Baseline Amyloid PET Centiloid Levels Show No Impact on Lecanemab ARIA-E Rates

Marwan Sabbagh, MD

In a new analysis of the phase 3 Clarity AD trial (NCT03887455), the study that led to lecanemab’s (Leqembi; Eisai) approval, findings showed a similar rate of amyloid-related imaging abnormalities due to edema (ARIA-E) when categorizing patients by baseline amyloid PET tertile centiloid levels and clinical subgroup. Apolipoprotein e4 (APOE4) zygosity was shown to have no impact on results across subgroups as well.¹

Presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, the analysis included 1107 patients with mild cognitive impairment (MCI; lecanemab: n = 552; placebo: n = 555) and 688 patients with mild AD (lecanemab: n = 346; placebo: n = 342). Using baseline centiloid tertiles, the event rates were 8.5% and 3.3% for the low tertile (≤68.185), 15.3% and 1.6% in the middle tertile (>68.185-101.245), and 13.4% and 0.9% in the highest tertile (>101.245) for lecanemab and placebo groups, respectively.

Led by Marwan Sabbagh, MD, a behavioral neurologist at Barrow Neurological Institute, there were no trends observed for ARIA due to hemosiderin deposition (ARIA-H). Overall, in the mild AD and MCI groups, ARIA-E rates were 12.7% and 12.4%, respectively, for those on lecanemab, and 1.4% and 2.1% for those on placebo. In addition, the rates of ARIA-H were similar between patients with MCI and mild AD.

READ MORE: Ofatumumab Demonstrates Sustained Efficacy in Recently Diagnosed and Treatment-Naive Relapsing Multiple Sclerosis Over 5 Years

Lecanemab, an approved amyloid-ß-directed antibody that selectively targets protofibrils, was granted traditional approval in July 2023 based on data from Clarity AD. Published in the New England Journal of Medicine, Clarity AD included 1795 patients with evidence of amyloid on PET or cerebrospinal fluid who were followed for an 18-month treatment period. At the conclusion of the analysis, lecanemab met its primary end point of change in Clinical Dementia Rating-Sum of Boxes score, with treated patients demonstrating a statistically significant 27% reduction.²

In Clarity AD, lecanemab also met secondary end points of 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 the Alzheimer's Disease Composite Scale (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.

More recently, in early April, Eisai formally submitted a supplemental biologics license application (sBLA) for a monthly intravenous (IV) maintenance dosing for the agent. In addition, the company noted at the time that its planning to submit a BLA for a weekly maintenance therapy dose of 360 mg using subcutaneous administration; however, will need to gain a fast track designation specific for the SC formulation to proceed with an FDA review.³

At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) Conference, data from the OLE of Clarity AD showed that a novel SC form of lecanemab resulted in greater amyloid plaque removal than biweekly IV administration. After 6 months of treatment, a subgroup of patients demonstrated a 14% increased amyloid plaque removal with the SC method than IV administration, the administration for which it was FDA-approved under.⁴

Click here for more coverage of AAN 2024.

REFERENCES
1. Sabbagh M, Li D, Dhadda S, et al. Impact of clinical subgroup and baseline amyloid PET centiloid levels on occurrence of ARIA in the lecanemab phase 3 Clarity AD study in early Alzheimer disease. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract 005590
2. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9-21. doi:10.1056/NEJMoa2212948
3. Eisai completes submission of Leqembi (lecanemab-irmb) supplemental biologics license application for IV maintenance dosing for the treatment of early Alzheimer disease to the US FDA. News release. Eisai. April 1, 2024. Accessed April 15, 2024. https://investors.biogen.com/news-releases/news-release-details/eisai-completes-submission-leqembir-lecanemab-irmb-supplemental
4. Irizarry M, Li D, Dhadda S, Hersch S, Reyderman L, Kramer L. Preliminary update on lecanemab safety in Clarity AD open-label extension, including subcutaneous formulation. Presented at: CTAD conference; October 24-27, 2023; Presentation 4.