Volume 4, Issue 1 p. 195-214
Featured Article
Open Access

Alzheimer's disease drug development pipeline: 2018

Jeffrey Cummings

Corresponding Author

Jeffrey Cummings

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

∗Corresponding author. Tel.: 702 483 6029; Fax: 702 722 6584.Search for more papers by this author
Garam Lee

Garam Lee

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

Search for more papers by this author
Aaron Ritter

Aaron Ritter

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

Search for more papers by this author
Kate Zhong

Kate Zhong

Global Alzheimer Platform, Washington, DC, USA

Search for more papers by this author
First published: 03 May 2018
Citations: 398

Abstract

Introduction

Treatments for Alzheimer's disease (AD) are needed due to the growing number of individuals with preclinical, prodromal, and dementia forms of AD. Drug development for AD therapies can be examined by inspecting the drug development pipeline as represented on clinicaltrials.gov.

Methods

Clinicaltrials.gov was assessed as of January 30, 2018 to determine AD therapies represented in phase I, phase II, and phase III.

Results

There are 112 agents in the current AD treatment pipeline. There are 26 agents in 35 trials in phase III, 63 agents in 75 trials in phase II, and 23 agents in 25 trials in phase I. A review of the mechanisms of actions of the agents in the pipeline shows that 63% are disease-modifying therapies, 22% are symptomatic cognitive enhancers, and 12% are symptomatic agents addressing neuropsychiatric and behavioral changes. Trials in phase III are larger and longer than phase II or phase I trials, particularly those involving disease-modifying agents. Comparison with the 2017 pipeline shows that there are four new agents in phase III, 14 in phase II, and eight in phase I. Inspection of the use of biomarkers as revealed on clinicaltrials.gov shows that amyloid biomarkers are used as entry criterion in 14 phase III disease-modifying agent trials and 17 disease-modifying agent trials in phase II. Twenty-one trials of disease-modifying agents in phase II did not require biomarker confirmation for AD at trial entry.

Discussion

The AD drug development pipeline is slightly larger in 2018 than in 2017. Trials increasingly include preclinical and prodromal populations. There is an increase in nonamyloid mechanisms of action for drugs in earlier phases of drug development. Biomarkers are increasingly used in AD drug development but are not used uniformly for AD diagnosis confirmation.

1 Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive, functional, and behavioral alterations 1, 2. AD is age related and is becoming markedly more common with the aging of the world's population. It is estimated that by 2050, one in every 85 people will be living with AD 3. Nearly eightfold as many people have preclinical AD as have symptomatic AD and are at risk for progressing to manifest disease 4. Disease-modifying therapies (DMTs) that will prevent or delay the onset or slow the progression of AD are urgently needed. A modest 1-year delay in onset by 2020 would result in there being 9.2 million fewer cases in 2050 3. Similarly, medications to effectively improve cognition or ameliorate neuropsychiatric symptoms of patients in the symptomatic phases of AD are needed to improve memory and behavior 5.

In this update of our annual review of the AD drug development pipeline, we provide a summary of the current state of progress in developing new therapies for AD 6, 7. We discuss each phase of the AD pipeline (I, II, and III) and describe DMTs, cognitive-enhancing agents, and treatments for behavioral disturbances in AD that are in development. We note the use of biomarkers in clinical trials. We describe evolving targets of the agents in the pipeline. We discuss trial infrastructure changes that may accelerate clinical trials and drug development. Our goal is to provide insight into the drug development process and to help drug developers and clinical trialists learn from the current pipeline experience.

2 Methods

This annual review is based on clinical trial activity as recorded in clinicaltrials.gov, a comprehensive US government database. The US law requires that all clinical trials conducted in the United States be registered on the site. The “common rule” governing clinicaltrials.gov was recently updated and mandated registration of all trials from sponsors with an Investigational New Drug or Investigational New Device 8, 9. Trials must be registered within 21 days of the enrollment of the first trial participant. Results for the primary outcome measures must be submitted to clincaltrials.gov within 12 months of completion of final data collection. Compliance with trial registration is high 10-12; compliance with results reporting is lower 13. Clinicaltrials.gov can be regarded as a comprehensive and valid data source for the study of clinical trials conducted in the United States. Not all non-US trials are registered on clinicaltrials.gov—especially phase I trials—and our findings may underrepresent the agents populating global phase I efforts.

Results reported here are based on trials registered on clinicaltrials.gov as of January 30, 2018. We include all trials of all agents in phase I, II, and III; some trials are presented as I/II or II/III in the database, and we use that nomenclature in the review. In our trial database, we entered the trial title; beginning date; projected end date; calculated duration; planned enrollment number; number of arms of the study (usually a placebo arm and one or more treatment arms with different doses); whether a biomarker was described; subject characteristics; and sponsorship by a biopharma company, National Institutes of Health, academic medical center, “other” entity such as a consortium or a philanthropic organization, or a combination of these sponsors. Using the clinicaltrials.gov classification, we included trials that were recruiting, active but not recruiting (e.g., trials that have completed recruiting and are continuing with the exposure portion of the trial), enrolling by invitation, and not yet recruiting. We did not include trials listed as completed, terminated, suspended, unknown, or withdrawn because information on these trials is often incomplete. We included all pharmacologic trials listed in the database; we did not include trials of nonpharmacologic therapeutic approaches such as devices, cognitive therapies, caregiver interventions, supplements, and medical foods. We did not include trials of biomarkers although we noted whether biomarkers were used in the trials of interest.

Drug targets and mechanism of action (MOA) of treatments are important aspects of this review. MOA was determined from the information on clinicaltrials.gov or from a comprehensive search of the literature. In a few cases, the mechanism is undisclosed and could not be identified in the literature, and we note these agents as having an “unknown” MOA. We grouped the mechanisms into symptomatic agents or DMTs. We divided the symptomatic agents into those that are putative cognitive-enhancing agents or those that address neuropsychiatric and behavioral symptoms. DMTs were divided into those targeting amyloid-related mechanisms, those that have tau-related MOAs, and those with “other” mechanisms such as neuroprotective agents, anti-inflammatory drugs, growth factors, or agents with metabolic effects. Stem cell therapies were included in the “other” category. Some agents have multiple effects and might be expected to have symptomatic and disease-modifying properties. We classified these drugs as symptomatic or DMTs based on the trial design. Agents in large, long (12–24 months) trials with biomarker outcomes are listed as DMTs. Those in smaller, shorter (3–6 months) trials with cognitive or behavioral outcomes and no biomarkers are listed as symptomatic. Agents could change classification as more information accrues.

3 Results

3.1 Overview

Fig. 1 provides an overview of all agents identified in the current AD pipeline. The main circles of the figure reveal the stage of development (I, II, and III), the colors pertain to the MOA of the agent, and the shape denotes the population in which the agent is being tested (normal volunteers, cognitively normal at-risk individuals, prodromal AD, and AD dementia).

Details are in the caption following the image

Agents in clinical trials for treatment of Alzheimer's disease in 2018 (from clinicaltrials.gov accessed January 30, 2018).

In total, there are 112 agents in the pipeline as shown on clinicaltrials.gov. We identified 26 agents in 35 trials in phase III, 63 agents in 75 trials in phase II, and 23 agents in 25 trials in phase I. Review of the MOAs of pipeline agents showed that 63% are DMTs, 22% are symptomatic cognitive enhancers, 12% are symptomatic agents addressing neuropsychiatric and behavioral changes, and 3% have undisclosed MOAs.

