(A-026) Identifying opportunities and challenges in the use of real-world data to support the ongoing benefit-risk evaluation of new treatments for Alzheimer’s Disease

Background: Alzheimer’s Disease (AD) is a neurodegenerative brain condition with limited drug options. Two new amyloid beta-directed antibody treatments, lecanemab and donanemab, have been authorised in some countries for mild cognitive impairment. Concerns have been raised about their benefit-risk balance given modest demonstrated efficacy and increased risk of potentially life-threatening amyloid-related imaging abnormalities (ARIA).

Objectives: Review the benefit-risk profile for lecanemab and donanemab, compare post-authorisation study requirements, and identify opportunities and challenges in using real-world data to provide evidence to support the ongoing evaluation of their benefits and risks.

Methods: Regulatory documents from the US FDA, UK MHRA, and Japan’s PMDA related to the authorisation and benefit-risk of lecanemab and donanemab were reviewed; with information extracted on clinical trial safety, product labelling, and post-authorisation study requirements.

Results: Based on phase 3 efficacy and safety data, MHRA restricted both products to ApoE ε4 heterozygotes or non-carriers and contraindicated patients with MRI findings suggestive of cerebral amyloid angiopathy and those receiving anticoagulants. FDA instead included a black box warning on the higher risk of ARIA in ApoE ε4 homozygotes, while PMDA included the same warning in product labelling. Other than ARIA, treatment emergent adverse events were predominantly mild and moderate in severity. Causes of death across trials for both products, other than ARIA, included pneumonia, suicide, and pulmonary embolism. For both products, FDA required a registry-based study designed to support further evaluation of ARIA and long-term safety. MHRA mandated a controlled access programme, to capture complete drug utilisation, and a category 1 Post Authorisation Safety Study for safety and effectiveness of risk minimisation. PDMA required a post-marketing use results survey covering all patients treated.

Conclusions: Post authorisation requirements have focussed on the risk of ARIA and effectiveness in subgroups. Registries are required to maximise coverage and collect more detailed patient data. However, international studies using electronic healthcare record (EHR) databases could support earlier evidence generation and mitigate expected slow uptake and uncertainties regarding reimbursement in some countries. EHRs may be particularly useful for studies of natural history, drug utilisation, and long-term safety, subject to confidence in the validity of ARIA records and availability of sufficient AD staging data. Studies to understand impacts on the quality of life of patients in the real world are also important to further characterise benefit-risk.