In early July, the US Food and Drug Administration (FDA) approved a treatment called donanemab for people with early-stage Alzheimer’s disease. It is the second drug shown to slow the condition’s progression, and the third FDA-authorised medication that clears the amyloid proteins that accumulate in the brains of people with Alzheimer’s.
The FDA’s approval of three new drugs – donanemab, lecanemab and aducanumab – in just over three years has led some to declare a leap forward in Alzheimer’s disease treatment. Japan, South Korea, China, Hong Kong and Israel have also approved lecanemab, while the United Arab Emirates has approved aducanumab.
Donanemab and lecanemab are the first drugs to curb the disease’s advancement: previous therapies only tried to counteract symptoms, such as memory loss. But the new treatments have been controversial and concerns linger about their safety. On 26 July, an advisory body to the European Union recommended against approving lecanemab, citing its risks.
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All of these drugs use antibodies engineered to target and remove amyloid proteins from the brain. The plaques these proteins form are believed to be critical in driving the progression of Alzheimer’s, an idea known as the amyloid hypothesis. However, this hasn’t been confirmed as the cause of the condition, which has raised concerns that we are moving ahead with drugs that target amyloids before we know for sure they are the culprit behind the disease.
The race to develop amyloid-clearing drugs began when a showed that removing amyloid plaques reversed cognitive deficits in rodents. Two decades on, however, all the drug candidates had failed in phase III clinical trials (see “Clinical trial phases”, below). This raised serious doubts about them as Alzheimer’s treatments and, consequently, about the amyloid hypothesis.
Aducanumab drug trials
One of those drugs was aducanumab, made by US firm Biogen. In 2015, the company launched two phase III clinical trials with almost 3300 people who had early-stage Alzheimer’s disease and amyloid plaques in their brains. Early results suggested the drug had little to no effect: although one trial showed that cognition declines at a roughly 20 per cent slower rate in those on a high dose of the drug than in those given a placebo, the second trial found no difference.
Biogen , but seven months later, . The company said a new analysis of longer-term outcomes from the second trial indicated that aducanumab did, in fact, slow cognitive decline. In 2020, Biogen submitted the drug for approval.
But many experts were concerned, especially given the drug’s risks. About , known as amyloid-related imaging abnormalities (ARIA), in which fluid leaks from blood vessels in the brain. Most cases of ARIA are asymptomatic and resolve on their own, but some can lead to headache, seizures or even death. Four deaths have been reported related to aducanumab, but Biogen said in a statement that none of the 11 deaths during phase III trials was attributable to the drug. Biogen didn’t respond to a request for comment on aducanumab’s side effects.
In 2020, an advisory panel to the FDA recommended against the drug’s approval. Yet in 2021, the FDA granted this, pointing to its ability to significantly clear amyloid plaques. In a statement, the FDA said the drug “is reasonably likely to predict a clinical benefit to patients”, but trials showed mixed results. The controversial decision prompted a government investigation and sowed further doubts about the amyloid hypothesis and the drugs resting on it. Biogen announced earlier this year it would discontinue aducanumab.
“It was very messy in the end and, unfortunately, it left a lot of uncertainty and lack of enthusiasm [for developing and prescribing aducanumab],” says at Columbia University, New York.
Donanemab and lecanemab bring new hope
Two other amyloid-clearing drugs have since alleviated some of the doubts left in aducanumab’s wake. The first, lecanemab, is made by Japanese pharmaceutical company Eisai. In a 2022 clinical trial of nearly 1800 people with early-stage Alzheimer’s disease and amyloid plaques, those given lecanemab had a 27 per cent slower rate of cognitive decline after 18 months compared with those given a placebo. This translates to a roughly 0.5-point difference on an 18-point cognitive scale.
While that may seem small, surveys show it has meaningful effects. A 2023 study found that declines in quality of life slowed by about 50 per cent in people taking lecanemab compared with those given a placebo. This was the first time a drug had been shown to slow the progression of Alzheimer’s.
