EMA won’t approve promising Alzheimer’s drug

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has rejected the marketing authorisation for Lekembi (lecanemab), a drug used to treat Alzheimer’s disease, due to its side effects.

Lecanemab is a drug from Eisai and Biogen that has so far been considered one of the most promising treatments for mild cognitive impairment in the early stages of Alzheimer’s disease. Specifically, it is an antibody to beta-amyloid (AB), a key protein that accumulates in the brains of people with Alzheimer’s disease.

However, the EAEA expert committee considered that the observed effect of Lekembi in slowing cognitive decline did not outweigh the risk of serious side effects associated with the drug, in particular the frequent occurrence of amyloid-related imaging abnormalities, which include swelling and possible bleeding in the brain of patients.

The EMA began the review process for the drug in January 2023. Results from the Phase III Clarity AD study, published in The New England Journal of Medicine in November 2022, showed that the drug reduced mild cognitive impairment by 27 percent in people with Alzheimer’s disease over 18 months of treatment.

The study involved 1,795 people with early forms of the disease. The treatment group was given a dose of 10 mg/kg lecanemab twice a week, and participants were divided into equal numbers to receive placebo or lecanemab.

Beginning at six months, at all time points, treatment demonstrated statistically significant changes from baseline compared with placebo.

Additionally, the drug also reduced brain amyloid levels measured by positron emission tomography (PET) compared with placebo after 18 months of treatment.

In the US, lecanemab received accelerated approval for the treatment of Alzheimer’s disease on January 6, 2023. On the same day, Eisai applied for approval to the US Food and Drug Administration (FDA) through the traditional route based on the results of a study that took place in July of this year.

Brain shrinkage

On the other hand, a study published in the scientific journal Neurology in 2023, which analyzed 31 clinical trials, warned of changes in brain volume with different types of anti-amyloid drugs for Alzheimer’s disease, including lecanemab. This study also linked the brain shrinkage to a more well-known side effect of the drugs, cerebral edema, which usually has no symptoms.

According to the review of studies, participants in two large studies of lecanemab at the highest dose of the drug approved in the United States reported an average of 28 percent greater brain volume loss after 18 months compared with placebo.

The authors also found that antibodies like lecanemab cause the brain’s ventricles to increase in size, indicating that they are filled with fluid. Specifically, in people who received the approved dose of lecanemab, their size increased by 36 percent more than in those who took a placebo.

“The monoclonal antibodies caused an acceleration of lateral ventricular enlargement by about 40 percent, a classic marker of neurodegeneration. This has only been seen with drugs that cause amyloid-related imaging abnormalities, and we found a striking correlation between the frequency of these abnormalities and the degree of ventricular enlargement,” study leader Scott Ayton told MedPage Today.

When the study results were published in November, Raquel Sánchez-Valle, head of the neurology service at the Hospital Clínic de Barcelona, ​​had already noted that 21.5 percent of patients treated with lecanemab had some changes in magnetic resonance imaging that were found to be related to amyloid-related imaging abnormalities, compared with 9.5 percent in the placebo group.

Brain hemorrhage

Several months earlier, in November 2022, the journal Science also described the death of a volunteer in a drug study due to a massive brain hemorrhage, the second to occur in the lecanemab study.

The woman had suffered a stroke and was given an anticoagulant, which caused bleeding. He also had cerebral amyloid angiopathy (CAA), a disease in which the smooth muscle in the walls of blood vessels in the brain is gradually replaced by amyloid deposits.

Lecanemab targets amyloid, and AAC experts say its use likely weakened the woman’s blood vessels, causing the bleeding. While it can be difficult to diagnose before death, even with brain scans, CAA occurs in about half of Alzheimer’s patients, so “it may be dangerous to prescribe lecanemab without clear warnings about its apparent interaction with anticoagulants,” according to the American Association for the Advancement of Science.

In its approval decision, the FDA included a warning that in “rare” cases the drug could cause “serious and life-threatening” side effects.

In this regard, Paresh Malhotra, head of the department of neurology at Imperial College London and consultant neurologist at Imperial College Healthcare NHS Trust (UK), explained that these side effects “are related to the patients’ genetics and also the fact that they are taking blood-thinning drugs.