3.2 Phase III

Phase III of the 2018 AD pipeline has 26 agents; 17 DMTs, one cognitive-enhancing agent, and eight drugs for behavioral symptoms (Fig. 1, Table 1). Among the DMTs, 14 addressed amyloid targets, one involved a tau-related target, one involved neuroprotection, and one had a metabolic MOA. The DMTs include six immunotherapies (all addressing amyloid). Of the DMTs, two are repurposed agents approved for use in another indication (insulin, albumin plus immunoglobulin). Of the drugs with amyloid targets, there were five Beta-site Amyloid precursor protein Cleavage Enzyme inhibitors, six immunotherapies, and three antiaggregation agents. Fig. 2 shows the MOAs of agents in phase III.

Table 1. Agents currently in phase III of Alzheimer's disease drug development (as of January 30, 2018)
Agent Agent mechanism class Mechanism of action Therapeutic purpose Clinicaltrials.gov ID Status Sponsor Start date Estimated end date
Aducanumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT02484547 Recruiting Biogen September-15 April-22
NCT02477800 Recruiting Biogen August-15 March-22
Albumin + immunoglobulin Anti-amyloid Polyclonal antibody Remove amyloid (DMT) NCT01561053 Active, not recruiting Grifols March-12 December-17
ALZT-OP1a + ALZT-OP1b (cromolyn + ibuprofen) Anti-amyloid, anti-inflammatory Mast cell stabilizer (cromolyn), anti-inflammatory (ibuprofen) Reduce neuronal damage; mast cells may also play a role in amyloid pathology (DMT) NCT02547818 Recruiting AZTherapies, Pharma Consulting Group, KCAS Bio, APCER Life Sciences September-15 November-19
AVP-786 Neurotransmitter based Sigma 1 receptor agonist; NMDA receptor antagonist Improve neuropsychiatric symptoms (agitation) NCT02442765 Recruiting Avanir September-15 July-18
NCT02446132 Recruiting-EXT Avanir December-15 March-21
AZD3293 (LY3314814) Anti-amyloid BACE1 inhibitor Reduce amyloid production (DMT) NCT02245737 Active, not recruiting AstraZeneca, Eli Lilly September-14 September-19
NCT02783573 Recruiting AstraZeneca, Eli Lilly July-16 March-21
NCT02972658 Recruiting-EXT AstraZeneca, Eli Lilly March-17 September-20
AXS-05 Neurotransmitter based Sigma 1 receptor agonist; NMDA receptor antagonist (dextromethorphan); serotonin norepinephrine reuptake inhibition (bupropion) Improve neuropsychiatric symptoms (agitation) NCT03226522 Recruiting Axsome Therapeutics July-17 September-19
CAD106 & CNP520 Anti-amyloid Amyloid vaccine, BACE inhibitor Remove/reduce amyloid (DMT) NCT02565511 Recruiting Novartis, Amgen, NIA, Alzheimer's Association, Banner Alzheimer's Institute November-15 May-24
CNP520 Anti-amyloid BACE Inhibitor Reduce amyloid production (DMT) NCT03131453 Recruiting Novartis, Amgen, Banner Alzheimer's Institute August-17 July-24
Crenezumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT02670083 Active, not recruiting Roche/Genentech March-16 July-21
NCT03114657 Recruiting Roche/Genentech March-17 October-22
E2609 (elenbecestat) Anti-amyloid BACE inhibitor Reduce amyloid production (DMT) NCT02956486 Recruiting Eisai, Biogen October-16 December-20
NCT03036280 Recruiting Eisai, Biogen December-16 December-20
Escitalopram Neurotransmitter based Serotonin reuptake inhibition Improve neuropsychiatric symptoms (agitation) NCT03108846 Not yet recruiting NIA, JHSPH Center for Clinical Trials September-17 March-21
Gantenerumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT02051608 Active, not recruiting Roche March-14 November-19
NCT01224106 Active, not recruiting Roche November-10 July-20
Gantenerumab and solanezumab and JNJ-54861911 Anti-amyloid Monoclonal antibody, BACE inhibitor Remove amyloid/reduce amyloid production (DMT) NCT01760005 Recruiting Washington University, Eli Lilly, Roche, NIA, Alzheimer's Association December-12 December-23
Icosapent ethyl (IPE) Neuroprotective Purified form of the omega-3 fatty acid EPA Protect neurons from disease pathology NCT02719327 Recruiting VA Office of Research and Development, University of Wisconsin, Madison December-16 November-21
Insulin intranasal (Humulin) Metabolic Replace insulin in the brain Enhance cell signaling and neurogenesis (cognitive enhancer) NCT01767909 Active, not recruiting University of Southern California, NIA, ATRI, Wake Forest University January-14 December-18
ITI-007 Neurotransmitter based 5-HT2A antagonist, dopamine receptor modulator Improve neuropsychiatric symptoms (agitation) NCT02817906 Recruiting Intra-Cellular Therapies, Inc. June-16 August-18
JNJ-54861911 Anti-amyloid BACE inhibitor Reduce amyloid production (DMT) NCT02569398 Recruiting Janssen November-15 April-24
Methylphenidate Neurotransmitter based Dopamine reuptake inhibitor Improve neuropsychiatric symptoms (apathy) NCT02346201 Recruiting Johns Hopkins, NIA January-16 August-20
MK-8931 (verubecestat) Anti-amyloid BACE inhibitor Reduce amyloid production (DMT) NCT01953601 Active, not recruiting Merck November-13 March-21
MK-4305 (suvorexant) Neurotransmitter based Dual orexin receptor antagonist Improve neuropsychiatric symptoms (sleep disorders) NCT02750306 Recruiting Merck May-16 April-18
Nabilone Neurotransmitter based Cannabinoid (receptor agent) Improve neuropsychiatric symptoms (agitation) NCT02351882 Recruiting Sunnybrook Health Sciences Centre January-15 January-18
Octohydroaminoacridine succinate Neurotransmitter based Acetylcholinesterase inhibitor Improve acetylcholine signaling (cognitive enhancer) NCT03283059 Recruiting Shanghai Mental Health Center, Changchun-Huayang High-tech Co., Jiangsu Sheneryang High-tech Co. August-17 February-20
GV-971 (Sodium Oligo-mannurarate) Anti-amyloid Inhibit amyloid aggregation Remove amyloid plaque load (DMT) NCT02293915 Recruiting Shanghai Green valley Pharmaceutical April-14 September-18
Solanezumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT02008357 Active, not recruiting Eli Lilly, ATRI February-14 July-22
TRx0237 (LMTX) Anti-tau Tau protein aggregation inhibitor Reduce tau-mediated neuronal damager (DMT) NCT02245568 Recruiting, Extension TauRx Therapeutics August-14 September-17
TTP488 (azeliragon) Anti-amyloid, anti-inflammatory RAGE antagonist Reduce amyloid uptake in brain and lower inflammation in glial cells (DMT/cognitive enhancer) NCT02080364 Active, not recruiting vTv Therapeutics April-15 January-19
NCT02916056 Recruiting – EXT December-16 November-20
Zolpidem Neurotransmitter based Positive allosteric modulator of GABA-A receptors Improve neuropsychiatric symptoms (sleep disorders) NCT03075241 Recruiting Brasilia University Hospital October-16 December-18
  • Abbreviations: ATRI, Alzheimer's Therapeutic Research Institute; BACE, Beta-site Amyloid precursor protein Cleaving Enzyme; DMT, disease-modifying therapy; EPA, eicosapentaenoic acid; GABA, gamma-aminobutyric acid; NIA, National Institute on Aging; RAGE, receptor for advanced glycation end products. NOTE. Twenty-six agents in 35 phase III clinical trials currently ongoing as of January 30, 2018 according to clinicaltrials.gov. NOTE. Bolded terms represent new entries into the 2018 phase III pipeline.
  • Phase II/III trials.
Details are in the caption following the image

Mechanisms of action of agents in phase III.