The only other drug with similar effects is donanemab from US pharmaceutical company Lilly. In of more than 1700 people with early-stage Alzheimer’s disease, donanemab slowed cognitive decline by almost 30 per cent. Combined, these results have provided the strongest evidence yet for the amyloid hypothesis. But they also make clear there are other processes driving the condition.
“The promise that we’ve been trying to deliver on as a field finally came to be,” says Noble. “These medications provide the best chance of slowing down something that we don’t otherwise have good treatments for.”
Which drug is most effective against Alzheimer’s?
No trial has compared donanemab and lecanemab head-to-head, so it is impossible to say if one is more effective than the other. However, Noble says donanemab may be slightly more potent based on clinical trial results. Yet this could be due to differences in the trials, not the drugs, says at Eisai.
For instance, a larger proportion of participants in the donanemab trial were at a later stage of the disease than those in the lecanemab trial. This means they probably experienced a more rapid rate of decline, making donanemab’s effects more pronounced, says Hersch.
There may also be differences in side effects between medications. In clinical trials, nearly 37 per cent of people taking donanemab developed ARIA compared with 15 per cent of those in the control group. In the lecanemab trial, the same was true for less than 22 per cent of participants taking the drug compared with almost 10Â per cent of the control group.
Most instances of ARIA didn’t cause serious complications. But about 6 per cent of those in the donanemab group had severe brain bleeds, which , according to a spokesperson for Lilly. Nearly 3 per cent of those given lecanemab developed severe brain bleeds. Three participants taking lecanemab also died during the trial, though Eisai says these can’t be attributed to the drug. An Eisai spokesperson says that four deaths during an extended phase of the clinical trial were possibly related to the drug.
Risks and drawbacks of the new Alzheimer’s drugs
“Certainly, there are risks associated with these drugs,” says Noble. Evidence suggests that people with a genetic variant known as APOE4, which is one of the strongest genetic risk factors for Alzheimer’s, are at a higher risk of severe brain bleeds. Noble says clinicians may want to consider genetic testing before starting people on these medications.
Ultimately, both lecanemab and donanemab lead to only modest changes in cognition and share a similar risk-benefit profile. “Some people are uncomfortable with the risks considering the relatively modest benefit,” says Noble. “Others are the first to line up and say, if it can do anything for me, I want to start it now.” But accessing the drugs isn’t simple or cheap. They require time-consuming infusions and regular brain scans, though Eisai has developed an injectable form of lecanemab.
The drugs differ a bit in how they work. Donanemab only clears plaques. Lecanemab does this too, but also targets amyloid proteins that haven’t accumulated yet. So people can stop using donanemab once scans show they no longer have plaques, but those on lecanemab are recommended to continue using it. A year’s supply of lecanemab costs $26,500 while donanemab costs $32,000.
Because it targets unbound amyloid proteins, lecanemab may be beneficial in treating people at an earlier stage of the disease, before plaques start forming. Studies looking into this are currently under way and should conclude in 2027, says Hersch.
“These aren’t perfect drugs. They aren’t a cure,” says Noble. “But they are game changers in that they’ve given us hope in making an impact on the disease in ways that we’d never really had before.”
Clinical trial phases
Pharmaceutical companies must show that a drug is safe and effective in order to seek its authorisation. They do so by testing the drug in several phases of clinical trials.
Phase I trials involve between 20 and 100 people with the condition being treated. Their purpose is to test the safety of a medication and to identify the proper dose.
Phase II trials usually include several hundred people, making them large enough to begin assessing a drug’s efficacy. They also provide additional data on any side effects.
Phase III trials are usually the final step before a drug is submitted for regulatory review. They can include several thousand people and they demonstrate whether a treatment works. Their size also makes it possible to identify rare side effects or long-term risks that may have gone undetected in smaller trials.
