Aducanumab, Lecanemab for Early AD: The Clinical Trials That Led to FDA Approval

Following the controversial approval of aducanumab in 2021 by the US Food and Drug Administration (FDA),1 the agency approved lecanemab in early 2023 based on results from a phase 2 study that found lecanemab decreased brain plaques in 856 participants with early Alzheimer’s disease (AD ).2,3 Both aducanumab and lecanemab were approved using the accelerated approval pathway, a program in which the FDA may approve therapies for serious medical conditions where there is an unmet medical need.

Lecanemab, a humanized monoclonal antibody that binds to amyloid-beta protofibrils, is the second drug in a new category of medications targeting amyloid-beta and is approved for the treatment of AD. Following the phase 2 trial, lecanemab showed encouraging results across primary and secondary endpoints in the multicenter, double-blind, phase 3 Clarity AD trial ( Identifier: NCT03887455), which have been hailed as more definitive and promising than findings from trials investigating aducanumab.4

Here, we review the results of the Clarity AD trial for lecanemab and the clinical trials that led to the approval of aducanumab, plus, we highlight the differences and concerns that loom regarding the 2 drugs.

Lecanemab: Clarity AD Results

In the phase 3 study published in November 2022 in The New England Journal of Medicine, van Dyck et al investigated the effects of lecanemab (10 mg via every 2 weeks) compared to placebo in patients aged 50-90 years with early AD, with 898 and 897 patients in each group, respectively.4

Compared to baseline scores on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; primary outcome), the lecanemab group showed an adjusted least-squares mean change of 1.21 at 18 months vs 1.66 in the placebo group (difference, -0.45; 95% CI, -0.67 to -0.23; P<.001), indicating a 27% reduction in cognitive decline with lecanemab vs placebo.4

In Clarity AD, LEQEMBI met the primary endpoint and all key secondary endpoints with highly statistically significant results…

A substudy of 698 patients demonstrated greater reductions in amyloid burden on positron emission tomography (PET) in the lecanemab group vs placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Results of other secondary endpoints also favored lecanemab (all P<.001), including changes in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14), the Alzheimer's Disease Composite Score (ADCOMS), and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL).4

Infusion-related reactions occurred in 26.4% of patients in the lecanemab group, and amyloid-related imaging abnormalities with edema or effusions (ARIA-E) were noted in 12.6% of this group, compared to 7.4% and 1.7% in the placebo group , respectively. Deaths were reported in 0.7% of the lecanemab group and 0.8% of the placebo group, although none of the deaths were deemed related to treatment or ARIA at the time the study went to print.4

However, in the same week that the Clarity AD results were published, Science reported that 2 trial participants had died from a brain hemorrhage in what some experts believe were treatment-related deaths.5 In response to a paper describing the second case, in which the hemorrhage occurred after the patient received tissue plasminogen activator (t-PA), the Clarity AD trial investigators wrote: “Although t-PA appears to be the proximate cause of death, this was an unusual case…. However, there have been earlier reports of fatal large catastrophic intracerebral hemorrhages after t-PA treatment in persons with cerebral amyloid angiopathy (CAA) in the absence of any antiamyloid medications.”6

Aducanumab: EMERGE and ENGAGE Results

In the 2 identically designed randomized, double-blind phase 3 trials (EMERGE [NCT02484547] and ENGAGE [NCT02477800]) that led to the accelerated FDA approval of aducanumab, a total of 1812 patients aged 50-85 years with early AD completed the studies. Participants were assigned to 1 of 3 groups receiving either a low dose (3 or 6 mg/kg target dose) or high dose (10 mg/kg target dose) of aducanumab or placebo every 4 weeks over a 76-week period.7

After both trials were halted due to interim futility data predicting a lack of clinical benefit, it was “later determined that the futility analysis yielded inaccurate predictions for the final outcomes,” the authors explained, because 2 of the “assumptions on which the futility analysis was based were violated.” Namely, these assumptions were that the 2 studies would demonstrate a similar treatment effect and that patients enrolled later in the trials would show similar effects as those enrolled early in the study. “As such, data collected per protocol and under double-blind conditions up until futility announcement were subsequently analyzed based on the prespecified analysis plan.”7

According to the results of these analyses, participants in EMERGE in the high-dose aducanumab group met the primary endpoint (change from baseline on the CDR-SB), with a difference of -0.39 compared to placebo (95% CI, -0.69 to -0.09; P =.012; 22% decrease). Participants in the high-dose EMERGE group also demonstrated less decline on secondary endpoints of scores on the MMSE (P = .049), ADAS-Cog13 (P = .010), and ADCS-ADL-MCI (P < .001) compared to placebo.7

