Reported Fatalities in the Donanemab Trial
During the Phase 3 TRAILBLAZER-ALZ 2 trial, which evaluated the efficacy and safety of the Alzheimer's drug donanemab, several fatalities were reported across both the donanemab and placebo groups. The most critical data relates to the treatment-related deaths, which were directly linked to a specific, severe side effect of the drug.
Donanemab-Related Deaths
The most widely cited figure comes from the trial's primary findings, which indicated that three participants receiving donanemab died from complications linked to amyloid-related imaging abnormalities (ARIA). ARIA is a known risk for this class of anti-amyloid monoclonal antibodies, which can manifest as brain swelling (ARIA-E) or microhemorrhages (ARIA-H). The three donanemab-related deaths were a direct result of these severe cerebral events.
Overall Mortality Figures
Beyond the specific ARIA-related deaths, regulators and experts have scrutinized the overall mortality figures. Initial data presented to the FDA revealed an imbalance in overall deaths between the two trial arms. Subsequently, an independent investigation was commissioned to gather more complete mortality data, including information on patients who had dropped out of the trial. This follow-up found a total of 19 deaths in the donanemab group versus 15 in the placebo group. However, the reliability and completeness of this additional data have been questioned by some experts, citing significant design flaws in how the trial handled patient dropouts.
The Role of Amyloid-Related Imaging Abnormalities (ARIA)
ARIA is a critical safety concern for donanemab and other anti-amyloid drugs. While often asymptomatic, ARIA events can be serious, and even fatal, as demonstrated in the trials. The risk of developing ARIA increases with certain genetic factors, such as the APOE ε4 allele, and appears to be higher in the early stages of treatment.
Key observations regarding ARIA from the trials:
- A significant portion of donanemab-treated patients developed signs of brain swelling (24%) and bleeding (31%).
- Most ARIA cases were mild-to-moderate, but a small percentage were symptomatic and serious.
- The risk of ARIA was highest in the initial phase of treatment, typically within the first six infusions.
- In response, an extra MRI scan was added early in the protocol, which successfully reduced the incidence of serious and symptomatic ARIA.
Comparing Donanemab's Safety Profile
To contextualize the donanemab trial data, it is helpful to compare it with another prominent anti-amyloid treatment, lecanemab (Leqembi). Both drugs have been associated with ARIA, although with differing rates and outcomes in their respective trials.
| Adverse Event | Donanemab (TRAILBLAZER-ALZ 2) | Lecanemab (Clarity AD) |
|---|---|---|
| Any ARIA (E or H) | ~36.8% | ~38.6% |
| ARIA-E (swelling) | 24% | 12.6% |
| Symptomatic ARIA-E | ~6.1% | Not specified |
| Treatment-related deaths from ARIA | 3 | 0 (in main trial), 3 (in extension) |
| Boxed Warning Status | Yes, for ARIA risks | Yes, for ARIA risks |
FDA Approval and Ongoing Monitoring
Despite the identified safety risks, including the fatalities, the FDA approved donanemab in July 2024, concluding that the benefits outweighed the risks for patients with early-stage Alzheimer's. The approval, however, came with a boxed warning for ARIA, the FDA's strongest warning, to alert both physicians and patients to the potential for serious brain swelling and bleeding. In addition, the FDA has mandated a post-market observational study to continue monitoring real-world safety data, including mortality and ARIA events. This ongoing surveillance is crucial for further understanding the drug's long-term safety profile outside the controlled environment of a clinical trial.
Conclusion
While Donanemab demonstrated clinical efficacy in slowing cognitive decline in patients with early Alzheimer's disease, the trial results highlighted significant safety concerns. The question of how many people died in the donanemab trial requires a nuanced answer: three deaths were directly attributed to the drug's side effect, ARIA, and overall mortality figures warrant continued scrutiny. The FDA's approval reflects a careful balancing of these risks and benefits, but underscores the necessity of continuous, vigilant monitoring for all patients receiving this treatment. For more detailed information on the study, refer to the FDA-approved label and research findings released by Eli Lilly and published in medical journals like JAMA.
