Donanemab Clinical Use Growing in U.S., Rejected in Europe

Like lecanemab before it, donanemab’s path to market has been slow and rocky. In the U.S., the antibody received Food and Drug Administration approval about nine months ago, but only a few hundred people are on it yet. In Europe, the Committee for Medicinal Products for Human Use on Thursday recommended against approving donanemab for clinical use.

  • European regulators turned down donanemab’s marketing application.
  • In the U.S., several hundred people are now taking donanemab.
  • New Appropriate Use Recommendations offer safety guidelines.

CHMP decided donanemab’s benefits do not outweigh its risks, given the high rates of ARIA—inflammation or brain bleeding related to the therapy. A quarter of people taking donanemab in the Phase 3 Trailblazer-Alz2 trial developed this side effect, twice the rate seen with lecanemab. More recent data from donanemab sponsor Eli Lilly suggest that modifying the titration schedule could cut this ARIA rate nearly in half, but those findings have not yet been validated. Also, in February, Lilly withdrew an application that asked CHMP to approve its amyloid tracer florbetapir for monitoring a person’s response to amyloid immunotherapy. The committee said additional studies are needed to show how well this tracking works.

Meanwhile, in the U.S., clinics are beginning to put procedures in place to incorporate donanemab into their practice. To aid in that process, scientists led by Gil Rabinovici at the University of California, San Francisco, published Appropriate Use Recommendations, including the adjusted titration schedule, in the March 27 Journal of Prevention of Alzheimer’s Disease (image below). The usage guidelines are more detailed than the FDA label, and they suggest greater caution in determining which patients to treat. Rabinovici previously offered an overview of these AUR at the 2024 Clinical Trials on Alzheimer’s Disease conference (Nov 2024 news).

Most Alzheimer’s researchers whom Alzforum contacted said they will use the AUR to help guide discussions with patients and make treatment decisions. However, many noted that prescribing physicians will also use their own judgment to determine whether a particular patient before them is a good candidate for the therapy. “There is some wiggle room,” Russell Swerdlow at Kansas University Medical Center, Kansas City, wrote to Alzforum.

Slow and Steady. The donanemab AUR describes a modified, stepwise titration scheme and an MRI schedule for safety monitoring. [Courtesy of Rabinovici et al., The Journal of Prevention of Alzheimer’s Disease, 2025.]

Safety First
For the first anti-amyloid antibody to receive traditional FDA approval, lecanemab, clinical use has crept up over the year and a half since (Jul 2023 community news; Jan 2024 news; May 2024 news). Its sponsors, Eisai and Biogen, reported that 13,500 people in the U.S. were taking it as of the end of January (Endpoints story). Donanemab, approved a year after lecanemab, has yet to catch up (Jul 2024 community news).

The new donanemab AURs are quite similar to those for lecanemab, which were issued two years ago (Apr 2023 conference news). For example, both suggest not prescribing the antibodies to people taking anticoagulants, which can amplify the risk of brain bleeds. Both also recommend against treating people with autoimmune disorders or other immunologic conditions, because they can be more susceptible to brain inflammation and edema.

Other recommendations reflect recent lessons. Trailblazer-Alz2 allowed people who had one area of superficial siderosis in the brain to enroll. These iron deposits indicate past bleeds. However, newer data link any amount of superficial siderosis to a higher risk of edema and death during immunotherapy, and the AURs recommend against treating people with any evidence of this pathology (Jan 2024 news; Jun 2024 community news).

Also excluded are people who carry ADAD mutations associated with high amounts of cerebral amyloid angiopathy, as well as people with Down’s syndrome, who tend to develop extensive CAA. CAA is associated with worse outcomes from immunotherapy (Aug 2023 conference news; Nov 2023 conference news).

