The Belgian Centre for Pharmacotherapeutic Information (BCFI) considers that additional studies are necessary to establish the efficacy, target population, safety and cost-effectiveness of aducanumab. The argument that medicine has so far not found any substantial answer against Alzheimer’s disease should not be misused to skip these steps.
In early June 2021, various media enthusiastically reported on the approval by the U.S. drug agency FDA of a new Alzheimer’s drug. It concerns the monoclonal antibody aducanumab, directed against the β-amyloid. Aducanumab is said to slow down the evolution of Alzheimer’s dementia, but cannot cure the disease.
The approval by the US FDA was through an “accelerated procedure”, used for drugs whose efficacy is still uncertain, but which are believed to offer an important therapeutic advantage over the currently available treatments. However, the approval of aducanumab is controversial and goes against the advice of its own expert panel.
Several interesting comments and opinions have already been published in BMJ1, JAMA2 and Dutch Journal of Medicine3. The main criticisms are:
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The assessment report is based on data from post hoc (subgroup) analyses of 2 unpublished clinical trials with conflicting results. These studies were previously discontinued because of futility (i.e. it was estimated at that time that it was unlikely that the study would lead to positive results at the primary endpoint). Such data are very sensitive to bias and are in principle considered, at best, as hypothesis generating.
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The clinical relevance of the effect found on the Clinical Dementia Rating-Sum of Boxes score is questioned (0.39 points on a scale of 0 to 18, while a difference of 1 or even 2 points is usually considered clinically relevant).
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Potentially serious brain abnormalities (point hemorrhages, white matter lesions, vasogenous cerebral edema) were seen on the brain scans of more than a third of the patients treated with high-dose aducanumab; in the placebo group, these abnormalities were only seen in 2.7% of the patients.
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There is a growing consensus that, in addition to the amyloid pathway, other mechanisms play a role in the onset of Alzheimer’s dementia. In recent years, other drugs have been developed that, like aducanumab, could successfully reduce the accumulation of β-amyloid in the brain. None of these agents have subsequently shown significantly favorable results on clinical endpoints. There is no plausible explanation as to why aducanumab, which is also exclusively directed against theamyloid pathway, would now lead to favorable results.
An application was also submitted by the manufacturer to the European Medicines Agency EMA, but the assessment is still ongoing.
Even after approval, there are a number of other things that could dampen the enthusiasm: the limited target patient population (although the FDA did not formulate any restrictions in this respect in its approval, aducanumab has only been studied in patients in a (very) early phase of Alzheimer’s disease), the intravenous route of administration (causes practical objections and additional costs) and not least the high cost (the predetermined annual cost in the United States is 56 000 $ or converted 46 000 €).
The BCFI agrees with the above criticisms and considers that the efficacy, target patient population, safety and cost-effectiveness of aducanumab have not been sufficiently demonstrated at present. This requires, in addition to the full publication of the results of the studies already carried out, new additional studies. The argument that medicine has so far not found any substantial answer to Alzheimer’s disease should not be used to expose patients to treatments with questionable efficacy and potentially serious undesirable effects, which, moreover, threaten to consume an unacceptably large proportion of the increasingly strained health budgets.
