Why the EMA Rejected Donanemab for Early Alzheimer’s Disease

Alzheimer's Drug Donanemab Gets Rejected by European Regulator: A Closer Look at the EMA's Decision

In a significant development for Alzheimer's disease (AD) treatment, the European Medicines Agency (EMA) has recommended the refusal of marketing authorization for donanemab, a monoclonal antibody intended to slow the progression of early Alzheimer’s disease. The EMA's Committee for Medicinal Products for Human Use (CHMP) concluded that the drug's benefits did not sufficiently outweigh the associated risks, particularly the risk of potentially fatal adverse events. This decision, though disappointing for the Alzheimer's community, sheds light on the challenges of developing effective therapies for this devastating condition.

What is Donanemab and How Does it Work?

Donanemab is a monoclonal antibody that targets amyloid beta plaques, which are a hallmark of Alzheimer's disease. These plaques accumulate in the brain, contributing to neuronal damage and cognitive decline. Donanemab works by binding to amyloid beta and facilitating its clearance from the brain, theoretically reducing the plaques and slowing disease progression.

The drug was designed for use in early symptomatic Alzheimer's disease, particularly in patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's. It is administered via monthly intravenous infusions and is intended to slow the progression of cognitive and functional decline in these patients. However, like many treatments in the Alzheimer’s space, donanemab has not been without its safety concerns.

Safety Concerns: The Risk of Amyloid-Related Imaging Abnormalities (ARIA)

The primary safety concern with donanemab, as highlighted by the EMA, revolves around amyloid-related imaging abnormalities (ARIA). ARIA refers to brain swelling and microbleeds that can occur as a result of the drug's action on amyloid plaques. While ARIA is often asymptomatic and temporary, it can lead to severe symptoms, including headache, dizziness, nausea, confusion, difficulty walking, vision changes, and even seizures.

In more severe cases, ARIA can lead to permanent neurological damage or be fatal. The EMA's CHMP specifically pointed to these risks when making their decision, noting that the occurrence of ARIA in the donanemab-treated group was significantly higher than in the placebo group. Although the majority of ARIA cases were asymptomatic, the risk of serious ARIA events leading to death could not be ignored.

The TRAILBLAZER-ALZ 2 Trial and Data Review

The TRAILBLAZER-ALZ 2 clinical trial was the primary source of evidence in support of donanemab's efficacy. The trial involved 1,736 patients with early symptomatic Alzheimer's disease, including both prodromal Alzheimer’s disease (mild cognitive impairment) and mild dementia due to Alzheimer’s. The primary endpoint of the study was the change in the integrated Alzheimer’s disease rating scale (iADRS), which measures both cognitive and functional abilities.

At the trial’s 76-week endpoint, results indicated that patients treated with donanemab had a mean worsening of 10 points on the iADRS scale compared to 13 points in the placebo group. While this suggested some benefit, the effect was modest and did not justify the risk of serious side effects. Even more concerning, the occurrence of ARIA was notably higher in the donanemab group, with 36.8% of treated patients experiencing ARIA, compared to just 14.9% in the placebo group. Among these cases, serious ARIA events occurred in 1.6% of the donanemab-treated group, with three deaths.

The Role of ApoE4 in Treatment Response

An important factor influencing the efficacy and safety of donanemab is the presence of the apolipoprotein E4 (ApoE4) gene variant. Individuals with one or two copies of the ApoE4 gene are at a significantly higher risk of developing Alzheimer's disease and also face an increased risk of serious side effects from amyloid-targeting therapies like donanemab.

In the TRAILBLAZER-ALZ 2 trial, ApoE4 carriers exhibited worse outcomes with donanemab treatment compared to non-carriers. However, the company sought to address this issue by proposing that donanemab be used only in patients without ApoE4. Despite this, the EMA determined that even in this more restricted group, the benefits did not justify the safety concerns, particularly given the fatal ARIA events observed in non-ApoE4 carriers.

EMA’s Conclusion and the Unmet Need for AD Treatments

The EMA’s decision to refuse marketing authorization for donanemab was driven primarily by the unacceptable risk of serious and potentially fatal side effects. The agency acknowledged the significant unmet medical need in the treatment of Alzheimer’s disease, as there are currently very few effective therapies that address the underlying mechanisms of the disease. However, the severity and frequency of ARIA in the donanemab-treated group raised significant safety concerns that could not be overlooked.

The decision also comes at a time when other amyloid-targeting therapies are also under scrutiny, as the effectiveness and safety of drugs like lecanemab (approved by the EMA in November 2023) continue to evolve. Although lecanemab has been approved for use in a specific subgroup of patients without ApoE4, donanemab’s broader application failed to meet the EMA’s stringent safety standards.

The Road Ahead for Alzheimer's Disease Treatment

The rejection of donanemab by the EMA underscores the challenges in the field of Alzheimer's treatment, particularly when it comes to balancing the benefits of slowing cognitive decline with the risks of severe adverse effects. Despite the promise shown in trials, Alzheimer’s disease remains an area of significant medical need, and the development of safer, more effective treatments will continue to be a priority for researchers and pharmaceutical companies.

In the meantime, the global medical community remains focused on identifying therapies that can provide real and lasting benefits for patients with Alzheimer’s, without compromising safety. The rejection of donanemab does not diminish the importance of continuing to explore innovative treatments for this devastating disease, but it serves as a reminder of the critical importance of safety in clinical development.