Of 11 Alzheimer’s centers Alzforum contacted, all said they would look closely at the AURs, and eight said they would likely use them as a guide. However, several centers emphasized that clinical judgment would be the final arbiter for who to treat. “We make decisions with patients and families on a case-by-case basis,” Joy Snider at Washington University in St. Louis wrote to Alzforum. She noted that clinicians there would consider treating someone with one area of superficial siderosis if they were otherwise good candidates for donanemab and had no other risk factors. They might also treat someone on anticoagulants, if the patient and family indicated they wanted to proceed after a discussion of the potential increased risk.

Apart from the AURs, Lilly recently reported that modifying the titration protocol to bring the donanemab dosage up in a stepwise fashion drops the risk of ARIA nearly in half (Nov 2024 conference news). Every center Alzforum contacted said it plans to use this new protocol. Some, such as the University of Texas Southwestern, Dallas, already do. Brendan Kelley at UT Southwestern noted one surprising wrinkle: Because the new protocol has not yet gotten the official nod from the FDA, some insurers are denying coverage for the drug when used this way. He said UT Southwestern is appealing these denials. At the Barrow Neurological Institute in Phoenix, Marwan Sabbagh said clinicians will implement the new protocol as soon as it earns official approval.

Who is Treated. The first 924 people in the U.S. to take amyloid immunotherapy (green) tended to have higher median household income (in thousands of dollars, left) and more education (right) than did Medicare patients in general (tan). [Courtesy of Mattke et al., Alzheimer’s & Dementia, 2025.]

Fewer Doses Appeal to Patients
Some centers have not yet started treating people with donanemab, but expect to soon. Michael Rosenbloom at the University of Washington, Seattle, said the first patients there will start the drug in April. Other centers have around 10 people on it so far, but noted demand is picking up. Zoe Arvanitakis at Rush University, Chicago, said they have a wait list. Snider noted that at WashU, 13 people are on donanemab, and they are adding about 10 per month. At some institutions, donanemab use has already taken off. Chad Hales at Emory University, Atlanta, said there are about 35 people on it there. At the Barrow Neurological Institute, 44 people take it, and at UT Southwestern, 60 do. By contrast, WashU has more than 300 people taking lecanemab.

What factors determine whether patients choose donanemab or lecanemab? All centers said that donanemab’s greater convenience, with monthly instead of twice-per-month infusions, was a selling point. This calculation may change now that lecanemab has been approved for monthly maintenance dosing, and especially if lecanemab gains approval for subcutaneous injections, which can be taken at home (Jan 2025 news). Many patients also liked the idea of stopping donanemab treatment after 12 to 18 months, as opposed to lecanemab’s ongoing treatment course. However, Snider noted that some patients consider stopping a downside, because they worry their disease will continue to progress once treatment stops. 

On the other hand, the reported lower rates of ARIA-E with lecanemab push other patients toward it. This is particularly important for APOE4 carriers, especially homozygotes, who have the highest risk of edema. In some countries, regulatory agencies do not allow E4 homozygotes to take amyloid immunotherapy, but in the U.S., this call is left up to physicians. Swerdlow said clinicians tend to steer APOE4 carriers toward lecanemab. Snider agreed, but noted this may change if the modified titration protocol for donanemab is approved, since data suggest this may bring down the risk for APOE4 carriers to nearly the level in noncarriers.

Other factors can also weigh into the decision. James Noble at Columbia University, New York, noted that drug availability can be an issue in some areas of the country. Vijay Ramanan at the Mayo Clinic in Rochester, Minnesota, said insurance coverage and out-of-pocket costs influence patients as well.