There is a movement toward treating patients with milder forms of AD including cognitively normal individuals with evidence of amyloid pathology (by cerebrospinal fluid [CSF] measures or amyloid positron emission tomography [PET]) or who have genetic profiles that place them at high risk for developing AD (Table 2). In phase III, there were six prevention trials enrolling cognitively normal participants. There were 12 trials of patients with prodromal AD/mild cognitive impairment (MCI) or prodromal/mild AD; 14 trials of patients with mild-moderate AD; and three trials of patients with mild-moderate/severe AD.

Table 2. Prevention trial by phase
Phase Agent Trial Sponsor Means of defining risk for AD dementia
III Solanezumab A4 Eli Lilly Amyloid PET
II/III CAD106, CNP520 Generation S1 Novartis Homozygous APOE4
II/III CNP520 Generation S2 Novartis Amyloid PET or CSF
II/III Icosapent ethyl (IPE) BRAVE-EPA VA Office of Research and Development Parental history of AD and increased prevalence of APOE4 allele
II/III JNJ-54861911 Early Janssen Amyloid PET or CSF
II/III Gantenerumab, solanezumab, JNJ-54861911 DIAN-TU Eli Lilly, Roche, Janssen, NIA Family history of autosomal dominant AD
II Crenezumab GN28352 Genentech Presenilin-1 E280 A mutation
I/II Probucol DEPEND Douglas Mental Health University Family history of AD
I Telmisartan HEART Emory University Parental history of AD
  • Abbreviations: AD, Alzheimer's disease; APOE, apolipoprotein E; BRAVE-EPA, Brain Amyloid and Vascular Effects of Eicosapontaenoic Acid; DEPEND, Dosage and Etiology of Protocols Induced apoE to Negate Cognitive Deterioration; DIAN-TU, Dominantly Inherited Alzheimer Network-Treatment Unit; HEART, Health Evaluation of African Americans Using RAS Therapy; NIA, National Institute on Aging; PET, positron emission tomography.

Phase III trials involved a mean of 860 participants and had a mean duration of 1841 days or 263 weeks (including the recruitment and the treatment period). DMT trials were longer than trials of agents with other MOAs (2139 days or 306 weeks; 121 treatment weeks) and larger—including an average of 1066 participants. The mean duration of cognitive enhancer trials was 914 days or 131 weeks (26 treatment weeks), and they included an average of 600 participants. Trials of drugs for behavioral symptoms average 1119 days or 160 weeks (15 treatment weeks) and included a mean of 314 patients. For DMTs, the average duration of treatment exposure is 121 weeks; the mean period from trial initiation to primary completion date (final data collection date for primary outcome measure) is 239 weeks. This indicates that 118 weeks—nearly equal to the treatment period—is the average anticipated recruitment time. When examined by trial population, prevention trials are 420 weeks in duration; trials for patients with MCI/prodromal/prodromal-mild AD are 289 weeks in duration; and trials for patients mild-moderate AD are 235 weeks in duration. Planned recruitment periods for these three types of trials are 164, 161, and 116 weeks, respectively.

3.3 Phase II

In 2018, there are 75 trials involving 63 agents in phase II of the AD pipeline (Table 3). Sixteen trials involved patients with prodromal or prodromal and mild AD, 28 were trials for mild-moderate AD, one included patients with MCI and mild-moderate AD, one was a prevention trial, one included patients with MCI or healthy volunteers, and one trial was for severe AD. Of the symptomatic agent trials, one was for preclinical AD, seven were for prodromal mild AD, 16 were for mild-moderate AD, and three were for mild-moderate or severe AD.

