Drug Repositioning for Alzheimer’s Disease: A Delphi Consensus and Stakeholder Consultation

Background Alzheimer’s Disease (AD) is an escalating global challenge, with over 40 million people affected and this number is projected to increase to over 100 million by 2050. While amyloid-targeting antibody treatments (lecanumab and donanemab) are a considerable step forward, the benefits of these therapies remain limited. This highlights the necessity for safe and effective compounds that offer greater therapeutic benefits to the majority of individuals with or at risk of AD. Drug repurposing allows for a cost-effective, time-efficient strategy to accelerate the availability of treatments due to the safety profiles already being known. MethodThis study focuses on the third iteration of the Delphi consensus programme aimed at identifying new high-priority drug candidates for repurposing in AD. An international expert panel comprised of published academics and/or clinicians, or industry representatives was convened. Through a combination of anonymized drug nominations, systemic evidence reviews, iterative consensus ranking, and a lay advisory input, drug candidates were evaluated and ranked based on rational, preclinical and clinical evidence and overall safety profiles.ResultsOut of the 80 candidates that were nominated by the expert panel, seven underwent review with only three candidates meeting the consensus criteria: (1) the live attenuated Herpes Zoster (HZ) vaccine (Zostavax), (2) Sildenafil, a PDE5 inhibitor, and (3) Riluzole, a glutamate antagonist. Each demonstrated relevant mechanisms for targeting neurodegenerative pathways, preclinical efficacy and tolerability in older individuals. The HZ vaccine additionally offers a potential for population-level dementia risk reduction. ConclusionThis Delphi consensus identified 3 high-priority drug repurposing candidates for Alzheimer’s Disease. With their favourable safety profiles and mechanistic plausibility, they are considered suitable for pragmatic clinical trials, including remote or hybrid designs. The PROTECT platform, which supports international cohorts in the UK, Norway and Canada, offers a well-established means to conduct such trials effectively, thus helping to accelerate the evaluation and the potential deployment of these drug candidates to benefit individuals.