On January 6, 2023, the FDA granted an accelerated approval for lecanemab (branded Leqembi by Eisai and Biogen) in the treatment of early Alzheimer’s dementia (AD) patients. On June 9, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee endorsed the full approval of lecanemab, which the FDA is expected to announce by July 6. The approval is based on the results of the clinical trial Clarity AD published by van Dyck et al. (2023) showing lecanemab reduced amyloid in the brain and slowed cognitive decline of the AD patients [1]. The purpose of this letter is to demonstrate the trial results provide no evidence for lecanemab’s efficacy in slowing cognitive decline.
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) measures cognition and function on a 0-18 points scale, higher scores indicating worse performance. In van Deck et al. (2023) [1], we read “A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001)”. As shown in Fig. S1B, CDR-SB score difference was -0.20 for women (52.3% of study population) and -0.73 for men (47.7%). Calculating a weighted average 47.7 x (-0.73) + 52.3 x (-0.20) gives -0.45. Conspicuously, in the van Dyck et al. (2023) paper [1], the terms “women” (female) and “men” (male), or their mean score changes, are never used or presented, only to be found in Fig. S1B of the Supplementary Appendix.
The -0.45 difference is often interpreted as 27% less cognitive decline (0.45/1.65) as the clinical benefit of lecanemab treatment. This is misleading and an erroneous conclusion. What matters in real world are the CDR-SB scores at the end of the 18-month trial, which were (baseline 3.2 included) 4.21 in the lecanemab and 4.66 in the placebo group, 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 [2]. Most important, even if lecanemab worked for men, it certainly did not work for women.
Further, -0.20 and -0.73 are clearly too different to originate (statistically) from the same population, but rather from two different populations centered around -0.20 and -0.73. Therefore, -0.45 does not characterize any population, does not represent anybody, it’s useless, and has no meaning.
APOE4 is a common variant of apolipoprotein E, with the frequency of 13.7%, and the biggest genetic risk factor of AD. It increases the risk, lowers the age of onset, and enhances the development and progression of AD [3]. One APOE4 gene (12% of population) increases AD risk 2-fold and two (2% of population) 12-fold.
The effects of APOE4 in the Clarity AD trial are given in Fig. S1B [1], which shows CDR-SB score differences between lecanemab and placebo groups as -0.75 for individuals without (-/-), -0.50 with one (+/-), and 0.28 with two (+/+) APOE4 genes. Of note, the 0.28 difference indicates lecanemab enhanced cognitive decline of AD patients with two APOE4 genes (15.5% of study population), the group of people in the most need for treatment and prevention of AD. Of note, from the data in Fig. S1B [1] on the % slowing of decline, we can calculate CDR-SB score increases from baseline to 18 month in the placebo group as 1.83 for (-/-) individuals, 1.67 for (+/-) individuals, and 1.27 for (+/+) individuals, indicating slower dementia progression in APOE4 carriers compared to non-carriers. For example, 1.27 - 1.83 = -0.28 would indicate that having two APOE4 genes is associated with 15% slower cognitive decline (0.28/1.83) in 18 months. Assuming the same 3.2 baseline regardless of the APOE4 status (not given in [1]), two APOE4 genes would provide a 5.6% (0.28/5.03) ‘protection’ against dementia progression Needless to say, these data are against what is known about APOE4 in the development of AD [3].
In conclusion, there is no evidence-based science behind lecanemab to show it’s clinically meaningful benefit in slowing cognitive decline. In contrast, lecanemab (and other anti-amyloid monoclonal antibodies) have consistently resulted in serious adverse events of ARIA, or amyloid related imaging abnormalities, seen in MRI pictures and caused by brain swelling and brain bleeding in AD patients that can be fatal [4,5], Therefore, the FDA is left with no other choice than reject the full approval of lecanemab.
Markku Kurkinen, Biomed Industries, Inc. San Jose, California, USA
The views and opinions expressed here are mine only and do not reflect those of Biomed Industries, Inc. I thank Timothy Dale, Alberto Espay, George Perry, Lloyd Tran, Zung Tran, and Peter Whitehouse for their critique, continued interest, help, and understanding.
References
[1] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T (2023) Lecanemab in early Alzheimer’s disease. N Engl J Med 388, 9-21.
[2] Lansdall CJ, McDougall F, Butler LM, Delmar P, Pross N, Qin S, McLeod L, Zhou X, Kerchner GA, Doody RS (2023) Establishing clinically meaningful change on outcome assessments frequently used in trials of mild cognitive impairment due to Alzheimer's disease. J Prev Alzheimers Dis 10, 9-18.
[3] Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC (2022) ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener 17, 72.
[4] Espay AJ, Herrup K, Daly T (2023) Finding the falsification threshold of the toxic proteinopathy hypothesis in neurodegeneration. Handb Clin Neurol 192, 143-154.
[5] Castellani RJ, Shanes ED, McCord M, Reish NJ, Flanagan ME, Mesulam MM, Jamshidi P (2023) Neuropathology of anti-amyloid-β immunotherapy: a case report. J Alzheimers Dis 93, 803-813.
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