Clinical drug development for dementia with Lewy bodies: past and present

ABSTRACT

Introduction: Dementia with Lewy bodies (DLB) is an under-researched area despite being the second most common type of degenerative dementia after Alzheimer’s disease. It is an area of unmet need with no approved symptomatic or disease-modifying therapies. The pharmacological management of DLB is complex and challenging because early trials of drugs for DLB have resulted in no demonstrable efficacy. Randomized controlled trials (RCTs) in the DLB population have only recently been initiated. Understanding results from previous and current clinical trials in DLB can provide insights for future research and development.

Areas covered: We provide an overview of the DLB drug development landscape and the current treatment strategies. We reviewed ClinicalTrials.gov to identify all clinical trials for the treatment of DLB.

Expert opinion: DLB drug development has significantly improved in recent years with eight agents now in clinical trials. However, more rigorous RCTs are urgently needed. Diagnostic criteria must be optimized to accurately diagnose patients for clinical trials and care. New biomarker strategies are necessary to improve diagnostic capabilities and trial designs, and novel drug targets should be identified to develop DLB specific disease-modifying therapies. Evaluating the current drug development landscape can provide insight into how best to optimize development practices.

KEYWORDS:

• Clinical trials
• dementia with Lewy bodies
• drug development
• Lewy body dementia
• Parkinson’s disease dementia
• synucleinopathy
• therapeutics

Article Highlights

• There is a need for novel therapeutics for dementia with Lewy bodies (DLB)

• There is a lack of randomized controlled trials (RCTs) for DLB therapeutics. Most studies in the past were case studies and open-label trials. RCTs for DLB have only recently been initiated.

• There are no drugs approved for DLB in the United States and Europe and current treatment strategies target symptomatic relief using drugs approved for other indications.

• There are eight agents currently in the DLB drug development pipeline and this includes two promising agents—pimavanserin and zonisamide. Symptom-specific targets are emerging as a therapeutic approach.

• Early trials of drugs for DLB have resulted in no demonstrable efficacy. Recent trials of two novel agents, intepiridine (RVT-101) and nelotanserin, failed to show drug-placebo difference in DLB patients.

• New biomarker strategies may enhance diagnostics and clinical trial designs, and new therapeutic targets may assist in the development of DLB specific disease-modifying therapies.

This box summarizes key points contained in the article.

Declaration of interest

MN Sabbagh receives Royalties from Harper Collins, stock/equity from uMethodHealth, BrainHealthInc, Optimal Cognitive Health Company and Versanum, Speakers Bureau from Peerview and Rockpointe and Consult/Advisor fees from Allergan, Biogen, Signant, Elsai, Neurotrope, Cortexyme, Roche, Regeneron, VTV Therapeutics and Alzheon.

J Cummings has received Consultancy fees from Acadia, Actinogen, Alkahest, Allergan, Alzheon, Avanir, Axsome, BiOasis, Biogen, Bracket, Casava, Ceresin, Cortexyme, Diadem, EIP Pharma, Eisei, Foresight, Genentech, Green Valley, Grifols, Hisun, Kyowa Kirin, Lundbeck, Merck, Otsuka, Proclera, QR, Resverlogix, Roche, Sumumed, Samus, Takeda, Third Rock, Toyama and United Neuroscience pharmaceutical and assessment companies.

JB Leverenz has received Consultancy fees from Aptinyx, Acadia, Biogen, Elsai, GE Healthcare, Genzyme/Sanofi and Takeda Pharmaceuticals and receives grants from GE Healthcare and Genzyme/Sanofi.

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

The work of the authors is supported by the Keep Memory Alive Foundation, The National Institute of General Medical Sciences grant [5P20GM109025] and National Institute of Health grant [R01AG059008, K01AG047279, P30AG062428, U01NS100610 and R13NS111954].