On January 6, Eisai and Biogen announced that Leqembi (lecanemab), an anti-amyloid beta (Aβ) monoclonal antibody (mAb), has been granted FDA approval under the accelerated approval pathway for the treatment of Alzheimer’s disease (AD) in patients with early AD. The accelerated approval was based on Phase II data (NCT01767311). Once attained, the companies submitted a supplemental biologics license application (sBLA) to the FDA seeking the conversion of Leqembi’s accelerated approval to a full approval based on data from the Phase III Clarity AD trial (NCT03887455).

Leqembi is the second anti-Aβ mAb approved by the FDA for the treatment of AD, following the FDA’s controversial approval of Biogen’s Aduhelm (aducanumab) in 2021. While Aduhelm was approved by the FDA based on the surrogate endpoint of Aβ clearance, as it failed to demonstrate significant clinical effect in its clinical trials, Leqembi has demonstrated both a reduction in Aβ and a reduced clinical decline of 27% compared with placebo at 18 months of treatment in Clarity AD, as measured by the primary endpoint, Clinical Dementia Rating-Sum of Boxes (CDR-SB). Although Leqembi is a clear improvement on Aduhelm, as it met its primary endpoint in Clarity AD, a 27% reduction in clinical decline is modest. As such, uncertainty remains among physicians as to whether this is a big enough reduction for patients to notice a real difference in their cognition.

A known side effect of amyloid-lowering therapies is the development of amyloid-related imaging abnormalities (ARIAs), including ARIA related to underlying vasogenic edema (ARIA-E). A further barrier for Aduhelm is that 35% of patients taking the approved dose of the drug developed ARIA-E in its pivotal Phase III trials, ENGAGE (NCT02477800) and EMERGE (NCT02484547). Here Leqembi again outperforms Aduhelm, as the rate of ARIA-E in Clarity AD was 12.5%. While this is an improvement, the incidence of ARIA remains a significant concern and the FDA has placed a warning for ARIA on the label for Leqembi in the warnings and precautions section. Additionally, the FDA has noted that magnetic resonance imaging (MRI) monitoring for ARIA should be conducted prior to treatment and again before the fifth, seventh, and fourteenth infusions of Leqembi. The incidence of ARIA is likely to remain a barrier for any anti-Aβ mAbs going forward.

Not only was the approval of Aduhelm controversial, but its launch was also chaotic, with an initial price of $56,000, which Biogen then halved to $28,000 following significant backlash. Despite the reduction in price, the US Centers for Medicare and Medicaid Services (CMS) limited the Medicare reimbursement of Aduhelm and subsequent similar products to AD patients participating in randomized controlled trials only, which has resulted in low uptake and poor sales for the drug. Although Eisai and Biogen have announced that Leqembi will be priced less than Aduhelm, at $26,500, the CMS limitation of Medicare reimbursement for patients in clinical trials will also apply to Leqembi, limiting its initial uptake.

The success of Leqembi will likely come down to the level of insurance coverage it receives, which will determine how widely available it will be. Achieving full approval from the FDA for the sBLA will be crucial for Leqembi’s prospects as the CMS have indicated that full approval of the drug could result in broader coverage. Ultimately, the CMS will have a huge impact on whether Leqembi will face a similar fate to Aduhelm, or whether it could become the first widely available disease-modifying treatment for AD. Any decision on coverage from the CMS will also likely impact the prospects of Leqembi’s closest competitor, Eli Lilly’s anti-Aβ mAb donanemab, which recently filed for an FDA accelerated approval with a Prescription Drug User Fee Act (PDUFA) date of February 6, 2023.