Safety Questions Follow Positive Results for Lecanemab in Alzheimer’s

The latest trial results show Biogen and Eisai’s investigational Alzheimer’s disease drug lecanemab slowed cognitive in early disease, but safety questions remain. While two deaths have been reported during clinical trials, the manufacturers do not believe the deaths were caused by the medication.

Michael Irizarry, M.D.

Deaths occurred in 0.7% of patients in the lecanemab and 0.8% of patients in the placebo group, and no deaths were related to lecanemab in the 18-month double-blind study period, Michael Irizarry, M.D., senior vice president of clinical research and deputy chief clinical officer of Alzheimer’s Disease and Brain Health at Eisai, told Formulary Watch.

However, Science reported that a 65-year-old woman with early Alzheimer’s disease in the clinical trial died from a massive brain hemorrhage that some researchers link to the drug. The clinical trial death, which described in an unpublished case report Science obtained, is the second thought to be associated with lecanemab, according to the publication.

“The two cases on lecanemab occurred in the open-label extension study. Both cases had significant comorbidities and risk factors including anticoagulation contributing to macrohemorrhage or death. Therefore, it is Eisai’s assessment that the deaths cannot be attributed to lecanemab,” the pharma maker said in a statement to Formulary Watch.

Lecanemab is an investigational anti-amyloid beta antibody being developed jointly by Eisai and Biogen for the treatment of mild cognitive impairment due to Alzheimer’s disease. It is currently under review by the FDA and a decision is expected by Jan. 6.

Biogen and Eisai released new clinical trial results at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference held in San Francisco and virtually November 29-December 2. In the core study and subsequent open-label extension study, rates of deaths with concurrent cerebral macrohemorrhage were 0.1% in both the placebo group (1/897) and the lecanemab group (2/1,608), Eisai said.

In the phase 2 Clarity AD study, the rate of macrohemorrhage in the subjects on both anticoagulants and lecanemab was 2.4% and 3.6% across the core phase and the open-label extension phases, Irizarry said. “Background rate of macrohemorrhage in AD patients on anticoagulation is not known,but is expected to be higher than in non-AD patients due to cerebral amyloid angiopathy (CAA); therefore, comparative risk is difficult to assess.”

Irizarry also noted that “the well-being of the patients enrolled in our clinical studies is always Eisai’s top priority. Eisai has established a rigorous safety monitoring process to ensure patient safety. This includes an independent data safety monitoring committee of external experts.”

The independent Data Safety Monitoring Board (DSMB) review of all ARIA-related safety data from the clinical study found that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause,” Irizarry noted.

Serious adverse events were experienced by 14% of participants in the lecanemab group and 11.3% of participants in the placebo group. Treatment-emergent adverse events occurred in 88.9% and 81.9% of participants in the lecanemab and placebo groups, respectively, Eisai and Biogen said in a news release. Treatment-emergent adverse events leading to drug withdrawal occurred in 6.9% and 2.9% of participants in the lecanemab and placebo groups, respectively.

The most common adverse events in the lecanemab group were infusion reactions, ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis), ARIA-E (edema/effusion), headache, and fall. Infusion reactions were largely mild-to-moderate and occurred on the first dose.

Despite adverse events, the Clarity AD study showed that lecanemab treatment resulted in “highly statistically significant results,” reducing clinical decline on the global cognitive and functional scale, compared with placebo at 18 months — a 27% slowing of decline, Eisai and Biogen said.

All key secondary endpoints also showed highly statistically significant results compared with placebo. In the amyloid PET sub-study, treatment with lecanemab showed statistically significant reduction in amyloid plaque burden at all timepoints starting at 3 months.

“We believe that the results of Clarity AD are an important step forward in the field of Alzheimer's disease…The insights from the Clarity AD data will deepen our understanding of the disease to pursue further advancement of the treatment of the disease,” Irizarry said.