Lecanemab reduces brain amyloid-β and delays cognitive worsening

Abstract

Lecanemab cleared amyloid-β in two-thirds and reduced the rate of cognitive and functional worsening in people with mild cognitive impairment and mild dementia due to Alzheimer disease in an 18-month double-blinded randomized placebo-controlled trial reported by van Dyck et al.

Lecanemab cleared amyloid-β in two-thirds and reduced the rate of cognitive and functional worsening in people with mild cognitive impairment and mild dementia due to Alzheimer disease in an 18-month double-blinded randomized placebo-controlled trial reported by van Dyck et al.

Main text

Investigators from Eisai reported a successful phase 3 trial of lecanemab, an antiamyloid monoclonal antibody that targets soluble amyloid-β protofibrils, in individuals with early symptomatic Alzheimer disease (AD).¹ Individuals with mild cognitive impairment or mild dementia due to AD (as diagnosed by clinical severity and elevated brain amyloid-β by CSF or PET) received lecanemab 10 mg/kg intravenously every 2 weeks or placebo in a multinational, randomized, parallel group trial with 1:1 assignment. After 18 months of treatment, the lecanemab-treated group experienced a statistically significant 27% reduction in decline on the primary outcome measure, the Clinical Dementia Rating Scale (CDR) sum of boxes. All secondary cognitive and functional outcome measures also showed statistically significant findings favoring lecanemab. Subgroup analyses generally favored lecanemab with the unexpected exception of people who were APOE e4 homozygotes. In a post hoc survival analysis, by 18 months, about 24% of the lecanemab-treated group had declined one “global” rating on the CDR compared with about 32% of the placebo-treated group.

Lecanemab was associated with amyloid-related imaging abnormalities (ARIAs) that included both the edema and microhemorrhage types in 21.5% of treated individuals.¹ About 9% of placebo-treated individuals also experienced new cases of ARIAs—mainly microhemorrhages. There was no excess mortality during the 18-month double-blind period of the trial, but in the subsequent open-label extension phase, three affected individuals had brain hemorrhage-related deaths that could be attributed to lecanemab treatment combined with anticoagulant therapies.²

Lecanemab was effective in reducing brain amyloid-β. After 18 months, 68% of treated individuals experienced complete clearance of amyloid-β by amyloid PET imaging.¹ Plasma markers of phospho-tau species that track with brain amyloid-β also showed comparable reductions. Furthermore, tau PET studies in a subset of participants showed less tau accumulation in the temporal lobe, though not elsewhere. A decrease in whole-brain volume was the only imaging biomarker that went in a counter-beneficial direction.

The modest reduction in rate of clinical decline may not be evident to most affected individuals. At the group level (no individual-level data have been presented), the treatment resulted in no improvement, nor was decline arrested. Longer-term observations are needed from the ongoing open-label extension trial. There is limited and complicated evidence about the benefits of lecanemab beyond 18 months from an earlier phase 2 trial³ that suggested lecanemab’s slowing of decline may be sustained, though not amplified, even after drug cessation and reinstitution 2 years later.

Lecanemab received an accelerated approval by the FDA on January 6, 2023. Eisai is seeking a regular approval over the next several months. Even with regular approval, the mechanics of coverage by Medicare and private insurers remains uncertain. The Centers for Medicare & Medicaid Services issued a press release on February 22, 2023 (https://www.cms.gov/newsroom/press-releases/cms-statement-response-alzheimers-associations-request-reconsider-final-national-coverage) indicating that a framework of coverage with evidence development (CED) would be applied to lecanemab even if the FDA granted regular approval. As of this writing, the infrastructure for a Medicare-compliant network of prescribers does not exist.

Lecanemab will face challenges in the marketplace. Affected individuals and their families will be engaging in a difficult task of weighing the modest benefits against the safety concerns. Some individuals who might be interested in receiving the drug will not be able to because of disease severity, medical comorbidities, considerable out-of-pocket costs, and the biweekly infusion schedule.

Lecanemab’s success deserves genuine praise. Its ability to delay decline coupled with similar observations from a phase 2 trial of donanemab⁴ (donanemab’s phase 3 trial will not report out until the second quarter of 2023) showed that amyloid-β removal had clinical benefits. The lecanemab trial provided clarification of the necessary features of amyloid-β removal—rapid and complete removal⁵—that led to a beneficial clinical impact when prior agents had failed. However, celebration should be quickly followed by sober reflection on the task ahead because lecanemab’s robust amyloid-β removal did not eliminate clinical worsening.

There are many possible reasons for the modest clinical benefits of amyloid-β removal. It is possible that removal was not as complete as depicted by PET imaging or fluid biomarkers, raising the possibility that lecanemab failed to target all relevant amyloid-β species.⁶ Alternatively, there is compelling evidence that once neurodegeneration appears outside of the medial temporal lobe, tauopathy and neurodegeneration become autonomous from amyloid-β accumulation.^7,8 Therapies aimed at targets downstream of amyloid-β accumulation are likely to be needed to achieve a greater clinical benefit. Alternatively, for monotherapy with amyloid-β removal to be successful, it might need to be initiated in asymptomatic people prior to the acceleration of tauopathy. Large-scale trials of lecanemab,⁹ as well as donanemab, in cognitively unimpaired people are currently recruiting and will test the idea that presymptomatic amyloid-β removal is beneficial. A long-running trial of an anti-amyloid antibody (solanezumab) that was not previously successful in removing brain amyloid-β in symptomatic individuals has been conducted in cognitively unimpaired persons with elevated brain amyloid-β, and its results will be reported in the next few months. Because of the low rate of incident cognitive impairment, secondary prevention trials are necessarily large and take several years.

The co-occurrence of multiple pathological processes in the brains of elderly people with cognitive impairment is another more daunting therapeutic barrier to treating people with symptomatic cognitive impairment. Multi-etiology dementia is the rule, not the exception, in the elderly.¹⁰ Cerebrovascular disease or one or more other neurodegenerative processes may independently contribute to symptomatic cognitive impairment. One of the chilling possibilities for the modest group-wise effects of lecanemab treatment in people with mild cognitive impairment and mild dementia who have elevated amyloid-β is that there are other relevant pathobiologies that are contributing and proceeding unchecked by amyloid-β reduction. A better understanding of malignancy of the several pathologic contributors to later-life cognitive impairment is key for focusing therapies.

Lecanemab treatment avidly removed amyloid-β and produced some clinical benefits. The treatment should be discussed with appropriate affected individuals. Lecanemab may have succeeded because its amyloid-β targets were better than prior efforts, and it was deployed in the right dose. But its limitations show that treatment of late-life cognitive impairment will require more complex approaches. The field is justified in celebrating, but the therapeutic challenge of AD has not gone away.