In a move that surprised many, the Food and Drug Administration has rejected Eli Lilly’s application for accelerated approval for its anti-amyloid antibody donanemab. The agency said there was not enough safety data, given that fewer than 100 people in the Phase 2 trial stayed on drug for one year. “No other deficiencies were identified,” Lilly noted in a January 19 press release. The company said its Phase 3 Trailblazer-Alz2 study remains on track to read out in June. If the results are positive, Eli Lilly will apply for traditional approval.

Unlike some previous FDA decisions, the news stirred up no strong feelings, with many saying the decision will have little impact on donanemab’s development. “I do not think this has any implications for the overall program involving these drugs,” Ron Petersen at the Mayo Clinic in Rochester, Minnesota, told Alzforum. Industry analysts agreed, noting that because the Centers for Medicare and Medicaid Services do not cover amyloid immunotherapy, an accelerated approval would have resulted in little clinical use (Endpoint news).

Some praised the FDA’s measured approach. “I think the FDA made a thoughtful decision,” said Eric Reiman at the Banner Alzheimer’s Institute in Phoenix. 

Lilly’s application for accelerated approval rested on Phase 2 data from Trailblazer-Alz1. In this 18-month study, 131 people started out on donanemab, but dosing was stopped once participants became amyloid-negative. This was defined as below 11 centiloids on one PET scan, or below 25 on two consecutive scans, which were done at six, 12, and 18 months. At six months, 40 percent of the cohort, or 52 people, were switched to placebo, leaving only 79 participants continuing on donanemab to one year (Mar 2021 news).

The 100-person stricture is unlikely to affect an approval based on Phase 3 data. Trailblazer-Alz2 enrolled more than 1,800 participants, according to Dawn Brooks at Eli Lilly. If a similar proportion as in Phase 2 stop treatment at six months, around 540 people would complete at least a year of treatment. “Lilly has collected sufficient 12-month exposures during Lilly’s ongoing Phase 3 Trailblazer-Alz 2 study,” Brooks wrote to Alzforum.

Eric Siemers of Siemers Integration LLC summed up the collective view. “At this point, the field just anxiously awaits the Phase 3 results for donanemab,” he wrote to Alzforum.—Madolyn Bowman Rogers


  1. I think this is just a quirk of the study design insofar as the drug was efficacious in lowering amyloid levels. The design called for stopping treatment when people reached threshold, and, consequently, a number of participants discontinued treatment at six months. This study design resulted in an insufficient number of participants remaining in the study for 12 months to allow the FDA to judge the safety of the drug.

    At least this is my take on the situation. I do not think this has any implications for the overall program involving these drugs. Lilly will be releasing their larger dataset in Q2.

  2. Based on the information provided, I believe that FDA made a thoughtful decision. The completed Phase 2 and ongoing Phase 3 donanemab trials typically stop treatment before 12 months, aiming to dramatically reduce amyloid plaque deposition in most patients before that time. Still, some patients and their providers may opt to continue treatment for longer than 12 months until there is no measurable biomarker evidence of plaques (e.g., using emerging blood tests in the future). FDA’s decision appears to anticipate that possibility, supporting their request for additional safety data in those treated for longer durations.

    I don’t think the decision will have a significant impact on the development, subsequent FDA review, and potential approval of donanemab. The Phase 2 Trial found a clinical benefit and I understand that the ongoing confirmatory Phase 3 trial will have more than 12 months of safety data when it is completed and the findings are announced later this year. Needless to say, the field hopes that the Phase 3 trial will confirm a  clinical benefit, have no additional adverse effects in those who have been treated for more than 12 months and, like lecanemab, receive serious consideration for full FDA approval.  

    It remains to be clarified whether one needs to continue a plaque-reducing treatment indefinitely or instead use it long enough to remove any measurable evidence of amyloid plaques. If one could remove amyloid plaques until there is no measurable evidence of amyloid plaque deposition using a suitable and affordable blood test and then continue to monitor persons annually to consider whether or when to reinstitute treatment, that could impact the affordability, convenience and widespread of plaque-removing antibodies in the treatment and future prevention of AD.

    Dr. Reiman and his Alzheimer’s Prevention Initiative (API) colleagues are collaborating with Lilly in Trailblazer ALZ-3, a prevention trial of donanemab in cognitively unimpaired persons with plasma ptau217 evidence of amyloid plaques.

  3. From a practical standpoint, the lack of accelerated approval should have little effect on the donanemab program. Because CMS does not reimburse for monoclonal antibodies for AD that receive accelerated approval (except through a CED study), significant clinical use would more than likely wait in any case for a full approval, assuming that CMS will reimburse for a drug given full approval. Assuming an FDA submission is made by Lilly for full approval shortly after the TRAILBLAZER-ALZ 2 Phase 3 study completes, the PDUFA requirement is for approval within eight months given a priority review. If the accelerated approval had been granted, the PDUFA date would have been after six months, so not a great difference. At this point, approval will hinge on the Phase 3 study results, which would have effectively been the case even with an accelerated approval. At this point the field just anxiously awaits the Phase 3 results for donanemab.

  4. This decision came as a surprise to me. However, I was not a fan of accelerated approval ever. A regular approval for donanemab was ultimately what was important, if of course the Phase 3 trial showed clinical benefits.

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Therapeutics Citations

  1. Donanemab

News Citations

  1. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit

External Citations

  1. press release
  2. Endpoint news

Further Reading