FDA Approves Safer, Slower Donanemab Titration

[25 July 2025 Editor's note: at its July meeting, the EMA's CHMP committee reversed its original negative opinion, and now recommends that the EMA grant a marketing authorization for Kisunla/donanemab to be used in ApoE4 non-carriers and heterozygotes].

Eight months after Eli Lilly reported that a more gradual titration for donanemab nearly halved the risk of ARIA-E, the U.S. Food and Drug Administration has given the modification the green light. The July 15 approval updates the label, legitimizing the change for payers and prescribers. Clinicians at most specialty clinics Alzforum contacted said the decision will make little practical difference, as they were already using the modified protocol. However, they welcomed the FDA’s seal of approval, noting it will smooth the way for insurance reimbursement.

  • Most tertiary neurology centers are already using the modified titration.
  • Clinicians expect the approval to reassure payers.
  • Some centers now favor donanemab for APOE4 homozygotes.

“The label change is a positive step,” Vijay Ramanan at the Mayo Clinic in Rochester, Minnesota, wrote to Alzforum. Andy Liu at Duke University in Durham, North Carolina, said the lower ARIA-E risk has encouraged clinicians there to prescribe donanemab more often. “It’s significantly changed the way our group looks at this medication,” he wrote.

Simple Change, Quick Uptake
The change is simple: Instead of administering 700 mg for each of the first three monthly doses, clinicians scale up stepwise, giving 350, 700, and 1,050 mg at those visits. In effect, they move one vial of antibody from the first to the third visit. As before, patients reach the full dosing of 1,400 mg by the fourth visit.

In Lilly’s Trailblazer-Alz6 trial, 14 percent of the 210 people on this dosing scheme developed ARIA-E in the first six months, compared with 24 percent on standard dosing. The difference was biggest for APOE4 homozygotes, who went from a rate of 57 to 19 percent. When edema did occur, it was less severe and less likely to cause symptoms. Plaque clearance was unchanged (Nov 2024 conference news). Twelve-month data from this trial was similar, showing an overall ARIA-E rate of 16 percent, and 24 percent for APOE4 homozygotes (May 2025 conference news). The trial continues for another six months.

The findings were so persuasive that 12 out of 15 programs Alzforum contacted said they have been using the modified protocol ever since. The only hiccup has been insurance reimbursement, with some payers declining to cover this “off-label” titration. In March, Brendan Kelley at the University of Texas Southwestern, Dallas, noted his clinic was appealing such denials (Mar 2025 news). Ian Grant at Northwestern University, Chicago, said clinicians there continued to use the standard titration because of insurance denials, but will now switch to the modified protocol. Other programs reported few problems. “We got a little pushback from our billing department over concerns it would not be reimbursed, but ended up not having any issues that I am aware of,” Joy Snider at Washington University, St. Louis, told Alzforum.

Meanwhile, the better safety profile has encouraged clinicians to prescribe Kisunla, and patients to take it. “The modified titration schedule does shift treatment preference a small amount toward donanemab,” said Russell Swerdlow at Kansas University Medical Center, Kansas City.

Two other programs noted their patients prefer donanemab. “We are prescribing donanemab much more often than lecanemab due to the need to have infusions less frequently,” Kelley said. Jason Karlawish at the University of Pennsylvania, Philadelphia, has likewise found that patients favor it. “Much of this is the consequence of a side-by-side comparative assessment of the time, effort, and risks expected,” he wrote.

Other programs see a relatively equal mix. “For new patients, the split is pretty even between the two medications, with slightly more opting for lecanemab,” Snider said. Ramanan agreed. “At our site, there remains a mix of lecanemab and donanemab usage, which likely reflects the broad array of patient-specific factors and preferences influencing each case,” he wrote.

One unexpected consequence of the new titration is the changing risk calculation for APOE4 homozygotes, who have the highest ARIA-E rates on amyloid immunotherapy. The 24 percent rate on the new titration is a fourth lower than for lecanemab, where homozygotes had a 32 percent incidence in the Phase 3 Clarity study. “The improved safety for APOE4 homozygotes has opened up the option to prescribe to that population,” Grant told Alzforum. Previously, his clinic did not offer amyloid immunotherapy to homozygotes. Liu said for this reason, many of the donanemab patients at his clinic are APOE4 homozygotes.

Robert Przybelski at the University of Wisconsin, Madison, believes that lecanemab, too, might benefit from a slower titration. “In geriatrics, we ‘start low and go slow’ with any medication,” he wrote. “We titrate lecanemab also on our own protocol, and may have seen fewer reactions as a result.”

Donanemab Use Inches Up
Donanemab use continues to grow at a slow pace since it was approved a year ago, and varies greatly by clinic (Jul 2024 community news). Five programs told Alzforum they currently have 10 or fewer patients on it. At large programs such as WashU and Yale School of Medicine in New Haven, Connecticut, about 10 percent of their 300-400 immunotherapy patients take donanemab. At Emory University in Atlanta, the University of Washington, Seattle, and UT Southwestern, the proportion on donanemab ranges from a fifth to a fourth to a third, respectively. At Stanford University and Northwestern, half the patients take it.

Nationwide, Lilly reported bringing in $21 million for donanemab in the first quarter of 2025, but has not disclosed the number of patients taking it. The drug has faced headwinds elsewhere, with the European Union rejecting it. Lilly is appealing the decision, with some analysts speculating that the better safety profile on the new titration might help tip the scales in the drug’s favor.—Madolyn Bowman Rogers

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Donanemab: Small Tweak in Titration, Big Gain in Safety?
  2. Next Act for Amyloid Immunotherapy: Be Safer, Target Tau, Too
  3. Donanemab Clinical Use Growing in U.S., Rejected in Europe
  4. Donanemab Approved in the U.S.

External Citations

  1. now recommends
  2. July 15 approval 
  3. rejecting 

Further Reading

No Available Further Reading

Annotate

To make an annotation you must Login or Register.