The Alzheimer’s community has grown accustomed to false hope, disappointment, and controversy. With around 55 million people worldwide affected by dementia, the need for effective treatment is undeniable. But efforts to develop a drug that could alter the course of Alzheimer’s disease by using antibodies to remove amyloid beta (Aβ) from the brain have suffered numerous setbacks over the past 20 years. Almost a decade ago, the first anti-Aβ antibodies tested in phase 3 trials, bapineuzumab and solanezumab, failed to improve clinical outcomes in mild to moderate Alzheimer’s disease. Hopes were dashed again in 2019, when two phase 3 trials of aducanumab, one of the next-generation anti-Aβ antibodies that specifically target Aβ aggregates, were stopped early due to futility. The resurrection of aducanumab and the controversial 2021 approval by the US Food and Drug Administration (FDA) under its accelerated approval program, which allows early approval of drugs in areas of unmet need based on se in a positive change in a surrogate endpoint, in this case, the reduction of amyloid in the brain, caused furor among the research community.
Against this backdrop, on November 29, results from the long-awaited CLARITY AD study of lecanemab, an antibody targeting larger Aβ oligomers, or protofibrils, were presented at the Alzheimer’s Disease Clinical Trials Conference in San Francisco, USA, and were published simultaneously. Anticipation had been building since the announcement, two months earlier, through a press release, of positive results. In the trial, 1795 people with mild cognitive impairment or early Alzheimer’s disease, plus evidence of amyloid on a PET scan or by CSF testing, were randomly assigned to receive 10 mg of lecanemab by intravenous infusion every 2 weeks, or a matched placebo. After 18 months of treatment, lecanemab reduced cognitive decline, as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), which quantifies symptom severity across a range of cognitive and functional domains, in a 27% compared to placebo, an absolute value. difference of 0.45 points (change from baseline 1.21 for lecanemab vs 1.66 with placebo, p<0.001). All key secondary criteria were met. The incidence of amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-Aβ antibodies and manifested as edema or microbleeds, occurred in 21% of the lecanemab group; most cases were asymptomatic and detected incidentally. However, reports of a second death in the ongoing open-label extension phase of the study, possibly linked to co-administration of the thrombolytic drug alteplase, have raised concerns about the safety of lecanemab in patients taking anticoagulant drugs. An initial decision on the drug's approval is expected from the FDA on January 6, 2023, and from the European Medicines Agency later in 2023.
After such a long and fruitless wait for a successful therapy for Alzheimer’s disease, a phase 3 trial showing efficacy in clinical outcomes is welcome news. However, a difference of 0.45 points on the CDR-SB, an 18-point scale, may not be clinically significant. A 2019 study suggested that the minimum clinically important difference for the CDR-SB was 0.98 for people with mild cognitive impairment and presumed Alzheimer etiology, and 1.63 for those with mild Alzheimer’s disease. In addition, the development of ARIA, seen in one in five patients taking lecanemab, could lead to unmasking and introduce bias.
Given these concerns, it remains to be seen whether lecanemab is the game-changer that some have suggested. Ongoing trials are evaluating the efficacy of subcutaneous administration and whether lecanemab can prevent the onset of dementia in patients with amyloid pathology but without clinical symptoms. However, the immediate impact of lecanemab should not be overstated. A decision on the cost has yet to be made, but it is likely to be prohibitive for low- and middle-income countries, where most people with dementia live. Many health systems lack the infrastructure to enable widespread deployment of lecanemab: the availability of PET imaging to determine treatment eligibility is spotty, memory clinics will need the staff to facilitate biweekly intravenous drug infusions, and the capacity of regular MRI scans to Detect ARIA will need to be scaled up. The results with lecanemab could pave the way for much-needed treatments for Alzheimer’s disease. But for now, the key public health message for Alzheimer’s remains the one set out in the 2020 Lancet Commission on Dementia Prevention, Intervention and Care: Targeting Modifiable Risk Factors for Dementia , such as hypertension, smoking, diabetes and obesity. maintain brain health throughout life.
For more information on early anti-Aβ antibody trials, see N Engl J Med 2014; 370: 322–33 and N Engl J Med 2014; 370: 311–21
For more information on minimal clinically important differences, see Alzheimers Dement 2019; 5: 354–63