in response to the European Medicines Agency’s refusal of marketing authorisation for Aduhelm (aducanumab)

In Zusammenarbeit mit PD Dr. Tobias Ruck und Dr. Christopher Nelke

On December 16th, the EMA voted against marketing authorisation for Aduhelm (aducanumab), which is intended for the treatment of early Alzheimer’s disease (AD). The EMA’s decision was preceded by accelerated approval for Aduhelm by the FDA. We acknowledge the rigorous scientific assessment performed by the EMA, but are concerned that depriving European patients of a potential treatment for AD is likely to have a negative impact. In this letter, we argue for the approval of Aduhelm for early AD under the premise of a conditional market authorization in a controlled framework.

The global urgency of dementia treatments
The number of patients living with dementia globally is estimated at around 50 million – a figure that has more than doubled since 1990. The burden of disease on patients, communities, and healthcare systems is growing. Dementia is driven by a complex interplay of neuropathological mechanisms, most commonly the accumulation of β-amyloid and tau as seen in AD accounting for 50% to 70% of cases. Loss of cognitive function is unrelenting and a significant cause of mortality in affected individuals. As our population ages, the number of patients suffering from dementia is expected to rise to 139 million by 2050, according to estimates by the WHO. Effective treatment approaches are urgently needed to address the global challenge of dementia. By delaying potential therapeutics, a large population of patients with early AD are likely to progress beyond the treatment window, further aggravating the burden of disease imposed by dementia.

The risk for unequal treatment access
Socioeconomic status must not dictate access to medical treatment. Conflicting market authorisation between the United States (and United Arab Emirates) and the European Union is likely to raise ethical concerns. Patients of higher socioeconomic status may well be better placed to access Aduhelm via international pharmacies, while patients who cannot afford this option do not have access to treatment. Aduhelm has become a choice for the healthcare system to offer. Differences in availability, however, restrict this choice only to patients that have the means to afford it. The arising inequality is a concern that must be considered.

Arguments for conditional market authorization
The FDA’s initially broad approval for Aduhelm was followed by controversy. While the benefit for Aduhelm in advanced AD is certainly questionable, patients with mild cognitive impairment or early AD may benefit. We believe that offering these patients a treatment option to potentially decelerate disease progression may ameliorate the immense burden imposed by AD. To shift the benefit/risk profile in favour of Aduhelm, we suggest a strict set of considerations:

  1. The target population must be strictly defined to improve treatment outcomes. As such, prerequisite diagnostics must ensure that AD is the predominant pathology and exclude patients with high cerebrovascular risk profiles (e.g. Cummings criteria). Including abnormal levels of phosphorylated tau could serve as requirement for treatment.
  2. Treatment should be clearly restricted to patients with early disease, i.e., mild cognitive impairment or early AD. Treatment will likely provide outcomes that are more favourable and thereby a more robust argument for the use of Aduhelm in clinical practice, if limited to patients with clear indication of early disease.
  3. Inclusion into patient registries should be mandatory upon treatment. Patient registries provide important insight into real-world data, including adverse effects and treatment success. A European registry of “β-amyloid-depleting therapies” can ensure standardized data collection and improve treatment feasibility.
  4. After clear evidence of β-amyloid depletion through Aduhelm, treatment might be paused in individual patients. A pulsatile treatment approach might improve feasibility and reduce the risk of adverse events. However, data supporting this notion is currently lacking. Collecting further data is important to further refine treatment strategies.
  5. Further, the risk/benefit-ratio assessment of Aduhelm should consider the occurrence of amyloid-related imaging abnormalities (ARIA). Patients must be informed of the potential risks and the administration of Aduhelm should be restricted to centres with experience in early AD. Established centres can provide the necessary infrastructure for MRI-based monitoring and detection of ARIAs, thereby reducing the adverse event profile.

Certainly, β-amyloid depletion is not a panacea for AD. However, as the European population ages, the burden of AD steadily grows. By implementing the above-mentioned criteria, Aduhelm could become a valuable treatment option within the treatment window for millions of patients with early disease. Strict patient selection and administration only in experienced centres could provide the basis for conditional market authorization.