Understanding the Hurdles: Why Was Donanemab Rejected by Regulatory Agencies?

October 8, 2025 •

4 min read

In January 2023, the U.S. Food and Drug Administration (FDA) initially rejected Eli Lilly's application for accelerated approval of its Alzheimer's drug, donanemab, citing a limited number of patients with adequate long-term data. This was not the only regulatory hurdle the treatment would face, as the European Medicines Agency (EMA) also refused authorization later due to an unfavorable risk-benefit assessment.

Quick Summary

Donanemab faced two major regulatory rejections: an initial FDA denial for accelerated approval due to limited long-term trial data, and a later EMA refusal based on safety concerns regarding brain swelling and microhemorrhages (ARIA). The FDA did, however, grant full approval in July 2024 after reviewing more extensive Phase 3 data from the TRAILBLAZER-ALZ 2 study.

Key Points

FDA Initial Rejection (2023): Donanemab was initially rejected for accelerated approval by the U.S. FDA because the Phase 2 trial design meant too few patients had at least 12 months of continuous drug exposure data.
EMA Rejection (2025): The European Medicines Agency (EMA) recommended against approving donanemab due to concerns that the drug's benefits did not outweigh the risks of potentially fatal events like brain swelling and bleeding (ARIA).
Subsequent FDA Approval (2024): Despite the initial setback, the FDA granted full approval for donanemab in July 2024 after reviewing robust data from the Phase 3 TRAILBLAZER-ALZ 2 study.
Safety Concerns (ARIA): A key safety risk is Amyloid-Related Imaging Abnormalities (ARIA), which are more common in donanemab recipients compared to placebo and especially risky for APOE ε4 carriers.
Differing Regulatory Approaches: The donanemab case highlights how different global regulators can reach contrasting conclusions on a drug's risk-benefit profile, with the EMA taking a more cautious stance than the FDA.
Context of Controversy: Investigations following the FDA's approval raised concerns about potential conflicts of interest among advisory panelists and the transparency of the trial data.

The Initial FDA Hurdle: A Request for More Data

In January 2023, Eli Lilly received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) concerning its application for accelerated approval of donanemab. The reason for the initial rejection was specific and related to the study's design, not a fundamental flaw in the drug itself. Lilly's Phase 2 trial, TRAILBLAZER-ALZ, allowed participants to stop treatment once their amyloid plaques were sufficiently cleared, a process that for many occurred within six months. As a result, the number of patients with at least 12 months of continuous drug exposure was insufficient for the FDA's requirements under the accelerated approval pathway. The FDA mandates robust long-term safety data, even when approving a drug based on a surrogate biomarker like amyloid plaque reduction. Donanemab's efficacy in removing amyloid was evident, but the short treatment duration for many participants meant the long-term safety and benefit information requested by the agency was not yet available.

The Turning Point: Full FDA Approval

Following the initial setback, Eli Lilly pressed on with its confirmatory Phase 3 trial, TRAILBLAZER-ALZ 2, which enrolled a much larger and more diverse population. The data from this trial, released later in 2023 and presented in peer-reviewed journals, demonstrated a significant slowing of cognitive and functional decline in patients with early symptomatic Alzheimer's disease. This comprehensive data package, which included long-term safety information, formed the basis for a new application for full FDA approval. In July 2024, the FDA granted this full approval, marking donanemab (brand name Kisunla) as the second Alzheimer's disease treatment to receive traditional approval based on solid Phase 3 data. This approval was seen as a major milestone, demonstrating that the FDA's initial rejection was a temporary hurdle related to data completeness, not an insurmountable barrier to the drug's eventual market entry.

The European Rejection: Risk vs. Benefit

While donanemab navigated a successful path to U.S. market access, it faced a different fate in Europe. In March 2025, the European Medicines Agency's (EMA) expert committee, the Committee for Medicinal Products for Human Use (CHMP), recommended against granting marketing authorization for donanemab. The core of the EMA's decision was that the benefits of the medication were not sufficient to outweigh the risks of potentially fatal events, specifically the known side effect of Amyloid-Related Imaging Abnormalities (ARIA). While the clinical trial data showed a modest slowing of disease progression, the EMA concluded that this benefit was too small to justify the significant safety risks, particularly brain swelling and bleeding associated with ARIA. This contrasted with the FDA's assessment, which found the benefits sufficient to warrant approval in the U.S..

Safety Concerns: A Closer Look at ARIA

ARIA, which presents as swelling (ARIA-E) or bleeding (ARIA-H) in the brain, is a significant safety concern for anti-amyloid antibody treatments like donanemab. While most ARIA cases are asymptomatic, severe and sometimes fatal events can occur. The risk of ARIA is heightened in individuals who carry the apolipoprotein E (ApoE) ε4 gene, a known risk factor for Alzheimer's disease. In the TRAILBLAZER-ALZ 2 trial, ARIA-E occurred in 24% of donanemab recipients, with 6.1% being symptomatic, and serious ARIA events led to three deaths. The EMA's committee, after considering the risks even within the non-ApoE ε4 population, maintained that the risk-benefit profile was unfavorable.

