Aducanumab, Lecanemab for Early AD: Clinical Trial Leading to FDA Approval

Following the controversial 2021 U.S. Food and Drug Administration (FDA) approval of aducanumab,¹ The FDA approved lecanemab in early 2023 based on results from a Phase 2 trial that found lecanemab reduced cerebral plaques in 856 participants with early Alzheimer’s disease (AD).^2,3 Both aducanumab and lecanemab were approved using the accelerated approval pathway. This is a program that allows the FDA to approve treatments for serious medical conditions that have an unmet medical need.

Lecanemab, a humanized monoclonal antibody that binds to amyloid-beta protofibrils, is the second agent in a new class of drugs that target 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 (ClinicalTrials.gov Identifier: NCT03887455). Aducanumab is under investigation.^Four

Here, we review the results of the Clarity AD trial of lecanemab and the clinical trial that led to the approval of aducanumab, and also highlight the differences and concerns about the two agents.

Lecanemab: Results from Clarity AD

A Phase 3 study announced in November 2022 of New England Journal of Medicinevan Dyck et al investigated the effects of lecanemab (10 mg every 2 weeks) compared with placebo in patients with early AD aged 50–90 years (898 and 897 patients in each group, respectively). .^Four

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

A substudy of 698 patients showed a significant reduction in amyloid burden on positron emission tomography (PET) between the lecanemab and placebo groups (difference, -59.1 centroids, 95% CI, -62.6 to -55.6).Results for other secondary endpoints also favored lecanemab (all P.<.001), Alzheimer's Disease Assessment Scale (ADAS-cog14), Alzheimer's Disease Composite Score (ADCOMS), and mild cognitive impairment, including changes in scores of the 14-item cognitive subscales of the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-MCI-ADL).^Four

Infusion-related reactions occurred in 26.4% of patients in the lecanemab group, with amyloid-related imaging abnormalities (ARIA- E) was accepted. , Respectively. Deaths were reported in 0.7% in the lecanemab group and 0.8% in the placebo group, but no deaths were considered treatment- or ARIA-related at the time the study was printed.^Four

However, the same week the Clarity AD results were announced, chemistry reported that two trial participants died from cerebral hemorrhages, which some experts believed were treatment-related deaths.^Five In a paper describing a second case in which bleeding occurred after a patient was given tissue plasminogen activator (t-PA), researchers from the Clarity AD trial wrote: It was a rare case… However, there was a previous report of fatal and devastating intracerebral hemorrhage after t-PA treatment in patients with cerebral amyloid angiopathy (CAA) who were not on any anti-amyloid drugs. ”⁶

Aducanumab: EMERGE and ENGAGE Results

Two identically designed, randomized, double-blind, phase 3 trials (EMERGE [NCT02484547] engage [NCT02477800]aducanumab), a total of 1812 early AD patients aged 50-85 years completed the trial. Participants received either low-dose (target dose of 3 or 6 mg/kg) or high-dose (target dose of 10 mg/kg) aducanumab or placebo. assigned to one of us.⁷

After both trials were stopped due to preliminary futility data predicting lack of clinical benefit, “it was later determined that the futility analysis resulted in an inaccurate prediction of the final outcome,” the authors said. explained. was based on but was violated. That is, these assumptions were that the two studies would show similar treatment effects, and that patients enrolled later in the trial would show similar effects to those enrolled earlier in the study. “Therefore, data collected under double-blind conditions per protocol until futility was announced were then analyzed based on a prespecified analytical plan.”⁷

The results of these analyzes showed that EMERGE participants in the high-dose aducanumab group achieved their primary endpoint (change from baseline in CDR-SB) with a difference of -0.39 compared to placebo (95% CI, -0.69 to -0.09; P. =.012; 22% reduction). Participants in the high-dose EMERGE group also had less reduction in secondary endpoints of MMSE (P =.049), ADAS-Cog13 (P =.010), and ADCS-ADL-MCI (P <.001) scores was shown. to placebo.⁷

ENGAGE did not reach the primary or secondary endpoints in either group compared to placebo.⁷

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

In the low-dose group of each study, changes were similar between the two groups.⁷

Among high-dose participants, 48% of patients on EMERGE and 31% of patients on ENGAGE had a “PET composite SUVR score of .1.10, the proposed threshold for distinguishing between Aβ-negative and positive patients.” said the authors. I have written.⁷

In 870 patients from EMERGE and 945 from ENGAGE, plasma p-tau¹⁸¹ Levels increased in the placebo group and decreased in both treatment groups, with a difference in 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 group compared with placebo.⁷

In both studies there was a positive correlation between plasma p-tau reduction¹⁸¹ Amyloid PET SUVR levels and reduction. Patient-level correlation analysis showed a modest correlation between amyloid PET SUVR and clinical endpoints for EMERGE, but not for ENGAGE.Significant decrease in plasma p-tau¹⁸¹ It correlated with less clinical decline in the treatment arms of both studies.⁷

Substudy participants of both studies showed a dose-dependent increase in CSF Aβ_1–42 levels, and EMERGE substudy participants also showed a dose-dependent decrease in CSF p-tau and t-tau levels. Structural MRI revealed a significant increase in change from baseline in lateral ventricular volume in all treatment groups in both studies compared to placebo (P. <.0001).⁷

ARIA-E represented the most common adverse events reported in both EMERGE and ENGAGE, with high versus low dose groups (approximately 35% vs. 26% in both studies) and ApoE ε4 carriers vs. Carriers (approximately 40% vs. 20% in the high-dose group in both studies).⁷

Neither study reported any treatment-related deaths.⁷

Lecanemab: Advantages, Disadvantages, and Next Steps

The developers of lecanemab pursued initial FDA approval through the same accelerated pathway through which aducanumab was approved, but lecanemab’s approval was based on results from Phase 2 trials. On the same day that the FDA expedited approval of this drug, the manufacturer said it submitted an additional biologics license application for conventional FDA approval based on Clarity AD’s phase 3 confirmation results. Announced. “In Clarity AD, LEQEMBI met its primary endpoint and all major secondary endpoints with highly statistically significant results…”, according to an Eisai press release.⁸

In addition, Hispanic and African American patients made up about a quarter of the U.S. sample in the Clarity AD trial, which reflects the composition of the Medicare population, but made up most of the EMERGE and ENGAGE trials. participants were Caucasian.^9,7 The authors of the latter trial acknowledged that the lack of participant diversity represented a limitation of these studies.⁷

Finally, there is a large price difference between the two drugs. Aducanumab launched at a price of about $56,000 a year, which was later cut in half. For lecanemab, the manufacturer recently announced a wholesale launch price of $26,500 per year.^Ten

Physicians have expressed concern that lecanemab offers modest benefits and appears to carry significant risks and potentially large financial costs.¹¹ In addition, results from a phase 2 trial (BAN2401-G000-201) revealed a reduction in brain volume in participants treated with lecanemab, similar to other anti-amyloid agents.³ This may actually indicate a risk of worsening neurodegeneration associated with these treatments, says neurologist Madhav Thambisetty, MD, of the Johns Hopkins University School of Medicine.¹² Experts want more data on this issue, as well as other as-yet-unpublished findings from Clarity AD.¹³

Meanwhile, the National Institute on Aging is funding two trials testing the effects of lecanemab in both individuals with amyloid lesions but insufficient cognitive decline to meet diagnostic criteria for dementia. . Onset AD.¹⁴