Table 3. Agents currently in phase II of Alzheimer's disease drug development (as of January 30, 2018)
Agent Agent mechanism class Mechanism of action Therapeutic purpose Clinicaltrials.gov ID Status Sponsor Start date Estimated end date
AADvac1 Anti-tau Active immunotherapy Remove tau (DMT) NCT02579252 Active, not recruiting Axon Neuroscience March-16 June-19
ABBV-8E12 Anti-tau Monoclonal antibody Remove tau (DMT) NCT02880956 Recruiting AbbVie October-16 June-21
ANAVEX 2-73 Anti-tau, metabolic Sigma-1 receptor agonist (high affinity); muscarinic agonist (low affinity); GSK-3β inhibitor Improve cell signaling (cognitive enhancer) and reduce tau phosphorylation (DMT) NCT02244541 Active, not recruiting Anavex Life Sciences December-14 October-16
NCT02756858 Recruiting, extension Anavex Life Sciences March-16 November-18
AstroStem Regenerative Autologous adipose tissue derived mesenchymal stem cells Regenerate neurons NCT03117738 Recruiting Nature Cell Co. April-17 November-18
Atomoxetine Neurotransmitter based Norepinephrine reuptake inhibitor Improve neurotransmission (cognitive enhancer) and improve behavioral symptoms NCT01522404 Active, not recruiting Emory University, NIA March-12 June-18
AZD0530 (saracatinib) Metabolic, anti-tau Tyrosine kinase Fyn inhibitor Improve synaptic dysfunction (cognitive enhancer), reduce tau phosphorylation (DMT) NCT02167256 Active, not recruiting Yale University, ATRI, AstraZeneca December-14 December-17
BAC Undisclosed Undisclosed mechanism Undisclosed NCT02886494 Recruiting Charsire Biotechnology December-16 November-19
NCT02467413 Not yet recruiting Charsire Biotechnology, A2 Healthcare Taiwan Corporation December-17 December-17
BAN2401 Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT01767311 Active, not recruiting Eisai December-12 November-18
Benfotiamine Metabolic Synthetic thiamine (B1) Improve multiple cellular processes (cognitive enhancer) NCT02292238 Recruiting Burke Medical Research Institute, Columbia University, NIA, ADDF November-14 November-19
BI 425809 Neurotransmitter based Glycine transporter 1 inhibitor Facilitate NMDA receptor activity (cognitive enhancer) NCT02788513 Recruiting Boehringer Ingelheim August-16 September-20
BIIB092 Anti-tau Monoclonal antibody Remove tau (DMT) NCT03352557 Not yet recruiting Biogen February-18 September-20
Bryostatin 1 Metabolic, anti-amyloid Protein kinase C modulator Improve cellular processes (cognitive enhancer) and reduce amyloid pathology (DMT) NCT02431468 Active, not recruiting Neurotrope Bioscience November-15 May-17
Candesartan Neuroprotective, metabolic, anti-amyloid Angiotensin receptor blocker Improve vascular functioning and effects on amyloid pathology (DMT) NCT02646982 Recruiting Emory University June-16 September-21
CB-AC-02 (Placenta derived-MSCs) Regenerative Stem cell therapy Regenerate neurons NCT02899091 Not yet recruiting CHA Biotech Co. September-16 June-18
Cilostazol Neuroprotective, metabolic Phosphodiesterase 3 antagonist Regulate cAMP and improve synaptic function (cognitive enhancer) NCT02491268 Recruiting National Cerebral and Cardiovascular Center, Japan July-15 December-20
CPC-201 (donepezil/solifenacin combination) Neurotransmitter based Cholinesterase inhibitor + peripheral cholinergic antagonist Improve acetylcholine signaling (cognitive enhancer) NCT02549196 Active, not recruiting Allergan October-15 September-17
Crenezumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT01998841 Active, not recruiting Genentech, NIA Banner Alzheimer's Institute December-13 February-22
CT1812 Metabolic Sigma-2 receptor modulator Improve synaptic dysfunction (cognitive enhancer) NCT02907567 Recruiting Cognition Therapeutics September-16 May-17
DAOIB Neurotransmitter based NMDA receptor modulation Enhance NMDA activity (cognitive enhancer) NCT02239003 Recruiting Chang Gung Memorial Hospital, Taiwan January-12 December-17
Deferiprone Neuroprotective, anti-amyloid Iron chelating agent Reduce reactive oxygen species that damage neurons; effect on amyloid and BACE pathology (DMT) NCT03234686 Recruiting Neuroscience Trials Australia January-18 December-21
DHP1401 Neuroprotective, metabolic Affects cAMP activity Improve synaptic function (cognitive enhancer) NCT03055741 Recruiting Daehwa Pharmaceutical Co. December-16 September-18
Dronabinol Neurotransmitter based CB1 and CB2 endocannabinoid receptor partial agonist Improve neuropsychiatric symptoms (agitation) NCT02792257 Recruiting Mclean Hospital, Johns Hopkins University March-17 December-20
E2609 Anti-amyloid BACE inhibitor Reduce amyloid production (DMT) NCT02322021 Active, not recruiting Eisai, Biogen November-14 April-18
Formoterol Metabolic β2 adrenergic receptor agonist Effects on multiple cellular pathways (DMT) NCT02500784 Recruiting Palo Alto Veterans Institute for Research, Mylan, Alzheimer's Association January-15 July-18
GV1001 Metabolic, anti-amyloid Telomerase reverse transcriptase peptide vaccine Effects on multiple cellular pathways including amyloid pathology (DMT) NCT03184467 Recruiting GemVax & Kael June-17 June-19
hUCB-MSCs Regenerative Stem cell therapy Regenerate neurons NCT02054208 Recruiting Medipost Co. February-14 July-19
NCT01547689 Active, not recruiting Affiliated Hospital to Academy of Military Medical Sciences, China March-12 December-16
NCT02513706 Not yet recruiting South China Research Center May-16 October-19
NCT02672306 Not yet recruiting South China Research Center May-16 October-19
NCT02833792 Recruiting Stemedica Cell Technologies June-16 June-18
NCT03172117 Recruiting Medipost Co. May-17 December-21
ID1201 Anti-amyloid, metabolic, neuroprotective Phosphatidylinositol 3-kinase/Akt pathway activation Effects on multiple cellular pathways including amyloid metabolism (DMT) NCT03363269 Recruiting IlDong Pharmaceutical Co April-16 December-18
Insulin detemir (intranasal) Metabolic Increases insulin signaling in the brain Enhance cell signaling and growth (DMT) NCT01595646 Active, not recruiting Wake Forest School of Medicine, Alzheimer's Association November-11 March-17
Insulin glulisine (intranasal) Metabolic Increases insulin signaling in the brain Enhance cell signaling and growth (DMT) NCT02503501 Recruiting Health Partners Institute August-15 September-18
IONIS MAPTRx Anti-tau Microtubule-associated tau (MAPT) RNA inhibitor; antisense oligonucleotides Reduce tau production (DMT) NCT03186989 Recruiting Ionis Pharmaceuticals, Biogen June-17 February-20
JNJ-54861911 Anti-amyloid BACE inhibitor Reduce amyloid production (DMT) NCT02406027 Active, not recruiting, Extension Janssen July-15 October-22
Levetiracetam Metabolic Anticonvulsant Reduce neuronal hyperactivity (cognitive enhancer) NCT02002819 Recruiting University of California, San Francisco June-14 December-17
Liraglutide Metabolic, neuroprotective Glucagon-like peptide 1 receptor agonist Enhance cell signaling (cognitive enhancer) NCT01843075 Recruiting Imperial College London January-14 March-19
Lithium Neurotransmitter based Ion channel modulator Improve neuropsychiatric symptoms (agitation, mania, psychosis) NCT02129348 Recruiting New York State Psychiatric Institute, NIA June-14 April-19
LM11A-31-BHS Neuroprotective Targets the p75 neurotrophin receptor Improve synaptic functioning (cognitive enhancer) NCT03069014 Recruiting PharmatrophiX Inc., NIA February-17 October-19