Regulatory Approvals and Rejections: Donanemab vs. Lecanemab

This regulatory divergence between the US and Europe for donanemab echoes the path of other anti-amyloid therapies. Lecanemab (Leqembi) also faced initial regulatory complexities but ultimately secured full FDA approval, though with a different dosing frequency and potentially lower ARIA rates compared to donanemab.


Feature	Donanemab (Kisunla)	Lecanemab (Leqembi)
Manufacturer	Eli Lilly and Company	Eisai and Biogen
Mechanism	Targets a modified form of amyloid beta in established plaques	Targets soluble aggregated amyloid beta species (protofibrils)
FDA Status	Full approval (July 2024)	Full approval (July 2023)
EMA Status	Recommended refusal (March 2025), under re-examination	Recommended for approval (Nov 2024), initially refused
Dosing Frequency	Monthly intravenous infusion	Bi-weekly intravenous infusion
Treatment Discontinuation	Possible after achieving a predefined level of plaque clearance	Typically ongoing, but may switch to monthly maintenance dose
Notable Side Effect	Higher reported rates of ARIA in trials	Lower reported rates of ARIA in trials
Specialist Oversight	Requires MRI monitoring and specialist clinical settings	Requires MRI monitoring and specialist clinical settings

The Broader Context of Regulatory Scrutiny

Beyond the specific data concerns, the donanemab regulatory journey reflects the broader challenges surrounding novel Alzheimer's treatments. Recent investigative journalism, such as a September 2024 article in The BMJ, has raised questions about the transparency and potential conflicts of interest within the FDA's advisory panel process for donanemab. Concerns were also raised regarding potentially incomplete safety records and the significant financial ties between expert advisors and pharmaceutical companies. This scrutiny highlights the intense pressure and high stakes involved in bringing potentially life-changing, yet risky, treatments to market for a devastating disease like Alzheimer's. It also underscores the varied approaches taken by different global regulatory bodies in assessing a drug's overall risk-benefit profile, with the EMA adopting a more cautious stance regarding donanemab's safety relative to its observed efficacy.

Conclusion

The path for donanemab was marked by significant regulatory hurdles. It was initially rejected for accelerated approval by the FDA due to incomplete long-term data, a specific consequence of its innovative trial design where many patients cleared their amyloid plaques quickly. While Eli Lilly successfully addressed this with more comprehensive Phase 3 trial data to secure full FDA approval, the journey didn't end there. The European Medicines Agency delivered a major rejection, deeming the clinical benefits insufficient to outweigh the risks, especially the potential for life-threatening ARIA. The story of donanemab's rejections serves as a powerful case study in modern pharmacology, illustrating the rigorous, and sometimes divergent, standards applied by global regulatory bodies when evaluating novel, disease-modifying therapies for complex and devastating conditions. It underscores the ongoing challenges of balancing innovative trial design, patient safety, and clinical efficacy in the highly scrutinized field of Alzheimer's treatment.

Visit the European Medicines Agency website for further details on drug evaluation procedures.

Frequently Asked Questions

In January 2023, the FDA rejected donanemab for accelerated approval because the clinical trial data lacked sufficient long-term safety information. The trial design allowed patients to stop treatment once their brain amyloid plaques were cleared, resulting in too few patients receiving the drug for the minimum 12 months required by the FDA's accelerated pathway criteria.

Yes. After the initial rejection, Eli Lilly provided comprehensive Phase 3 trial data, leading to full FDA approval for donanemab (Kisunla) in July 2024 for patients with early symptomatic Alzheimer's disease.

The EMA rejected donanemab in March 2025 because it determined that the drug's clinical benefits, which showed a modest slowing of decline, did not outweigh the significant risks, particularly the danger of brain swelling and bleeding (ARIA), which can be fatal.

ARIA, or Amyloid-Related Imaging Abnormalities, are a common side effect of anti-amyloid treatments like donanemab, involving brain swelling (ARIA-E) and microhemorrhages (ARIA-H). While often asymptomatic, severe cases can occur, and the risk is higher for patients with the APOE ε4 gene, requiring careful monitoring via MRI scans.

The FDA's decision, based on the larger Phase 3 trial, concluded that donanemab's benefits outweighed its risks, approving it for the U.S. market. The EMA, however, assessed the same data but concluded the risk-benefit profile was unfavorable, leading to its rejection for the European market.

Yes. Following the FDA approval, an investigation published in The BMJ in September 2024 raised concerns about the transparency of the regulatory process, potential conflicts of interest among FDA advisory panelists, and allegations of underreported adverse events in trials.

Both faced regulatory hurdles, but donanemab was initially delayed by the FDA for incomplete long-term data before securing full approval, whereas lecanemab (Leqembi) received full FDA approval a year earlier. Furthermore, donanemab faced a rejection in Europe (EMA), while lecanemab was recommended for approval.