Emerging drugs for dementia with Lewy Bodies: a review of Phase II & III trials

ABSTRACT

Introduction

Despite faster cognitive decline and greater negative impact on patients and family caregivers, drug development efforts in Dementia with Lewy Bodies (DLB) fall behind those for Alzheimer’s Disease (AD). Current off-label drug DLB treatment options are limited to symptomatic agents developed to address cognitive deficits in AD, motor deficits in Parkinson’s Disease, or behavioral symptoms in psychiatric disease. Aided by recent improvements in DLB diagnosis, a new focus on the development of disease-modifying agents (DMA) is emerging.

Areas covered

Driven by evidence supporting different pathological mechanisms in DLB and PDD, this review assesses the evidence on symptomatic drug treatments and describes current efforts in DMA development in DLB. Specifically, our goals were to: (1) review evidence supporting the use of symptomatic drug treatments in DLB; (2) review the current DMA pipeline in DLB with a focus on Phase II and III clinical trials; and (3) identify potential issues with the development of DMA in DLB. Included in this review were completed and ongoing drug clinical trials in DLB registered on ClinicalTrials.gov (no time limits set for the search) or disseminated at the 2023 international conference on Clinical Trials in AD. Drug clinical trials registered in non-US clinical trial registries were not included.

Expert opinion

Adoption of current symptomatic drug treatments used off-label in DLB relied on efficacy of benefits in other disorders rather than evidence from randomized controlled clinical trials. Symptoms remain difficult to manage. Several DMA drugs are currently being evaluated as either repurposing candidates or novel small molecules. Continued improvement in methodological aspects including development of DLB-specific outcome measures and biomarkers is needed to move the field of DMA drug development forward.

KEYWORDS:

• Dementia with Lewy Bodies drugs
• Lewy body dementia
• clinical trials
• disease-modifying therapies
• symptomatic treatments

Article highlights

• Dementia with Lewy Bodies (DLB) is a common cause of dementia yet there are no treatments yet approved for use in the United States. Instead, most current treatments are off-label.

• Biomarkers of alpha-synuclein, the building block of Lewy bodies, are under development with current approaches including skin biopsy and cerebrospinal fluid analyses.

• To date, phase 2 trials of DLB medications have largely not met primary outcomes.

• A number of novel compounds and repurposed agents are currently in clincal, some with the potential for disease modification.

Declaration of interest

James E Galvin declares being a Co-Principal Investigator on grants R01AG071643 (CT1812/Cognition Therapeutics) and R01AG080536 (Neflamapimod/EIP). M I Tolea declares being a Co-Investigator on R01AG071643 (CT1812/Cognition Therapeutics) and site-Principal Investigator on both clinical trials. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.