On July 2, the U.S. Food and Drug Administration (FDA) approved a new drug for treating Alzheimer’s disease. Donanemab, or Kisunla, is the third drug approved to target one of the causes of Alzheimer’s: the buildup of amyloid protein in the brain. Based on the data provided by the drug’s manufacturer, Eli Lilly, for the FDA to review, it’s the most effective drug yet in slowing cognitive decline associated with the disease.
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Studies reviewed by the FDA showed that the drug slowed progression to the next more-advanced stage of the disease by 39%, which translates to anywhere from four to seven months longer during which people can be more independent and function without extensive support from caregivers. Over that period, those receiving donanemab showed about 40% less decline in their ability to perform daily tasks such as keeping appointments, making meals, and using household appliances.
By comparison, lecanemab (Leqembi), made by Eisai and approved in Jan. 2023, can slow cognitive decline by 27% compared to a placebo over 18 months. The makers of the other amyloid-targeting drug, aducanumab (Aduhelm), which in 2021 became the first such medication approved, decided to remove it from the market by the end of 2024.
Donanemab’s effectiveness likely comes from its ability to specifically target the toxic plaques of amyloid that accumulate in the brain and strangle nerve cells until they eventually shrivel away. The drug is a monoclonal antibody that seeks out a portion of the amyloid protein that develops over time in the brain. “After it sits in the brain, like cholesterol, it builds up over time and changes,” says John Sims, senior medical director at Lilly. “Donanemab is very purposefully built with the postal codes for amyloid specific to brain plaques. That’s why, as far as we know today, donanemab is probably the most effective plaque-clearing antibody out there.”
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Another feature that sets the drug apart is that it was designed as a finite treatment, similar to the way cancer therapies are used, to aggressively remove amyloid plaques over a certain period of time after which patients can stop taking it. Doctors can then monitor patients for any signs of re-accumulation of amyloid. If those deposits build up again and hit a certain threshold, patients would start getting the drug again.
In studies the company presented to the FDA, after 18 months on the drug, nearly 70% of people no longer showed visible signs of amyloid in their brain scans.
That’s not to say it won’t come back; it likely will. “I think to get from a negative amyloid state to the lowest level of amyloid might take on average four years, but we have ongoing studies to study that,” says Sims. “Right now, we don’t know how best to take care of people whose amyloid comes back—it’s an unanswered question.”
The panel of experts the FDA convened earlier in June agreed that there was not enough data yet to provide specific advice to doctors about if and when to stop donanemab treatment, but the label on the drug does allow doctors to consider stopping donanemab if the drug successfully clears amyloid and the plaques are no longer detectable on patients’ brain scans.
That reflects a potentially new direction for Alzheimer’s treatments that wasn’t possible before drugs like donanemab were able to remove most of the damaging plaques from patients’ brains. Dr. David Hyman, chief medical officer at Lilly, says the company plans to continue studying people who have stopped donanemab after clearing it from their brains to get a better understanding of how quickly the protein starts to re-accumulate, and to determine when patients might need to start getting the drug again. Lilly will also study patients who were not able to clear their amyloid during the 18-month study period and learn more about whether different patients might need different treatment cycles.
Potentially shorter cycles of treatment could also save patients and insurers money. Lilly says a six-month course will cost about $12,500, a year’s treatment $32,000 and 18 months of infusions $48,696. About 17% of the patients in the company’s studies no longer showed visible amyloid in their brain scans after six months, about 47% at 12 months and 69% at 18 months.
Donanemab has another advantage over the existing approved treatment. While patients get infusions of lecanemab twice a month, they only need one infusion a month of donanemab. “For elderly patients who are most likely eligible for this drug, and their caregivers, it’s a significant reduction in burden having an infusion once a month vs. twice a month,” says Dr. Howard Fillit, founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation.
Eventually, treatments like donanemab could and should be used even earlier in the disease, as amyloid starts building up but before patients experience cognitive problems. Among people in Lilly’s study at the earliest stages of Alzheimer’s, the drug was linked to an up to 60% slowing of cognitive decline, and Sims says that models from his scientists estimate that donanemab could lead to as much as 90% slowing of cognitive decline, if it’s started in patients early enough. “The overwhelming lesson from our dataset is that the earlier you identify a patient and give them treatment, the bigger impact you can have,” says Dr. David Hyman, chief medical officer for Eli Lilly. “Where the field is going, and where we are going with donanemab, is evaluating it as a preventive therapy. We are moving to care for healthy people rather than treatment for sick people.”
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Identifying patients who don’t yet have symptoms remains a challenge, however, especially since current methods such as PET scans and spinal fluid tests are expensive and invasive, and not accessible to many older patients. “We have a lot of work to do as a field to close the last-mile care gaps in this patient population,” says Hyman. “My biggest concerns are—can we identify patients early enough in the course of their disease, can we have a physician workforce that is trained in administering these medicines, do we have the infusion capacity to treat patients who can benefit, and can we monitor these patients [with brain scans]?”
Finding better ways to track markers of Alzheimer’s proteins, such as in the blood, could be critical to expanding use of the new treatments. In its studies submitted to the FDA, Lilly relied on a blood test for identifying people as early as possible—sometimes even before they are even aware they might have Alzheimer’s—using another Alzheimer’s related protein called tau. Lilly is collaborating with Roche to make the test more available to doctors who can order it as a way to find patients most likely to benefit from donanemab. Amyloid blood tests could similarly help doctors to monitor patients and inform their decisions about when to stop donanemab and when patients might need to start infusions again when amyloid starts to re-accumulate. These tests are not fully approved by the FDA are currently available on a limited basis to doctors who order them to help make treatment decisions for their patients. While the FDA’s expert committee discussed the utility of tau testing, they decided not to recommend it as a requirement for prescribing the drug, since the test’s limited availability might further restrict patients’ access to donanemab.
In coming years, Alzheimer’s experts also anticipate that simply targeting amyloid won’t be enough. Amyloid-based treatments do come with serious side effects, including bleeding and inflammation in the brain. That’s why anyone taking these drugs, including donanemab, need to get regular MRIs to monitor for signs of trouble. The risk is manageable, however, and doctors can taper down the dose or stop infusions for short periods.
More effective treatments will also become necessary, since not everyone improves on amyloid-targeting drugs. Amyloid, tau, and another protein, alpha synuclein, are all involved in the disease somehow, and targeting each in different ways in different patients will be key to a more comprehensive treatment for the disease. “Anti-amyloid treatments might help some people, but some people might break through and continue to progress,” says Sims. “Hopefully in the future doctors will be able to say, ‘You need an amyloid treatment, or maybe some tau therapy, or even alpha synuclein therapy.’ Ideally, they would tailor treatments to people’s disease.”
These are issues Alzheimer’s doctors have never wrestled with until now, because there haven’t been effective treatments that could remove toxic proteins in significant ways. But with better therapies like donanemab, monitoring patients for changes in the levels of those proteins will become more of a priority.