L-Serine Neuroprotective Amino acid Stabilize protein misfolding (DMT) NCT03062449 Recruiting Dartmouth-Hitchcock Medical Center, Brain Chemistry Laboratories March-17 August-18
LY3002813 Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT03367403 Recruiting Eli Lilly December-17 December-20
LY3202626 Anti-amyloid BACE Inhibitor Reduce amyloid production (DMT)
NCT02791191 Recruiting Eli Lilly June-16 June-19
Methylene Blue Anti-tau Tau protein aggregation inhibitor Reduce neurofibrillary tangle formation (DMT) NCT02380573 Active, not recruiting Texas Alzheimer's Research and Care Consortium July-15 July-18
MLC901 Neuroprotective, anti-inflammatory Natural product consisting of several herbs Multiple cellular pathways (cognitive enhancer) NCT03038035 Recruiting National University Hospital, Singapore December-16 June-19
Montelukast buccal film Anti-inflammatory Leukotriene receptor antagonist Reduce inflammation (cognitive enhancer) NCT03402503 Not yet recruiting IntelGenx Corp. February-18 October-19
MP-101 Neuroprotective Enhances mitochondrial functioning Improve neuropsychiatric symptoms (psychosis) NCT03044249 Recruiting Mediti Pharma May-17 November-18
VX-745 (neflamapimod) Metabolic Selective p38 MAPK alpha inhibitor Affect multiple cellular processes including inflammation and cellular plasticity (DMT) NCT03402659 Recruiting EIP Pharma, VU University December-17 July-19
Nicotinamide (Vitamin B3) Anti-tau, neuroprotective Histone deacetylase inhibitor Tau-induced microtubule depolymerization (DMT) NCT03061474 Recruiting University of California, Irvine July-17 February-19
Nicotine transdermal Neurotransmitter based Nicotinic acetylcholine receptor agonist Enhance acetylcholine signaling (cognitive enhancer) NCT02720445 Recruiting University of Southern California, NIA, ATRI, Vanderbilt University January-17 December-19
Nilotinib Anti-tau, anti-amyloid Tyrosine kinase inhibitor Reduce amyloid and tau production (DMT) NCT02947893 Recruiting Georgetown University January-17 March-19
Octagam 10% Anti-amyloid 10% human normal immunoglobulin Remove amyloid (DMT) NCT03319810 Not yet recruiting Sutter Health October-17 October-18
ORM-12741 Neurotransmitter based Alpha-2c adrenergic receptor antagonist Improve neuropsychiatric symptoms (agitation) NCT02471196 Active, not recruiting Orion Corporation, Janssen August-15 December-17
Pimavanserin Neurotransmitter based 5-HT2A inverse agonist Improve neuropsychiatric symptoms (agitation) NCT03118947 Recruiting Acadia February-17 June-20
NCT02992132 Active, not recruiting Acadia November-16 February-18
Piromelatine Neurotransmitter based Melatonin receptor agonist; 5-HT 1A and 1D serotonin receptor agonist Enhance cellular signaling (cognitive enhancer) NCT02615002 Recruiting Neurim Pharmaceuticals November-15 March-18
Posiphen Anti-amyloid Selective inhibitor of APP production Reduce amyloid production (DMT) NCT02925650 Recruiting QR Pharma, ADCS March-17 December-18
Probucol Neuroprotective, anti-inflammatory Non-statin cholesterol reducing agent Induce APOE activity and improve synaptic functioning (cognitive enhancer) NCT02707458 Not yet recruiting Douglas Mental Health University Institute, Weston Brain Institute, McGill University April-16 May-18
Rasagiline Neuroprotective, metabolic, anti-amyloid Monoamine oxidase B inhibitor Enhance mitochondria activity and inactivate reactive oxygen species (cognitive enhancer), also effect on amyloid pathology (DMT) NCT02359552 Recruiting The Cleveland Clinic, Teva May-15 February-19
Riluzole Neuroprotective Glutamate receptor antagonist; glutamate release inhibitor Inhibit glutamate neurotransmission (cognitive enhancer) NCT01703117 Recruiting Rockefeller University November-13 November-19
RO7105705 Anti-tau Monoclonal antibody Remove tau (DMT) NCT03289143 Recruiting Genentech October-17 September-22
Rotigotine Neurotransmitter based Dopamine agonist Enhance dopamine neurotransmission (cognitive enhancer) NCT03250741 Recruiting I.R.C.C.S. Fondazione Santa Lucia June-16 June-18
S47445 Neurotransmitter based AMPA receptor agonist Enhance NMDA receptor activity (cognitive enhancer) NCT02626572 Active, not recruiting Servier February-15 December-17
Sargramostim (GM-CSF) Anti-amyloid, neuroprotective Synthetic granulocyte colony stimulator Stimulate innate immune system to remove amyloid pathology (DMT) NCT01409915 Active, not recruiting University of Colorado, Denver, The Dana Foundation March-11 December-17
S-equol Neuroprotective, anti-amyloid Estrogen receptor B agonist Improve synaptic functioning by competing with amyloid pathology (DMT) NCT03101085 Recruiting Ausio Pharmaceuticals, University of Kansas May-17 October-19
Simvastatin + L-Arginine + Tetrahydrobiopterin (SLAT) Neuroprotective, anti-amyloid HMG-CoA reductase inhibitor and antioxidant Reduce cholesterol synthesis thereby reducing amyloid production (DMT) NCT01439555 Active, not recruiting University of Massachusetts, Worcester November-11 December-17
STA-1 Neuroprotective Antioxidant properties of echinacoside Reduce oxidative stress (cognitive enhancer) NCT01255046 Not yet recruiting Sinphar Pharmaceuticals December-15 December-18
SUVN-502 Neurotransmitter based 5-HT6 antagonist Improve neuronal signaling (cognitive enhancer) NCT02580305 Recruiting Suven Life Sciences September-15 September-18
Telmisartan Neuroprotective, anti-inflammatory Angiotensin II receptor blocker, PPAR-gamma agonist Improve vascular functioning (DMT) NCT02085265 Recruiting Sunnybrook Health Sciences Centre, ADDF March-14 March-21
UB-311 Anti-amyloid Active immunotherapy Reduce amyloid (DMT) NCT02551809 Active, not recruiting United Neuroscience October-15 December-18
Valacyclovir Neuroprotective, anti-inflammatory Antiviral agent Protect against HSV-1/2 infection and inflammation (DMT) NCT02997982 Recruiting Umea University December-16 December-17
NCT03282916 Not yet recruiting New York State Psychiatric Institute, NIH, NIA December-17 August-22
Xanamema Neuroprotective Blocks 11-HSD1 enzyme activity Decrease cortisol production and neurodegeneration (DMT) NCT02727699 Recruiting Actinogen Medical, ICON Clinical Research March-17 March-19
  • Abbreviations: ADCS, Alzheimer's Disease Cooperative Study; ADDF, Alzheimer's Drug Discovery Foundation; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; APOE, apolipoprotein E; APP, amyloid precursor protein; ATRI, Alzheimer's Therapeutic Research Institute; BACE, Beta-site Amyloid precursor protein Cleaving Enzyme; cAMP, cyclic adenosine monophosphate; CB, cannabinoid; DMT, disease-modifying therapy; GM-CSF, granulocyte-macrophage colony-stimulating factor; GSK, GlaxoSmithKline; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme; HSD, hydroxysteroid dehydrogenase; HT, hydroxytriptamine; hUCB-MSCs, human umbilical cord-derived mesenchymal stem cells; MAPK, mitogen-activated protein kinase; NIA, National Institute on Aging; NMDA, N-methyl-D-aspartate; PPAR, peroxisome proliferator-activated receptor; SNRI, serotonin-norepinephrine reuptake inhibitors. NOTE. Sixty-three agents in 75 phase II clinical trials currently ongoing as of January 30, 2018 according to clinicaltrials.gov. NOTE. Bolded terms represent new entries into the 2018 phase II pipeline.
  • Phase I/II trials.

