Posted July 7, 2023

On July 6, 2023, the U.S. Food and Drug Administration (FDA) announced full approval for Leqembi™, the brand name for lecanemab (BAN-2401), for the treatment of Alzheimer’s disease. The availability of a therapy for early stages of the disease is a tremendous milestone for Alzheimer’s patients and caregivers. This breakthrough will spark important research into other therapeutic options.

Leqembi is a monoclonal antibody developed by pharmaceutical companies Eisai and Biogen designed to reduce the amount of amyloid beta in the brain. The current approval is for the treatment of mild cognitive impairment due to Alzheimer’s disease (AD); clinical research that could allow wider use is ongoing. The Amyloid Cascade Hypothesis of AD postulates that preventing or reversing the aggregation and accumulation of amyloid beta in the brain, if done sufficiently early in the disease process, can prevent a series of downstream consequences that include neuroinflammation, neurodegeneration and cognitive decline.

Earlier this year, the FDA granted Leqembi approval through its accelerated approval process, which requires only that a drug show benefit against a surrogate biomarker that is expected to lead to eventual clinical benefit to patients. Approval may be revoked and the drug later removed from the market if a confirmatory clinical trial does not demonstrate such benefit. Leqembi demonstrated highly effective reduction of amyloid in the brains of treated patients in a Phase 2 clinical trial, and thus was awarded accelerated approval.

Eisai and Biogen announced positive results on cognitive function from a Phase 3 clinical trial just a few weeks before accelerated approval was awarded, and immediately applied for regular full approval as well. The Phase 3 clinical trial included 1,800 participants with mild cognitive impairment. The monoclonal antibody treatment was administered as an infusion via IV two times every month. Twenty-five percent of participants were African American or nonwhite, making it one of the most diverse late-stage clinical trials for treating Alzheimer’s disease. The trial met its primary endpoint: Leqembi significantly slowed down cognitive decline compared with untreated/placebo trial participants as measured by the global cognitive and functional rating scale called the CDR-SB. After 18 months of treatment, the rate of cognitive decline of the patients receiving Leqembi was 27% slower than those in the control group. The difference between the treated and untreated participants was greatest at the 18-month mark, when the trial ended, suggesting—but not proving—that the drug’s benefits over placebo might grow with longer treatment.

With this full approval, the FDA added a “black box” warning to Leqembi’s label alerting clinicians to the risk of ARIA side effects. ARIA represents brain swelling or bleeding, and while usually asymptomatic, in rare cases can be serious and life threatening. Black box warnings are the most serious cautions that the FDA issues. The warning states that genetic testing should be performed before starting Leqembi because APOE4 carriers are at higher risk of ARIA; however, it does not require this testing. Monitoring for ARIA is done with MRIs. The use of blood thinners also may be associated with an increased incidence of brain hemorrhage complicated by ARIA, and the label includes cautions about the use of blood thinners while taking the drug.

Leqembi received the recommendation for full approval by a team of experts, convened by the FDA, based on the demonstration of clinical benefit in the Phase 3 trial. When the FDA announced accelerated approval, the Centers for Medicare & Medicaid Services (CMS) released a statement restricting reimbursement for monoclonal anti-amyloid immunotherapy treatment to participants in clinical trials only. However, the Veterans Administration did agree to provide coverage based on the FDA’s accelerated approval. Earlier this summer, CMS announced that if a drug in this class was awarded full regular approval, Medicare would cover its use if the treating physician participated in a data-collection system (“registry”) established by CMS to monitor the risks and benefits of the drug. Thus, with this FDA decision, Medicare now will cover Leqembi for enrolled patients who have been diagnosed with mild cognitive impairment or mild Alzheimer’s disease and whose doctor provides information to the registry. Another drug in this class, donanemab from Eli Lilly, also has demonstrated biological and clinical efficacy in a late-stage trial; it will be considered for full FDA approval in 2024.

The list price for one year of treatment with Leqembi is $26,500, with 80% covered by Medicare. The actual treatment cost for Leqembi is much greater once the costs of brain imaging and infusions are added. Eisai is in the process of developing subcutaneous dosing of Leqembi that could reduce the amount of time patients need to spend at their doctor’s office getting the infusions.

According to the drug’s label, treatment with Leqembi is appropriate for patients with mild cognitive impairment or in the mild dementia stage of disease with evidence of amyloid beta plaques, which is the population studied in Leqembi’s clinical trials; this represents about a quarter of Alzheimer’s patients in the United States. For the rest of the patient population—at earlier or more advanced stages of Alzheimer’s—Leqembi’s safety and effectiveness have not yet been established in necessary late-stage clinical trials.

This is the first time that a treatment targeting amyloid for Alzheimer’s disease has received full approval from the FDA. Another monoclonal antibody, Biogen’s Aduhelm™, was approved through the accelerated approval program in 2021 after a controversial series of decisions. The FDA agreed that Aduhelm was effective at clearing amyloid plaques, although the Phase 3 clinical trial data showed conflicting effects on cognitive decline. Aduhelm still needs to demonstrate clear clinical benefit before full approval is possible. Given the accelerated approval process, CMS had declined to cover Aduhelm for Medicare patients outside of clinical trials, setting a precedent that any future amyloid antibodies also would need full FDA approval before Medicare recipients could expect coverage. The full approval of Leqembi marks a watershed moment for the Alzheimer’s field: the first disease-modifying treatment to achieve clinical benefit offers real hope for patients. As is common for the first drug for treatment of any disease, Leqembi is a starting point and not an end point. Cure Alzheimer’s Fund celebrates this milestone achievement and the many, many scientists and clinical trial participants whose dedication led to this moment.