Title : What’s Leqembi got to do with alzheimer dementia
Abstract:
Lecanemab is the humanized IgG1 version of the mouse monoclonal antibody mAb158, which selectively binds to large, soluble Aβ protofibrils [1].
On January 6, 2023, Lecanemab (Leqembi) was approved by the FDA under an accelerated approval pathway based on the observed reduction of amyloid beta plaque quantified using positron emission tomography (PET) imaging. FDA concluded that “the reduction in plaques is reasonably likely to result in clinical benefits”
On June 9, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee of six members endorsed 6-0 the full approval of lecanemab, which the FDA is expected to announce by July 6. The purpose of this talk is to demonstrate the clinical trial data pub- lished by van Dyck et al, 2023 show no evidence for lecanemab’s efficacy in slowing cog- nitive decline.
Lack of Proof of Efficacy
The primary endpoint was the change from baseline in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) at 18 months of treatment. CDR-SB measures cognition and function on a 0-18 points scale, higher scores indicating worse performance. In the trial of 1795 indi- viduals, CDR-SB score increased from the 3.2 baseline to 4.41 in 18 months in the lecanemab group, a change of 1.21, and to 4.86 in the placebo group, a change of 1.65, cal- culated as “adjusted least-squares mean change”. The - 0.45 difference (4.41 - 4.86) be- tween the groups is often interpreted as 27% less cognitive decline (0.45/1.65) as the clini- cal benefit of lecanemab treatment. This is misleading and an erroneous conclusion. What matters in real world at the end of the trial are the CDR-SB scores in the lecanemab and pla- cebo groups, which give lecanemab a clinical benefit of 9.3% (0.45/4.86), which is unlikely to make any difference for people living with early AD.
Safety Issues:
Overall, in Study 301 Core program and open label extension (OLE) the incidence of death was 6.9/1000 person years or 16 deaths amongst 2331 participants in the clinical trials of lecanemab.
The main safety problem associated with lecanemab, is amyloid related imaging abnormali- ties (ARIA), cerebral hemorrhage, and infusion-related reactions and hypersensitivity.
ARIA is classified as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA-H generally occurs in association with an occurrence of ARIA-E. The presence of the ApoE E ε4 allele increases the risk of ARIA, with greater risk observed in homozygotes than heterozygotes.
The use of antithrombotic medication, particularly, anticoagulation therapy, may increase the risk for cerebral hemorrhage in patients taking lecanemab.
These risks need to be considered in the benefit-risk discussion between prescribers and pa- tients/caregivers when making the decision to initiate therapy.
Costs and Reimbursement
On June 1, 2023 Centers for Medicare & Medicaid Services (Medicare) outlined plans to broadly cover a new class of Alzheimer’s drugs indicating the drugs must have traditional approval from the Food and Drug Administration. In addition, physicians must participate in registries designed to collect information on how the drugs work in the real world, as op- posed to the tightly controlled environment of clinical trials. We believe patient registries would not hinder the accessibility of the drug and support the approach from CMS. The col- lection of information and bioanalytic data will benefit CMS, the drug companies, and other stakeholders to validate the efficacy and safety of lecanemab post marketing approval.
According to Kaiser Family Foundation, if 5% of the 6.7 million older adults in the US with Alzheimer’s disease take Leqembi, at the annual list price of $26,500, this would add $8.9 billion to Medicare Part B spending annually (assuming all are enrolled in Part B). If just 10 percent of the 6.7 million older adults with Alzheimer’s disease take Leqembi, the has esti- mated that it would cost $17.8 billion—or nearly half of what Medicare Part B spent on all drugs in 2021.
Conclusion
The development of aducanumab and lecanemab was guided by the amyloid hypothesis, which proposes Alzheimer’s disease begins in the brain with the accumulation, aggregation, and amyloid formation. For 30 years, the amyloid hypothesis has almost singularly guided biomedical research, drug discovery, and clinical development in Alzheimer’s disease. The biomarker data of aducanumab showed reduction of amyloid beta plaque, but no evidence was presented to correlate biomarker changes to cognitive benefits.
The FDA approval of aducanumab and lecanemab is not a proof of the validity of the amy- loid hypothesis. The amyloid hypothesis is misleading and too good to be true.
The accelerated approval of lecanemab was based on the observed reduction of amyloid beta plaque. Dr. Alois Alzheimer never suggested plaques and tangles were the cause of de- mentia. Based on the clinical data of lecanemab submitted to the FDA, lecanemab has not demonstrated a proof of efficacy and safety to warrant the full FDA approval.
We believe that people with Alzheimer’s disease deserve a drug that is safe, effective, and affordable.
