Alzheimer's disease drug development pipeline: 2019

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Abstract

Introduction

Alzheimer's disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices.

Methods

We reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD.

Results

There are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase 1 trials. There is an increase in the number of agents in each phase compared with that in the 2018 pipeline. Nineteen agents in trials target cognitive enhancement, and 14 are intended to treat neuropsychiatric and behavioral symptoms. There are 96 agents in disease modification trials; of these, 38 (40%) have amyloid as the primary target or as one of several effects. Eighteen of the antiamyloid agents are small molecules, and 20 are monoclonal antibodies or biological therapies. Seven small molecules and ten biologics have tau as a primary or combination target (18%). Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Novel biomarkers (e.g., neurofilament light), new outcomes (e.g., AD Composite Score [ADCOMS]), enrollment of earlier populations, and innovative trial designs (e.g., Bayesian adaptive designs) are new features in recent clinical trials.

Discussion

Drug development continues robustly at all phases despite setbacks in several programs in the recent past. Continuing unmet needs require a commitment to growing and accelerating the pipeline.

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Most cited references 26

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High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Akinori Nakamura, NAOKI KANEKO, Victor Villemagne … (2018)

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

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Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

Yuki Mukai, Tiffini Smith Voss, Christine Furtek … (2018)

BACKGROUND Alzheimer’s disease is characterized by the deposition of amyloid-beta (A β ) plaques in the brain. A β is produced from the sequential cleavage of amyloid precursor protein by β -site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by y-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the A β level in the cerebrospinal fluid of patients with Alzheimer’s disease. METHODS We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was −8.4 in the 12-mg group, −8.2 in the 40-mg group, and −8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events.(ClinicalTrials.gov [Related object:] .)

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Compliance with Results Reporting at ClinicalTrials.gov

Monique L Anderson, Karen Chiswell, Eric Peterson … (2015)

The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.

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Author and article information

Contributors

Jeffrey Cummings

Journal

Journal ID (nlm-ta): Alzheimers Dement (N Y)

Journal ID (iso-abbrev): Alzheimers Dement (N Y)

Title: Alzheimer's & Dementia : Translational Research & Clinical Interventions

Publisher: Elsevier

ISSN (Electronic): 2352-8737

Publication date PMC-release: 09 July 2019

Publication date Collection: 2019

Publication date (Electronic): 09 July 2019

Volume: 5

Pages: 272-293

Affiliations

[a ]Department of Brain Health, University of Nevada, Las Vegas (UNLV), School of Integrated Health Sciences, Las Vegas, NV, USA

[b ]Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA

[c ]CNS Innovations, Henderson, NV, USA

Author notes

[∗ ]Corresponding author. Tel.: +702.701.7926; Fax: +702.722.6584. cumminj@ 123456ccf.org

Article

Publisher ID: S2352-8737(19)30029-0

DOI: 10.1016/j.trci.2019.05.008

PMC ID: 6617248

PubMed ID: 31334330

SO-VID: 8bea3259-99bc-4dbc-b1a2-666c98e52dce

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Alzheimer's disease drug development pipeline: 2019

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Abstract

Introduction

Methods

Results

Discussion

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Alternative approaches to Alzheimer's Disease

Most cited references 26

High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

Compliance with Results Reporting at ClinicalTrials.gov

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Contributors

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