Of the 63 agents, there were 36 DMTs, 21 cognitive-enhancing agents, five drugs for behavioral symptoms, and one agent with an unknown MOA (Fig. 1; Table 3). Among the DMTs, 18 involved amyloid targets, nine addressed tau-related targets, one had a mechanism relevant to both amyloid- and tau-related targets, and eight had other MOAs (e.g., neuroprotection, metabolic, or anti-inflammatory). The DMTs include 11 immunotherapies (six addressing amyloid and five addressing tau). Of the DMTs, 12 are repurposed agents approved for use in another indication. There are eight trials involving stem cell therapies.

Of the drugs with amyloid targets, there were three Beta-site Amyloid percursor protein Cleavage Enzyme inhibitors, six immunotherapies, and two antiaggregation agents. Four agents involved antiaggregation and neuroprotection, and three agents were antiaggregation, neuroprotective, and metabolic agents. Fig. 3 shows the MOAs of agents in phase II.

Details are in the caption following the image

Mechanisms of action of agents in phase II.

Phase II trials are shorter in duration and smaller in terms of participant number than phase III trials: Phase II trials had a mean duration of 1221 days or 174 weeks (recruitment plus exposure period) and included an average of 156 participants in each trial. The average treatment period is 39 weeks.

3.4 Phase I

Phase I first-in-human trials are generally conducted in healthy volunteers and sometimes include a cohort of healthy elderly to begin to assess whether age affects the metabolism or excretion of the test agent. In some cases, phase I/IIa trials assess preliminary efficacy in patients with AD. Immunotherapies have the potential for long-term modification of the immune system, making participation of normal controls impermissible; these agents are typically assessed in patients with AD in phase I. Phase I includes single ascending dose trials assessing gradually increasing single doses and multiple ascending dose trials where individuals receive doses for 14–28 days 14-16. Single ascending dose and multiple ascending dose studies usually include cohorts of 6–12 individuals assigned to drug or placebo (commonly four on placebo and eight on drug in a 12 person cohort). Food effects on drug absorption and drug-drug interactions are also assessed in phase I studies.

There are 23 agents in 25 trials in phase I. Of these, there were 17 DMTs, four cognitive-enhancing agents, and two agents of unknown MOA. No agents addressing neuropsychiatric symptoms were included. Of the 17 DMTs in phase I in 2018 (Fig. 1; Table 4), five were immunotherapies directed at amyloid-related targets, four had tau-related MOAs, one addressed both amyloid and tau targets, and seven had other mechanisms (e.g., neuroprotection, metabolic, regenerative, or anti-inflammatory). The MOA was not identified for two agents.

Table 4. Agents currently in phase I of Alzheimer's disease drug development (as of 1/30/2018)
Agent Agent mechanism class Mechanism of action Therapeutic purpose Clinicaltrials.gov ID Status Sponsor Start date Estimated end date
Aducanumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT01677572 Active, not recruiting Biogen October-12 October-19
AGN-242071 Undisclosed Undisclosed Undisclosed NCT03316898 Not yet recruiting Allergan November-17 June-18
Allopregnanolone injection Metabolic, neuroprotective GABA receptor modulator Improve neurogenesis (cognitive enhancer) NCT02221622 Recruiting University of Southern California, NIA August-14 December-17
BIIB076 Anti-tau Monoclonal antibody Remove tau (DMT) NCT03056729 Recruiting Biogen February-17 April-19
Bisnorcymserine (BNC) Neurotransmitter based Butyrylcholinesterase inhibitor Acetylcholine neurotransmission (cognitive enhancer) NCT01747213 Recruiting NIA January-13 July-18
Crenezumab Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT02353598 Active, not recruiting Genentech February-15 September-23
hMSCs Regenerative Stem cell therapy Regenerate neurons NCT02600130 Recruiting Longeveron LLC August-16 October-19
Idalopirdine (Lu AE58054) Neurotransmitter based 5-HT6 receptor antagonist Improve neuronal signaling (cognitive enhancer) NCT03307993 Recruiting H. Lundbeck A/S September-17 January-18
Insulin aspart (Intranasal) Metabolic Increases insulin signaling in the brain Enhance cell signaling and growth (cognitive enhancer) NCT02462161 Recruiting Wake Forest School of Medicine, NIA, General Electric May-15 July-18
JNJ-63733657 Anti-tau Monoclonal antibody Remove tau (DMT) NCT03375697 Recruiting Janssen January-18 February-19
KHK6640 Anti-amyloid Anti-Aβ peptide antibody Remove amyloid (DMT) NCT03093519 Active, not recruiting Kyowa Hakko Kirin Co. March-17 June-18
Lu AF20513 Anti-amyloid Polyclonal antibody Remove amyloid (DMT) NCT02388152 Active, not recruiting H. Lundbeck A/S March-15 October-18
LY3002813 Anti-amyloid Monoclonal antibody Remove amyloid (DMT) NCT02624778 Recruiting Eli Lilly and Company December-15 June-20
LY3303560 Anti-tau Monoclonal antibody Remove tau (DMT) NCT02754830 Recruiting Eli Lilly and Company April-16 April-18
NCT03019536 Recruiting Eli Lilly and Company January-17 February-20
NDX-1017 Regenerative Hepatocyte growth factor Regenerate neurons NCT03298672 Recruiting M3 Biotechnology, ADDF, Biotrial Inc. October-17 June-18
NP001 Anti-inflammatory Immune regulator of inflammatory monocytes/macrophages Activate immune system (DMT) NCT03179501 Recruiting Neuraltus Pharmaceuticals, University of Hawaii September-17 December-17
NPT088 Anti-amyloid, Anti-tau IgG1 Fc-GAIM fusion protein Clear amyloid and tau (DMT) NCT03008161 Recruiting Proclara Biosciences December-16 December-18
Oxaloacetate (OAA) Metabolic Mitochondrial enhancer Enhance multiple cellular processes (DMT) NCT02593318 Recruiting University of Kansas Medical Center October-15 October-18
RGN1016 Undisclosed Undisclosed mechanism Undisclosed NCT02820155 Recruiting National Taiwan University June-16 February-17
Salsalate Anti-inflammatory Non-steroidal anti-inflammatory Reduce neuronal injury (DMT) NCT03277573 Recruiting University of California, San Francisco July-17 October-18
TAK-071 Neurotransmitter based Muscarinic M1 receptor modulator Enhance acetylcholine neurotransmission (cognitive enhancer) NCT02769065 Recruiting Takeda May-16 March-18
Telmisartan Neuroprotective, anti-inflammatory Angiotensin II receptor blocker, PPAR-gamma agonist Improve vascular functioning and effects on amyloid pathology (DMT) NCT02471833 Recruiting Emory University April-15 March-18
TPI-287 Anti-tau Microtubule protein modulator Reduce tau-mediated cellular damage (DMT) NCT01966666 Active, not recruiting University of California, San Francisco November-13 November-17
Vorinostat Neuroprotective Histone deacetylase inhibitor Enhance multiple cellular processes including tau aggregation and amyloid deposition (DMT) NCT03056495 Recruiting German Center for Neurodegenerative Diseases, University Hospital, Bonn, University of Gottingen September-17 October-19
  • Abbreviations: ADDF, Alzheimer's Drug Discovery Foundation; BACE, Beta-site Amyloid precursor protein Cleaving Enzyme; DMT, disease-modifying therapy; GABA, gamma-aminobutyric acid; hMSCs, human mesenchymal stem cells; NIA, National Institute on Aging; PPAR, peroxisome proliferator-activated receptor. NOTE. Twenty-three agents in 25 phase I clinical trials currently ongoing as of January 30, 2018 according to clinicaltrials.gov. NOTE. Bolded terms represent new entries into the 2018 phase I pipeline.

Phase I trials had an average duration of 982 days or 140 weeks (recruitment and treatment period) and included a mean number of 73 participants in each trial.

3.5 Trial sponsors

Across all trials, 56.6% are sponsored by the biopharma industry, 31.6% by Academic Medical Centers (with funding from National Institutes of Health, industry, or other entities), and 8.8% by others. Table 5 shows the sponsor of agents is different by trial phases.

Table 5. Trial sponsor for each phase of development
Sponsor N of trials (%)
Phase I Phase II Phase III
Biopharma 13 (52.0) 37 (49.3) 26 (74.3)
Academic Medical Centers 6 (24.0) 19 (25.3) 3 (8.6)
National Institutes of Health (NIH) 1 (4.0) 0 0
NIH and industry 0 2 (2.7) 0
Consortium/foundation 0 3 (4.0) 0
NIH and Academic Medical Centers 2 (8.0) 3 (4.0) 2 (5.7)
Industry and consortium/foundation 2 (8.0) 2 (2.7) 1 (2.9)
Other combinations 1 (4.0) 9 (12.0) 3 (8.6)

3.6 Biomarkers

Table 6 shows the biomarkers used as outcome measures in current phase II and phase III AD clinical trials as described in the federal website; not all trial descriptions in clinicaltrials.gov note if biomarkers are included in the trial.

