicines. It’s not entirely clear, for example, how early in the course of the disease they should be given, or which patients will respond best to treatment. Notably, Lilly’s trial specifically recruited people who were positive for another protein connected to Alzheimer’s, “tau,” and saw a larger drug effect in those with “intermediate” as opposed to “high” levels.
Additionally, there is not yet agreement on how meaningful these drugs will be for patients and their caregivers. Some believe their effects will be even more pronounced if given to Alzheimer’s patients before they show symptoms. But to Lyketsos, the donanemab study together with the one backing Leqembi — in which cognition declined 27% slower for patients in the drug arm — suggest there may be a ceiling to the effectiveness of anti-amyloid therapy.
“I’m certainly going to be very conservative at first” when prescribing these drugs, Lyketsos said, adding that age, stage of disease and other, potentially confounding health issues like diabetes will factor into his decision. Still, “I suspect there will be patients that I advise against who get it anyway.”
Doctors believe it will be important to set appropriate expectations for patients interested in these kinds of medicines.
“The disease is still going to progress, and they have to understand that,” Greenberg said. “This isn’t a home run. It’s a bunt-single. But it’s getting us on base and it’s making an impact.”
“It's buying people more time,” Vassar said. “It may be in the range of six months to a year of more time where they are more capable, and to a lot of people that means a lot.”
Lilly intends to submit a marketing application for donanemab to the Food and Drug Administration by the end of June, which, if accepted for review, would lead to an approval verdict within the next year.
Also this summer, the FDA will decide whether to grant Leqembi a full approval. If the agency does, it’s expected that insurers will allow far more patients to receive anti-amyloid drugs. In particular, the Center for Medicare and Medicaid Services will cover treatment more broadly, via patient registries rather than only within clinical trials, should Leqembi secure a full approval.
CMS has also said it may reconsider its current policy — considered highly restrictive — as more data on anti-amyloid drugs becomes available.
While doctors await these decisions, as well as the release of full donanemab results, there’s already debate around which of these drugs, if any, has an edge.
Comparing results of clinical trials can be challenging. They’re often designed with different main goals, patient recruitment criteria and data analysis plans. So without a study pitting donanemab directly against Leqembi, it’s like “comparing green apples with red apples,” according to Lyketsos.
To Vassar, it’s a bit too early to say whether he would be more likely to prescribe donanemab or Leqembi. He’d need to see more data. But his initial feeling is that Lilly’s drug has shown “probably slightly better efficacy, but there’s a stronger risk of ARIA, maybe because donanemab more aggressively removes amyloid from the brain.”
Another way the drugs might differ is in dosing. While both of Biogen’s medicines are administered chronically, Lilly set up its trial so that patients stopped receiving donanemab once their amyloid levels dipped below a certain threshold. And that dosing plan, according to doctors, may be advantageous, as many patients would likely prefer a finite number of treatments.
“Why continue the drug if there's no more amyloid left in the brain to clear?” Vassar said, adding that Lilly’s trial design was “'very logical and rational.”
“The concerns I've always had with [Leqembi and Aduhelm] is: when do you stop?,” Lyketsos said. With donanemab, “there is some sense of when you stop.”