In ENGAGE, neither primary nor secondary endpoints were reached in either arm compared to placebo.7

In substudies, 488 patients from EMERGE and 585 patients from ENGAGE were assessed via amyloid PET, and both groups demonstrated dose- and time-dependent reductions in amyloid PET standardized uptake value ratio (SUVR) at 78 weeks. In the high-dose arms compared to placebo, the difference in the adjusted mean change from baseline was -0.278 (95% CI, -0.306 to -0.250; P <.0001) for the EMERGE group and -0.232 (95% CI, -0.256 to -0.208; P<.0001) among participants in ENGAGE.7,6

Changes were similar between the 2 groups for the low-dose arms of each study.7

Of participants in the high-dose arms, 48% of patients from EMERGE and 31% of patients from ENGAGE showed a “PET composite SUVR score of .1.10, a proposed threshold that distinguishes between Aβ-negative and -positive patients,” the authors wrote.7

In 870 patients from EMERGE and 945 patients from ENGAGE, plasma p-tau181 levels increased in the placebo groups and decreased in the treatment arms of both groups, with differences in the adjusted mean change from baseline of .0.667 (95% CI, .0.860 to .0.474; P<.0001) and .0.777 (95% CI, .0.931 to .0.623; P<.0001), respectively, in the high-dose arms compared to placebo.7

In both studies, there was a positive correlation between reductions in plasma p-tau181 levels and reductions in amyloid PET SUVR. In patient-level correlation analyses, findings indicated modest correlations between amyloid PET SUVR and clinical endpoints in EMERGE but not in ENGAGE. Greater reductions in plasma p-tau181 were correlated with less clinical decline in the treatment arms of both studies.7

Participants from the substudy from both studies showed dose-dependent increases in CSF Aβ1–42 levels, and participants in the EMERGE substudy also demonstrated dose-dependent reductions in CSF p-tau and t-tau levels. Structural MRI revealed a significant increase in the change from baseline in lateral ventricle volume in all treatment arms from both studies compared to placebo (P<.0001).7

ARIA-E represented the most common adverse events reported in both EMERGE and ENGAGE, with higher incidence rates observed in the high-dose vs low-dose groups (roughly 35% vs 26% in both studies) and in ApoE ε4 carriers vs noncarriers ( roughly 40% vs 20% of the high-dose arms in both studies).7

No treatment-related deaths were reported in either study.7

Lecanemab: Advantages, Drawbacks, and Next Steps

While the developers of lecanemab pursued initial FDA approval via the same accelerated pathway in which aducanumab was approved, the approval of lecanemab was based on results of the phase 2 trial. On the same day the FDA granted accelerated approval of the drug, the manufacturers announced they have submitted a supplemental Biologics License Application for traditional FDA approval based on the phase 3 confirmatory Clarity AD results. “In Clarity AD, LEQEMBI met the primary endpoint and all key secondary endpoints with highly statistically significant results….” according to the press release by Eisai.8

Additionally, patients who were Hispanic and African American comprised approximately one-fourth of the US sample in the Clarity AD trial, which reflects the composition of the Medicare population, while most participants in the EMERGE and ENGAGE trials were White.9,7 The authors of the latter trials acknowledged that the lack of participant diversity represents a limitation of these studies.7

Finally, there is a significant price difference between the 2 drugs: aducanumab launched with a price of roughly $56,000 per year, which was later cut in half. For lecanemab, the manufacturer recently announced a wholesale launch price of $26,500 per year.10

Physicians have expressed concerns that lecanemab appears to offer only a modest benefit with significant risks and potentially great financial cost.11 In addition, results from the phase 2 trial (BAN2401-G000-201) revealed reductions in brain volume in participants treated with lecanemab, as seen with other antiamyloid drugs.3 This may actually indicate a risk for worsening neurodegeneration associated with these therapies, noted neurologist Madhav Thambisetty, MD, of Johns Hopkins University School of Medicine.12 Experts have called for more data regarding this issue and other yet – to be published findings from Clarity AD.13

Meanwhile, the National Institute on Aging is funding 2 trials testing the effects of lecanemab in both individuals with amyloid pathology but insufficient cognitive decline to meet criteria for a dementia diagnosis and in combination with another drug (E2814) in individuals with genetic susceptibility to early onset AD.14

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