The U.S. Food and Drug Administration converted Leqembi (lecanemab-irmb), indicated to treat adult patients with Alzheimer’s disease, to traditional approval after determining that a confirmatory trial verified clinical benefit. Leqembi is the first amyloid beta-targeted antibody to convert from accelerated approval to traditional approval for the treatment of Alzheimer’s disease. The drug works by reducing amyloid plaques that form in the brain, a defining pathophysiological characteristic of the disease.
Leqembi was approved in January under the Expedited Approval pathway. This pathway allows the FDA to approve drugs for serious conditions where there is an unmet medical need, based on clinical data demonstrating the drug’s effect on a surrogate endpoint (in the case of Leqembi, plaque reduction of amyloid in the brain) that is reasonably likely to predict clinical benefit for patients. As a post-marketing requirement for accelerated approval, the FDA required the applicant to conduct a clinical trial, often called a confirmatory study, to verify the anticipated clinical benefit of Leqembi. The effectiveness of Leqembi was evaluated using the results of Study 301 (CLARITY AD), a phase 3 randomized controlled clinical trial.
“Today’s action is the first verification that a drug targeting the underlying pathological process of Alzheimer’s disease has demonstrated clinical benefit in this devastating disease,” said Teresa Buracchio, acting director of the Center for Neuroscience Evaluation and Evaluation. FDA Drug Investigation. “This confirmatory study verified that it is a safe and effective treatment for patients with Alzheimer’s disease.”
Alzheimer’s disease is an irreversible, progressive brain disorder that affects more than 6.5 million Americans. The disease slowly destroys memory and thinking skills and, eventually, the ability to perform simple tasks. While the specific causes of Alzheimer’s disease are not fully understood, it is characterized by changes in the brain, including the formation of amyloid beta plaques and neurofibrillary tangles, or tau, that result in the loss of neurons and their connections.
Study 301 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 1,795 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia at the disease stage and confirmed presence of amyloid beta pathology. Patients were randomized 1:1 to receive placebo or Leqembi at a dose of 10 milligrams (mg)/kilograms (kg), once every two weeks.
Leqembi demonstrated a statistically significant and clinically meaningful reduction in decline from baseline to 18 months in the primary endpoint, the Clinical Dementia Rating Scale Sum of Boxes score, compared to placebo. Statistically significant differences between treatment groups were also demonstrated on all secondary endpoints, including the Cognitive Subscale 14 of the Alzheimer’s Disease Rating Scale.
On June 9, the FDA convened the Central and Peripheral Nervous System Drugs Advisory Committee to discuss whether Study 301 provided evidence of clinical benefit of Leqembi for the treatment of Alzheimer’s disease. All committee members voted affirmatively that the study results verified the clinical benefit of Leqembi for its indicated use.
The most common side effects of Leqembi were headache, infusion-related reactions, and amyloid-related imaging abnormalities (ARIAs), a side effect known to occur with the class of antibodies that target amyloid. ARIA most often present as temporary swelling in areas of the brain seen on imaging studies that usually resolve over time and may be accompanied by small spots of bleeding in or on the surface of the brain. Although ARIA is often not associated with any symptoms, symptoms can occur and include headache, confusion, dizziness, vision changes, and nausea. ARIA may also infrequently present with severe, life-threatening brain edema that may be associated with seizures and other severe neurological symptoms. Intracerebral hemorrhages can occur in patients treated with this class of medications and can be fatal.
Leqembi-treated patients who are homozygous for the ApoE ε4 allele have a higher incidence of ARIA, including symptomatic, severe and severe ARIA, compared to heterozygotes and non-carriers. The prescribing information states that ApoE ε4 status testing should be performed before starting treatment with Leqembi to inform the risk of developing ARIA.
The use of anticoagulant medication was associated with a greater number of intracerebral hemorrhages in patients taking Leqembi compared to placebo. The prescribing information recommends caution when considering the use of Leqembi in patients taking anticoagulants or with other risk factors for intracerebral hemorrhage.
Leqembi is contraindicated in patients with severe hypersensitivity to lecanemab-irmb or any of its inactive ingredients. Adverse reactions may include angioedema (swelling) and anaphylaxis (allergic reaction).
Leqembi should be started in patients with mild cognitive impairment or mild stage dementia of Alzheimer’s disease, the population in which the treatment was studied in clinical trials. The label indicates that there are no safety or efficacy data on starting treatment at earlier or later stages of the disease than those studied.
Leqembi approval was granted to Eisai Inc.