Table 6. Biomarkers as outcome measures in phase II and phase III trials for agents in the Alzheimer's disease drug development pipeline (clinicaltrials.gov; January 30, 2018)
Biomarker N of trials (%)
Phase III Phase II
CSF amyloid 13 (37.1) 17 (22.7)
CSF tau 14 (40.0) 17 (22.7)
FDG-PET 5 (14.3) 10 (13.3)
vMRI 9 (25.7) 7 (9.3)
Plasma amyloid 2 (5.7) 5 (6.7)
Plasma tau 0 1 (1.3)
Amyloid PET 11 (31.4) 8 (10.7)
Tau PET 0 1 (1.3)
  • Abbreviations: CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose; PET, positron emission tomography; vMRI, volumetric magnetic resonance imaging.

AD biomarkers served as secondary outcomes in 18 phase III DMT trials and 20 phase II DMT trials. The most common biomarkers used were CSF amyloid, CSF tau, volumetric magnetic resonance imaging, and amyloid PET. One study reported using tau PET as a secondary outcome.

Amyloid biomarkers can be used to establish the presence of amyloid abnormalities and support the diagnosis of AD. Of the 25 phase III DMT trials, five trials used amyloid-PET as an entry criterion, two used CSF-amyloid, and seven used either amyloid-PET or CSF-amyloid. Ten out of 38 phase II DMT trials used amyloid-PET as an entry criterion, five used CSF-amyloid, and two used either amyloid-PET or CSF-amyloid. Eleven DMT trials in phase III and 21 in phase II did not require biomarker confirmation of AD for trial entry.

3.7 Comparison to 2017 pipeline

Compared with the 2017 pipeline, there are four new agents in phase III (AXS-05, octohydroaminoacridine succinate, escitalopram, and zolpidem), 14 in phase II (BIIB092, deferiprone, DHP1401, GV1001, ID1201, IONIS MAPTRx, LM11A-31-BHS, LY3002813, MLC901, MP-101, montelukast, VX-745, RO7105705, and rotigotine), and eight in phase I (NDX-1017, salsalate, vorinostat, BIIB076, JNJ-63733657, NP001, NPT088, and AGN-242071). Only one of the four new agents in phase III, (octohydroaminoacridine succinate) was previously present in phase II. Of the new agents in phase II, three of the 14 were previously noted in phase I (LY3002813, RO7105705, and VX-745). There are seven repurposed agents in phase III and 24 in phase II of the AD pipeline.

Eight agents listed in phase III in 2017 7 failed in clinical trials as of January 30, 2018. These included the 5-HT6 inhibitors idalopirdine and intepirdine 17. Three trials studying solanezumab (EXPEDITION studies) in prodromal/mild AD have been terminated as the study's primary end point was not met. The TOMMORROW studies (TOMM40301 and 303) studying pioglitazone were terminated in early 2018. Other trials failing to meet their primary outcomes included AC-1204, aripiprazole, MK-8931, nilvadipine and azeliragon. Two phase III trials for brexpiprazole as treatment for agitation in AD have completed and a third phase III trial is planned to begin in 2018.

Six agents were listed in phase II in 2017 and are not listed in any phase in 2018 and are no longer in development at this time (they could re-enter development). Trials of four agents were completed in 2017 and are not listed in the 2018 pipeline: BI409306, adenosine triphosphate, PQ912, and T-817MA. The trial status for NewGam 10% intravenous immunoglobulin changed to “unknown” because it has not been updated for more than 2 years on clinicaltrials.gov. Trials for the following five agents in phase I in 2017 were either completed or terminated and are not listed in the 2018 pipeline: BPN14770, PF-06751979, NGP 555, HTL0009936, and LY2599666.

4 Discussion

The Food and Drug Administration approved 46 new drugs (not including new doses, new formulations, or combinations of existing agents) in 2017. Six agents were approved for central nervous system disorders: edaravone for amyotrophic lateral sclerosis, cerliponase alfa for Batten disease, valbenazine for tardive dyskinesia, deutetrabenazine for chorea associated with Huntington's disease, ocrelizumab for relapsing-remitting and primary progressive multiple sclerosis, and safinamide for patients with Parkinson's disease experiencing “off” episodes (https://fda.gov/drugs/DevelopmentApprovalProcess). Three of these agents are DMTs (edaravone, cerliponase alfa, and ocrelizumab), and three are symptomatic therapies for amelioration of motor disorders. There were no new drug approvals for treatment of AD; none have been approved since 2003 5.

Review of the 2018 AD drug development pipeline shows that most agents have MOAs directed at disease modification (63% across all phases); 23% are cognitive-enhancing agents, and 12% are drugs directed at controlling neuropsychiatric symptoms (three agents have undisclosed MOAs). A few new agents have entered the pipeline when compared with the 2017 review 7: there are eight new agents in phase I, 14 in phase II, and four in phase III. Several agents have exited the pipeline including: five in phase I, five in phase II, and eight in phase III.

5-hyroxytryptamine-6 receptor antagonists have represented a substantial segment of the AD drug development pipeline with several agents exploring this cognitive enhancing mechanism. SAM-531 (also PF-052-12365) was assessed in a clinical trial of patients with mild-moderate AD not on therapy with memantine or a cholinesterase inhibitor. The trial was interrupted after an interim analysis suggested that all doses in the trial were futile. SB742457 (intepirdine) had evidence of efficacy in a phase II clinical trial 18 but failed to meet primary outcomes in a more recent phase III trial 19. Similarly, LU-AE-58054 (idalopirdine) achieved a significant benefit on the Alzheimer's Disease Assessment Scale–Cognitive Subscale 20 in phase II but failed to meet its primary outcomes in three phase III trials 17. Other agents in this class are currently in trials (Suvn-502) or have shown efficacy in preclinical models (PRX-07034Z) 21. Although recent trials have not demonstrated a drug-placebo difference with 5-HT6 antagonists, unresolved issues regarding the diagnosis of AD in trials not requiring biomarker confirmation, failure of decline of placebo groups in some trials, recruitment of atypical forms of AD (due to exclusion of standard of care with memantine and cholinesterase inhibitors), and dose preclude definitive conclusions about efficacy of this mechanism based on the existing trials.

Phosphodiesterases (PDEs) comprise a group of 11 families of enzymes that regulate cyclic adenosine monophosphate and cyclic guanosine monophosphate and are involved in neuroplasticity and memory consolidation 22-25. Several PDE inhibitors have been assessed in clinical trials of AD or MCI 26, and there are currently three PDE inhibitors in phase I and three in phase II. Three of the agents are PDE9 inhibitors, two are PDE 4 inhibitors, and 1 is a PDE 3 inhibitor. Trial outcomes will determine if PDE inhibitors produce cognitive benefit, if inhibition of one of the enzymes is more effective, and what population of patients is more benefited by treatment.

