FDA AdComm Recommends Antiamyloid Therapy Donanemab as New Treatment for Alzheimer Disease


In a pivotal, large-scale, phase 3 trial, donanemab met its primary end point, demonstrating more pronounced effects in patients with early-stage Alzheimer disease who had low/medium tau status.

Martin J. Sadowski, MD, PhD  (Credit: NYU Langone)

Martin J. Sadowski, MD, PhD

(Credit: NYU Langone)

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has voted that the data from the phase 3 TRAILBLAZER-ALZ-2 trial (NCT04437511) assessing donanemab (Eli Lilly), an investigational agent in development for Alzheimer disease (AD), was sufficient enough in demonstrating clinical benefit. In the coming weeks, the agency will give its final decision as to whether the therapy will be approved.1

At the conclusion of the hearing, the committee voted 11-0 (11 Yes; 0 No; 0 Abstain) that the evidence presented showed that donanemab is effective for the treatment of AD in the population enrolled in clinical trials with mild cognitive impairment (MCI) and mild dementia. In determining the vote, the committee members also factored in whether there was efficacy across the entire population, or in just a subset of patients (e.g., those with low, medium, and high tau levels).

"Extremely positive," Martin J. Sadowski, MD, PhD, a professor of neurology, psychiatry, and pharmacology at the NYU Grossman School of Medicine and director of the NYU Alzheimer Drug Trial Program, told NeurologyLive® when asked to share his reaction. "The 11:0 vote of the advisory panel represents a solidifying consensus among neurologists that anti-Aß antibodies are a valid disease-modifying strategy for treating patients with AD."

If approved, donanemab, a humanized IgG monoclonal antibody, would be the third antiamyloid therapy to gain the FDA's greenlight, following the conditional approval of aducanumab (Aduhelm; Biogen) in 2021, and lecanemab (Leqembi; Eisai) in 2023—although aducanumab no longer remains on market after it was removed earlier this year. The proposed indication for donanemab would be for patients with MCI or mild dementia stages of disease, administered as a 700-mg intravenous infusion every 4 weeks, followed by 1400 mg every 4 weeks. In the presentation, Eli Lilly noted that its proposed dosing regimen may be stopped once brain amyloid plaque is cleared.

"Clearance of Aß deposits from the brain by aducanumab renders the ensuing course of the disease indolent, slowing clinical progression of the disease," Sadowski said when questioned on how donanemab would benefit patients with AD.

"Provides more effective clearance of Aß than lecanemab. Complete Aß clearance can be achieved within 6 months and 12 months in 35% and 50% of individuals treated with donanemab, respectively," Sadowski said when asked how this treatment differs from others for AD. "This means lower health care costs and greater convenience for the patients. Dosing also is more convenient every 4 weeks versus every 2 weeks but causes more adverse events."

Toward the end of the meeting, the committee resoundingly agreed that the data supported the effectiveness of donanemab. Members of the committee brought up concerns with the idea of requiring tau imaging and were aligned that this is not feasible currently, considering the sophisticated nature of tau testing and practical concerns that may come with it at this time. During the discussion, panelists noted they felt as though the evidence was strong, noting the effects donanemab may have on delaying staging for patients, especially at earlier stages. Some felt discomfort extending the treatment to no- or low-tau–level groups, considering patients with this status were not included in the major phase 3 study.

Throughout the meeting, questions were raised about the safety of donanemab, including its impact on amyloid-related imaging abnormalities (ARIA), for which was found in nearly one-fourth of patients in the phase 3 trial. Across the study and its open-label extension, there were 5 ARIA-related deaths in patients on donanemab, none of which were apolipoprotein (APOE)e4 homozygotes. ARIA-E risk was consistently driven by APOE e4 genotype, number of baseline microhemorrhages, presence of superficial siderosis at baseline, and +/– baseline amyloid.

Do you agree with the FDA AdComm's assessment of donanemab for treatment of Alzheimer disease?


In donanemab’s defense, the manufacturers noted that symptoms of ARIA can mimic ischemic stroke. They considered offering several recommendations if the drug were to be approved, including having patients carry a medical information card indicating that they are being treated with donanemab. Additionally, they recommended healthcare providers be aware that ARIA can present with focal neurologic symptoms that can mimic stroke, and should considered the potential for ARIA and potential benefits and risks when considering the use of a thrombolytic agent in a donanemab-treated patient with symptoms of stroke.

TRAILBLAZER-ALZ-2 was a large-scale, phase 3, double-blind, placebo-controlled trial that featured 1736 patients with early-stage AD who received either donanemab (n = 860) or placebo (n = 876) every 4 weeks for up to 72 weeks. Spanning across 277 medical sites in 8 countries, the primary outcome of the study was least-square mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. The study comprised of patients with either low/medium tau pathology (68.1%; n = 1182) or high tau pathology (31.8%; n = 552). Of note, it excluded those with no/very low tau.2

In the low/medium tau population, LSM change from baseline in the iADRS score at 76 weeks was –6.02 (95% CI, ­–7.01 to –5.03) in the donanemab group and ­–9.27 (95% CI, –10.23 to ­–8.31) in the placebo group, otherwise a 35.1% (95% CI, 19.90-50.23) slowing of disease progression. The impacts were less pronounced in the overall population, with between-group score differences of 2.92 (95% CI, 1.51-4.33; P <.001), representing a 22.3% (95% CI, 11.38-33.15) slowing of disease progression.

