In the fifth edition of our special newsletter SCHLAGLICHT – New Medications for Dementia, Anne Keefer, research associate at digiDEM Bayern, discusses the publication by an international group of researchers led by Prof. Alberto J. Espay of the University of Cincinnati. In the article titled Recalibrating the Risk-Benefit Profiles of Lecanemab and Donanemab: Scales, Immunoreactivity, and Changes in Amyloid-β42, The study, published in the Journal of Alzheimer's Disease, examines the benefit-risk ratio of new monoclonal antibodies for the treatment of Alzheimer's disease. (DOI: 10.3233/JAD-240171).
Lecanemab and Donanemab are so-called monoclonal antibodies for the treatment of Alzheimer's disease. The benefit-risk ratio of these medicinal treatments is currently controversially debated in science. There are some criticisms regarding the methodological execution of the approval studies, and the interpretations of the research results are also being critically questioned.
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Criticism of the methodological execution
‚Amyloid-related imaging abnormalities‘ (ARIA) refer to acute pathological changes in the brain that can be observed in approximately 40% of Alzheimer’s patients treated with monoclonal antibodies. In imaging studies, ARIA appear as cerebral edema or microbleeds. As soon as such an abnormality was detected in a study participant, treatment with the monoclonal antibodies was discontinued and more frequent imaging was recommended. This approach resulted in a deviation from the study protocol, in which both the medication and the frequency of imaging diagnostics had been precisely defined prior to the start of the study. Since the study participants, their relatives and caregivers, the participating study physicians, and study staff could observe these deviations, conclusions might have been drawn as to which of the subjects were in the treatment group and which were in the control group. So-called blinding—that is, the fact that all participants are unaware of the allocation of subjects to the treatment and control groups—is a particularly important feature of clinical trials to ensure that research results are not influenced, either consciously or unconsciously.
Accordingly, it was questionable whether the subjects and the research team actually didn't know which group the participants belonged to. This means: The blinding could have been compromised – certain questions from the study participants and the evaluation of information by the research team would therefore no longer be unbiased and could have led to an overestimation of the efficacy of the monoclonal antibodies as a result of the acquired knowledge.
Regarding the blinding, Prof. Alberto J. Espay also points out another criticism. The control group received a saline solution instead of monoclonal antibodies. However, this does not elicit an immune response, unlike the monoclonal antibodies in the study participants in the treatment group. Espay's conclusion is therefore: At least in view of methodological shortcomings, the scientific evidence for the benefit of monoclonal antibodies is questionable.
The survey instruments are crucial
In the studies, the cognitive abilities of the participants were measured using different instruments. For example, the ‚Mini-Mental State Examination‘ (MMSE) and the ‚Alzheimer's Disease Assessment Scale–Cognitive Subscale‘ (ADAS-Cog13) are objective scales for assessing cognitive abilities. Another assessment instrument, on the other hand, is the ‚Clinical Dementia Rating Scale – Sum of Boxes’ (CDR-SB). In this method, study staff conduct a guided interview with the participant and a relative or caregiver. This type of data collection leads to a more subjective assessment of cognitive abilities than with the MMSE or the ADAS-Cog13.
It is striking that with the more objective assessment instruments, such as the MMST and ADAS-Cog13, the clinical relevance of the measured results – i.e., the efficacy of the drug treatment – was less significant than with the more subjective form of assessment. The authors, led by Prof. Alberto J. Espay, suspect that due to incomplete blinding, the efficacy of the drug treatment is erroneously greater when assessed with a subjective assessment instrument (CDR-SB). This can be explained, on the one hand, by the fact that subjects who believe they are receiving drug treatment are more likely to report better cognitive abilities than individuals who assume they are not receiving treatment. On the other hand, it may be that study personnel assess the cognitive abilities of participants they suspect are receiving drug treatment better than individuals they believe to be in the control group without drug treatment.
Re-evaluation of study results necessary
Based on the criticisms presented regarding the study methodology of three relevant approval studies, Prof. Alberto J. Espay and colleagues argue that the study results must be re-evaluated, and therefore, the risk-benefit ratio of monoclonal antibodies must be critically questioned.