In the March 2025 Alzheimer’s and Dementia, scientists led by Soeren Mattke at the University of Southern California Brain Health Observatory, Los Angeles, reported that the first 924 patients in the U.S. to receive amyloid immunotherapy were more likely to be white, wealthy, and highly educated than are Medicare patients in general (image above). “Those initial results point to the need to improve equitable access to treatment,” Mattke and colleagues noted.—Madolyn Bowman Rogers

Comments

  1. Our center began offering donanemab earlier this year.

    Patient discussions around decisions of prescribing lecanemab versus donanemab principally reflect the data and findings which were already known, as published in the randomized, controlled, clinical trial (RCT), and, when available, in the open-label extension studies. The Appropriate Use Recommendations for lecanemab provide helpful context and are generally similar to the RCT. I anticipate continuing to use the primary study data along with the AUR for donanemab (or others in the future) in a similar manner.

    In considering a path toward increasing access and availability for the broader field of neurologists, I would think that an AUR of sorts for lecanemab versus donanemab would be most helpful, but I’m not aware such a document exists.…More

    To date, factors leading to decisions on which drug to use include clinical experience, drug availability, ARIA risk—including that relative to APOE genotype—and logistics, including timing/schedule. These all weigh into patient-centered, risk-benefit discussions.

    The recent FDA decision around post-18-month lecanemab dose adjustments from twice to once monthly has been a recent factor in my patient discussions, primarily around logistics. Should any of the medications become available in other forms, I anticipate that will factor into elements of logistics informing choice. A missing piece remains long-term outcome data. While some models have been published, once better long-term outcome data are available, I anticipate that information will help better frame treatment decisions.

    View all comments by James Noble
    • User Profile Image Bart De Strooper
      UK Dementia Research Institute@UCL and VIB@KuLeuven
    • Posted:

    A similar situation occurred with lecanemab, which was rejected by the EMA on the grounds that its benefits did not sufficiently outweigh the risks of potentially fatal ARIA events. In the case of donanemab, the decision appears to have been influenced by data suggesting that the risk of ARIA-related bleeding may also be elevated in individuals who do not carry the ApoE4 allele, making targeted exclusion of high-risk patients more difficult.

    At present, it remains unclear whether there is a clinically meaningful difference in the safety profiles of lecanemab and donanemab, and this distinction requires urgent clarification. It is concerning that the EMA continues to apply such restrictive criteria to the approval of innovative therapies for Alzheimer’s disease.…More

    View all comments by Bart De Strooper

Make a Comment

To make a comment you must login or register.

References

Therapeutics Citations

  1. Kisunla
  2. Leqembi

News Citations

  1. Donanemab: Small Tweak in Titration, Big Gain in Safety?
  2. FDA Grants Traditional Approval to Leqembi
  3. Rising Leqembi Prescriptions Are Straining Clinic Capacity
  4. Gaining a Foothold: Amyloid Immunotherapy in Clinical Practice
  5. Donanemab Approved in the U.S.
  6. Next Goals for Immunotherapy: Make It Safer, Less of a Hassle
  7. Brain of Woman Who Died on Leqembi Shows Worst-Case Scenario
  8. Is ARIA an Inflammatory Reaction to Vascular Amyloid?
  9. Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA
  10. Leqembi Maintenance Dosing Approved in the U.S.

Mutations Citations

  1. Trisomy 21

External Citations

  1. recommended against
  2. withdrew
  3. Endpoints story
  4. Jun 2024 community news

Further Reading

Primary Papers

  1. Rabinovici GD, Selkoe DJ, Schindler SE, Aisen P, Apostolova LG, Atri A, Greenberg SM, Hendrix SB, Petersen RC, Weiner M, Salloway S, Cummings J. Donanemab: Appropriate use recommendations. Alzheimer's and Dementia, 2025 Alzheimers & Dementia
  2. Mattke S, Yue S, Becker A, Liu Y. Demographic and clinical characteristics of initial patients receiving amyloid-targeting treatments in the United States after regulatory approval. Alzheimers Dement. 2025 Mar;21(3):e70054. PubMed.

Annotate

To make an annotation you must Login or Register.

AlzAntibodiesAlzBiomarkerAlzRiskBrain BanksGeneticsAlzGeneHEXMutationsProtocolsResearch ModelsTherapeutics