TRAILBLAZER-ALZ-2 was a follow-up to the phase 2 TRAILBLAZER-ALZ study (NCT03367403), which served as the basis for the original biologics license application of donanemab. The FDA responded to Eli Lilly’s application with a complete response letter, noting that the company needed to provide data from at least 100 patients who received a minimum of 12 months of continuous treatment with donanemab.3 At the time, the agency indicated that the data to meet the exposure expectation would likely need to include unblinded safety data from TRAILBLAZER-ALZ-2 upon completion.

TRAILBLAZER-ALZ, which began in 2017, met its primary end point, with donanemab slowing decline on the iADRS by 32% compared with placebo at 18 months. The company claimed improvement on all secondary end points of cognition and function, although not all were statistically significant. In addition, amyloid-related imaging abnormalities (ARIA), a concern for antiamyloid therapies, were found in 27% of treated patients, with 6% becoming symptomatic. The study included more than 100 patients; however, it was designed so that patients would complete the treatment course once they reached a predefined level of amyloid plaque clearance.4

TRAILBLAZER-ALZ-2 originally began as a phase 2 study but was enlarged to a phase 3 registrational study. The primary outcome, change in iADRS, was judged using a disease-progression model, rather than solely on change at the final time point. Within the low/medium tau population, investigators observed between-group differences of –0.67 (95% CI, –0.95 to –0.40; 36.0% slowing of clinical progression) for CDR-SB, 1.83 (95% CI, 0.91-2.75; 39.9% slowing of clinical progression) for ADCS-iADL, and –1.52 (95% CI, –2.25 to –0.79; 32.4% slowing of clinical progression) for ADAS-Cog13, at week 76. In this same cohort, donanemab-treated patients had a 38.6% (HR, 0.614; 95% CI, 0.471-0.800; P <.001) lower risk of progression to the next clinical stage on CDR-Global over the 76-week treatment time frame.

These data, presented at the 2023 Alzheimer’s Association International Conference (AAIC), further highlighted the therapy’s impact on relevant AD progression. At 76 weeks, brain amyloid plaque levels decreased by 88.0 centiloids (95% CI, –90.20 to –85.87) with donanemab treatment and increased by 0.2 centiloids (95% CI, –1.91 to 2.26) in the placebo group in the low/medium tau population. In this group, 80.1% (95% CI, 76.12-83.62) of donanemab-treated patients achieved amyloid clearance by week 76 whereas no patients on placebo achieved the same. In terms of plasma phosphorylated tau (p-tau)217, an exploratory outcome, investigators observed differences of –0.25 (95% CI, –0.28 to –0.22; P <.001) tau standardized uptake value ratio (SUVR) in the low/medium tau population relative to placebo and –0.22 (95% CI, –0.24 to –0.20; P <.001) in the combined population at 76 weeks.5

In TRAILBLAZER-ALZ-2, donanemab demonstrated a safety profile that was similar to phase 2 findings and consistent with class effects observed with amyloid plaque-lowering therapies. In total, 24% of patients experienced ARIA-E, with most ARIA-E events found to be largely mild to moderate radiographically. In terms of timing, ARIA-E first occurred after receiving up to 3 donanemab infusions in most cases (58%). First ARIA-E events radiographically resolved in 98% of participants, with a mean resolution time of around 10 weeks. Of note, 6% of patients on active treatment experienced recurrent ARIA-E.

The therapy was also assessed in TRAILBLAZER-ALZ-4, a randomized trial comparing treatment effects to aducanumab (Aduhelm; Biogen), the first approved antiamyloid therapy that was recently discontinued from market. After 6 months of treatment, 37.9% of donanemab-treated patients (n = 71) achieved amyloid clearance vs 1.6% of those on aducanumab (n = 69; P <.001). In the intermediate tau subpopulation, 38.5% of donanemab-treated patients vs 3.8% of aducanumab-treated patients achieved amyloid clearance (P = .008).6

1. FDA Peripheral and Central Nervous System Drugs Advisory Committee (PCNS). https://www.youtube.com/live/LPdOPydM18E. June 10, 2024. Accessed June 10, 2024.
2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239
3. US Food and Drug Administration Issues Complete Response Letter for Acceleterated APproval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed January 19, 2022. prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html
4. Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N J Med. Published online March 13, 2021. doi: 10.1056/NEJMoa2100708.
5. Mintun M, Solomon P, Sims JR, Salloway S. Donanemab in early symptomatic Alzheiemr’s disease: efficacy and safety in TRAILBLAZER-ALZ 2, a phase 3 randomized clinical trial.
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