FDA Approves Alzheimer’s Medication Lecanemab

The FDA has issued an accelerated approval for Biogen/Eisai’s second Alzheimer’s disease (AD) medication, lecanemab. Now with the name brand name Leqembi, it is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody approved to treat patients with mild cognitive impairment or mild dementia stage of disease. The approval was based on a surrogate marker, the ability to clear amyloid beta plaque in the brains of patients with Alzheimer’s disease.

"The approval of Leqembi provides new hope to patients with Alzheimer's disease. Patients at an early stage of the disease and their caregivers can now consider a new treatment option with their doctors,” said Christopher A. Viehbacher, president and CEO of Biogen, in a statement. “Our focus now is on the path forward, working alongside Eisai with the goal of making Leqembi available to patients who may benefit from this treatment as soon as possible.”

Leqembi will have a wholesale acquisition cost of $26,500 a year — below the estimated $37,600 annual quantified societal value determined by Eisai executives — but still higher than the cost-effectiveness range of between $8,500 and $20,600 that the Institute for Clinical and Economic Review has suggested in a draft review. ICER analysts remain uncertain about using amyloid removal as a surrogate marker for clinical benefit in Alzheimer’s disease.

Related: ICER: Draft Review Suggests Lecanemab’s Cost-effectiveness Range of $8,500-$20,600

Researchers evaluated Leqembi’s efficacy in a double-blind, placebo-controlled, dose-finding study of 856 patients with Alzheimer’s disease using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque. They found that patients receiving lecanemab, 10 milligram/kilogram every two weeks, had a statistically significant reduction in brain amyloid plaque from baseline to week 79.

But using amyloid clearance as a surrogate marker in Alzheimer’s has been controversial ever since the companies' other Alzheimer’s therapy, Aduhelm (aducanumab), received accelerated approval in June 2021 after an advisory committee voted against it.

“While the approval of Aduhelm generated a significant amount of discussion among external stakeholders, CDER’s work during the review of the aducanumab application led to a leap in our understanding of amyloid as a surrogate marker and a greater understanding of the role that a reduction in amyloid plaque may play in a slowing of the disease,” FDA CDER Director Dr. Patrizia Cavazzoni, said in a press release.

“As a result, today’s approval of Leqembi was also based upon reduction in this surrogate endpoint of amyloid plaque. This class of drugs shows promise in changing the outcome of AD – a disease that deeply impacts the lives of patients and their families,” Cavazzoni added.

Clinical trial results generated some excitement when lecanemab also showed improvement in cognitive decline. Lecanemab resulted in statistically significant results, reducing clinical decline on the global cognitive and functional scale, compared with placebo at 18 months by -0.45, representing a 27% slowing of decline.

But shortly after these results were released, safety questions emerged. In a letter published January 4 in the New England Journal of Medicine, doctors at the Northwestern University Feinberg School of Medicine in Chicago reported on the case of a 65-year-old patient who was participating in a clinical trial of lecanemab. The patient experienced an ischemic stroke and subsequently died.

“The extensive number and variation in sizes of the cerebral hemorrhages in this patient would be unusual as a complication of t-PA solely related to cerebrovascular amyloid. The findings raise the possibility of cerebral hemorrhages and necrotizing vasculopathy associated with t-PA infusion in a patient with cerebrovascular amyloid who had received lecanemab,” the authors wrote.

While Eisai presented clinical trial results at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference held in San Francisco and virtually November 29-December 2 that included information on deaths, this particular case was not included, Eisai said in a statement provided to Formulary Watch.

“The CTAD presentation included an analysis of the safety information, particularly reports of ARIA [Amyloid Related Imaging Abnormalities], known to us at the time. This case was not reported as an ARIA-related death at CTAD because the information provided to Eisai to date does not indicate that ARIA occurred or that it was suspected to be linked to the death,” the pharma maker said. "Eisai has been working diligently to learn more about this case. Unfortunately, as of yet, the investigator has not been provided access to the hospital records.”

Formulary Watch originally reported on the 65-year-old patient death, reported by Science in early December. 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 at the time.

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 told Formulary Watch in December.

“The reports of deaths in the lecanemab treated patients is similar to the placebo group and does not suggest an increase in deaths overall or from any individual cause,” Eisai said.

Regarding the new NEJM report, Eisai told Formulary Watch that “as a general comment on the unfortunate occurrences of participants in clinical trials who pass away, any evaluation of a death or deaths, must consider the age of the population and their other medical conditions as well as the length of the study.”

“The rates of deaths and causes of deaths that we are observing in the lecanemab studies are consistent with the those expected in people this age, as well as what was observed in our long-term ARICEPT experience,” Eisai added. “ARIA and infusion reactions are important side effects that can be seen with lecanemab treatment. Eisai is committed to working with the FDA to ensure that, if approved, the lecanemab product information will provide the necessary information for healthcare providers, patients and their families to determine if lecanemab is the right therapy for that patient, and to understand how to monitor the patient for potential side effects, such as ARIA.”