In the pivotal phase 3 Clarity AD trial, lecanemab (Biogen) demonstrated significant impacts on primary and secondary end points, with additional promising results on biomarker analyses and safety.
As part of a keynote speech at the 2022 Clinical Trials on Alzheimer Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California, a group of investigators highlighted the therapeutic potential of lecenemab (Biogen & Eisai), an investigational agent being assessed for patients with early Alzheimer disease (AD).1
Lecanemab, formerly known as BAN2401, is a humanized monoclonal antibody that eliminates toxic amyloid-ß protofibrils. The agent remains under review by the FDA, with a potential PDUFA action date of January 6, 2023. Submitted under the accelerated approval pathway—the same pathway that Biogen’s aducanumab (Aduhelm) was approved under in 2021—the application was supported by data from the phase 2b proof-of-concept trial, known as Study 201 (NCT01767311).2
A panel of various AD experts presented data and context on the phase 3 Clarity AD study (NCT03887455), which will serve as complementary data to verify the clinical benefit of lecanemab post approval. The first data set from this study was released in September 2022, with lecanemab showing a statistically significant 27% reduction in the primary end point of Clinical Dementia Rating-Sum of Boxes (CDR-SB) when compared with placebo over an 18-month treatment period (P = .00005).
"We’re very fortunate that the Clarity AD trial approximated as best as these trials can, a real-world population. With an age range that’s broader than most of these trials, a larger inclusivity of diversity than what we often see, and multiple comorbidities, which are often exclusionary in similar trials,” Sharon Cohen, MD, a presenter on the panel and trial investigator of Clarity AD, said in the Q&A session.1 "Patients had an opportunity to join this trial, but we had the opportunity to learn that they can benefit from this therapy rather than this being a question mark."
The study included 1795 people with early AD randomly assigned 1:1 to treatment of 10 mg/kg biweekly of lecanemab or placebo. An estimated 25% of the total enrollment in the US included Hispanic and African American individuals with early AD, and the overall cohort demographics were generally comparable to the Medicare population.
Lecanemab also met secondary end points in Clarity AD, including change in amyloid PET centiloids (difference in least-squares [LS], –50.12; P <.0001) and Alzheimer’s Disease Assessment Scale-Cognitive 14 (LS difference, –1.442; P = .00005) relative to placebo over the 18-month period. Additionally, it outperformed placebo on ADCOMS (LS difference, –0.00; P = .00002), and Alzheimer’s Disease Cooperative study-Activities of Daily Living (LS difference, 2.016; P <.00001). Specifically, it slowed disease progression on ADCOMS by 24% and disease progression on ADCS MCI-ADL by 37% at the same time point.
Sensitivity analyses, presented by Christopher Van Dyck, MD, director of the Yale Alzheimer’s Disease Research Center, also highlighted lecenemab’s effect. Using mixed model regression modeling, the treatment difference at 18 months was –0.394 on CDR-SB when repeated to evaluate the impact of the COVID-19 pandemic, which was similar to the overall treatment difference of –0.45 between groups. When censoring assessments after the occurrence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), the treatment difference was –0.500, a 30% slowing of disease progression.
As for safety, the incidence of ARIA-E was within expectations. ARIA-E occurred in 12.5% of the lecanemab group and 1.7% in the placebo group. Symptomatic ARIA-E occurred at a rate of 2.8% in the lecanemab group and 0.0% in the placebo group. The rate of ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H) was 17.3% for lecanemab compared with 9.0% for placebo, while symptomatic ARIA-H occurred at a rate of 1.4% in the lecanemab group and 0.2% in the placebo group.
The safety data was presented by Marwan Sabbagh, MD, a behavioral neurologist in the Alzheimer’s and Memory Disorders Program at Barrow Neurological Institute. Overall, there were no significant trends in changes over time for any of the laboratory, ECG, or vital sign parameters. Infusion-related reactions, which occurred in 26.4% of those on lecanemab, were largely mild-to-moderate and occurred on the first dose (75%). Notably, most subjects (65%) only had 1 infusion-related reaction.
ARIA-E events were largely mild-to-moderate radiographically (91%) and asymptomatic (78%). In the 2.8% of subjects with symptomatic ARIA-E, commonly reported symptoms were headache, visual disturbance, and confusion. Most individuals with mild radiographic ARIA-E did not worsen and could continue dosing without drug interruption. Overall, the ARIA-E and ARIA-H were less common in apolipoprotein (APOE) e4 noncarriers vs carriers, with higher frequency in APOE e4 homozygous carriers vs APOE e4 heterozygous carriers.
On biomarker analyses, which were presented by Randall Bateman, MD, neurologist and Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University in St. Louis, and director of the Dominantly Inherited Alzheimer Network, cerebrospinal fluid (CSF) and plasma phosphorylated tau181 (p-tau181) continued to increase in the placebo group while those on lecanemab showed levels that returned to normal at all time points measured. This indicated that lecanemab’s removal of amyloid improves downstream tau phosphorylation at amyloid responsive 181 site. There was no difference in change of CSF neurofilament light (NfL) between the groups; however, with larger sample size, trends began to show significance for those on lecanemab (P = .06) at 18 months. Notably, CSF total tau increased for those on placebo while decreasing for those on active drug.
Cohen, a neurologist and assistant professor at the University of Toronto, also added that “[the data] gives me confidence that there’s a broad swath of people who have common variety Alzheimer disease, not the idealized trial participant, who will benefit. But of course, there will be subgroups at more risk, and will be more important to have risk-benefit discussions with clinicians to inform patients and families about risk."