Biomarkers are important for the develeopment of both symptomatic and disease-modifying drugs. The use of biomarkers has become widespread in trials of DMTs, but biomarkers for symptomatic agents are more unusual. PDE9 inhibitors reduce CSF cyclic guanosine monophosphate, a second messenger that activates intracellular protein kinases. Measures of cyclic guanosine monophosphate have been used as a translational biomarker to establish target engagement and dose-response relationships in both humans and nonhuman primates 27, 28.

An increasing number of agents are directed at tau-related targets. Neurofibillary tangles, consisting of aggregates of phosphorylated microtubule-associated tau protein, are one of two major pathological hallmarks of AD 1, 2, 29. Seminal clinicopathological correlation studies conducted by Braak and Braak 30, demonstrating that neurofibrillary tangle burden more closely correlate with cognitive decline than amyloid plaque load, indicate that agents directed against aberrant tau protein could serve as important anti-AD agents. Normal tau protein goes through multiple biological transformations in AD, and strategies to target tau are diverse. Fig. 4 depicts tau's role in AD pathogenesis and shows the purported MOA of candidate therapies directed at tau biology.

Details are in the caption following the image

Site of action of anti-tau agents.

Tau remains an important but largely untested target for disease modification in AD. The first anti-tau programs were directed at reducing tau aggregation. The preliminary results of these studies were largely disappointing, and agents directed against tau aggregation are being re-evaluated 31. More recently, immunotherapy strategies have achieved ascendency in the pipeline with seven tau immunotherapies entering phase I or II testing. Among the unknowns for tau immunotherapy programs are: (1) which is the most appropriate tau epitope to target, (2) what site of activity is required for effectiveness (intraneuronal vs. extracellular), and (3) what level of target engagement is required for efficacy 32. The emergence of tau radioligands detectable by PET may provide key insights into these questions 33; this technology remains expensive, has limited availability, and understanding of its interpretation is evolving.

A concerning observation derived from this AD pipeline review is the lack of agents targeting the moderate to advanced stages of AD. Only 26 trials permit inclusion of participants with scores of 14 or less, and only 12 include participants with scores of 10 or less. Together, these studies intend to enroll only 1720 participants. With over 15 million people affected by AD dementia worldwide 34, there is an urgent need to develop more effective symptomatic treatments for moderate to advanced stage disease. The paucity of agents directed at this population represents a significant weakness of the AD drug development pipeline.

A challenge for AD drug development is the lack of surrogate biomarkers. Surrogate markers—measures of disease that can be substituted for a clinical end point (i.e., hemoglobin A1c in diabetes)—predict clinical outcomes and accelerate drug development 35. In the current AD landscape, there are few biomarkers and no accepted surrogate markers. The primary utility of existing AD biomarkers is to improve diagnostic accuracy 36, and these have been incorporated into current research criteria 37-39. Previous research shows that misdiagnose rates in AD clinical trials can exceed 20% 40 and could contribute importantly to trial failure. Diagnostic verification is particularly important in trials of DMTs. Review of the 2018 pipeline reveals that a surprisingly low percentage of trials of DMTs require diagnostic biomarkers for entry or as secondary outcomes. The development and use of biomarkers for AD clinical trials remain a crucial unmet goal for the field.

Successful drug development requires effective recruitment of clinical trial participants and efficient execution of clinical trials in addition to drugs that are produced by rigorous disciplined drug development processes. Challenges of recruitment have become especially acute as prevention trials have become more numerous. Participants are cognitively normal, are not health-care seeking, and may not know their risk status. There are currently several efforts in the AD drug development arena that address these critical issues. Online registries are increasingly used to identify and educate possible trial participants. These registries vary in nature, with some collecting a minimum of information (age, interest in trials) and others collecting extensive cognitive, clinical, and demographic information 41, 42. The over-arching purpose of these registries is to identify interested individuals that can be assessed for appropriateness for clinical trials and enlist them if they have the prespecified biomarker profile required for trial participation. Optimizing the use of registries to enhance trial recruitment will be among the important lessons from studying the current registries.

Clinical trial efficiency can be improved with more rapid clinical trial site start up (facility review, budget acceptance, and so on), pre-certified raters, use of a single institutional review board, and rapid recruitment of appropriate participants. Addressing each of these aspects of efficient trial site function can help accelerate clinical trial execution and drug development. In the United States, the Global Alzheimer Platform, the National Institutes of Health, the Alzheimer's Association TrialMatch program, the Alzheimer's Clinical Trial Consortium, and other initiatives are striving to improve trial efficiency 41, 43. In Europe, the European Prevention of Alzheimer's Dementia program is part of the Innovative Medicines Initiative and is addressing many of the same issues, especially as they apply to phase II clinical trials 44.

Clinicaltrials.gov has shortcomings that are important to recognize when considering the data presented here. The information provided may not represent the entire universe of AD drug development: not all phase I trials, especially those conducted outside the United States, may be registered in the database and our phase I data may underestimate the number of phase I candidates. Trials are required to be registered within 21 days of entering the first patient into the trial 9, but not all sponsors may meet this deadline. The Food and Drug Administration Modernization Act requires all trials to be registered, and the International Committee of Medical Journal Editors requires trials to be registered to be eligible for publication 45; recent reviews show a high rate of compliance with the registration rules 10-12. The clinicaltrials.gov database is the most comprehensive of any existing trial database and provides credible data for drawing conclusions about AD drug development. We stopped entering new data into our database at a time that allowed submission, peer review, and publication; the data presented are a few months out-of-date (data collection stopped on January 30, 2018).

This review of the 2018 AD drug development pipeline demonstrates the continuing commitment of the scientific community, pharmaceutical industry, and regulatory agencies to develop new drugs of AD. Trends evidenced in the 2018 pipeline include more trials in preclinical and prodromal populations and greater use of biomarkers to support the diagnosis of AD. Every trial is a learning opportunity and informs the drug development process. Success depends on establishing targets critical to the disease process, developing efficacious agents, and conducting trials rigorously.

Research in Context

  1. Systematic review: New treatments for Alzheimer's disease (AD) are urgently needed. The drug development process progresses from phase I to phase II and phase III. Trials are listed on the federal government database clinicaltrials.gov.
  2. Interpretation: A study of the clinicaltrials.gov database reveals that there are 112 agents in the pipeline; of these, 26 are in phase III, 63 in phase II, and 23 in phase I. More tau-related targets are included for drugs in the current pipeline than previously. Clinical trial organizations are evolving to support clinical trial performance.
  3. Future directions: More agents are required in the pipeline to assure successful development of new treatments for AD. The number and success of pipeline agents depends on basic science research and efficient trials.

Acknowledgments

J.C. acknowledges the funding from the National Institute of General Medical Sciences (Grant: P20GM109025) and support from Keep Memory Alive.

Disclosures: J.C. has provided consultation to Acadia, Accera, Actinogen, ADAMAS, Alkahest, Allergan, Alzheon, Avanir, Axovant, Axsome, BiOasis Technologies, Biogen, Boehringer-Ingelheim, Eisai, Genentech, Grifols, Kyowa, Lilly, Lundbeck, Merck, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Servier, Suven, Takeda, Toyama, and United Neuroscience companies. G.L. and A.R. have no disclosures. K.Z. is an employee of the Global Alzheimer Platform.