Repurposed agents in the Alzheimer's disease drug development pipeline.

This study is based on the activity of clinical trials reported on ClinicalTrials.gov . By US law, all clinical trials conducted within the US must be registered within 21 days of the enrollment of the first participant [ 15 , 16 ]. ClinicalTrials.gov is a comprehensive and valid data source for the study of clinical trials conducted in the US. Most, but not all, non-US trials are registered on clinicaltrials.gov ; Phase I trials conducted outside the US are often not registered and our findings may underrepresent the agents populating global Phase I efforts. We used a previously constructed trial database that included the data of interest [ 10 – 14 ] and report on all trials currently testing repurposed agents in Phases I, II, and III. The results reported here are based on trials registered on ClinicalTrials.gov as of February 27, 2020. We used ClinicalTrials.gov labeling and included trials that were recruiting, active but not recruiting, enrolling by invitation, and not yet recruiting. We do not include trials of stem cell therapies among the interventions reviewed. Our focus on repurposed agents places an importance on drugs with an FDA-approved indication(s). Agents were considered to be repurposed based on the information recorded on Drugs@FDA ( fda.gov/drugsatfda ), a US government database containing drug products approved since 1939 that is updated daily [ 17 ]. The approved use for each drug was determined by the most recent label provided by Drugs@FDA. Some drugs have more than one FDA-approved indication, and this is noted. Agents were further classified based on the therapeutic area for which each drug is prescribed as determined by its approved indication. Based on this classification, we examined the therapeutic area origin of agents being studied across all AD trials. Some agents are being studied in multiple ongoing trials; we defined these agents as “unique” agents. Varieties of a particular compound seen in two or more trials (i.e., dosing, routes of administration) were noted. Some trials are investigating multiple repurposed drugs in separate treatment arms (e.g., telmisartan vs perindopril) or in combination (e.g., losartan, amlodipine, and atorvastatin as a single treatment). For the purposes of this study, we treat the former as separate therapeutic trial agents; the latter is considered a single agent with respect to its clinical trial because the intent of the trial is to study the effects of the fixed combination as a single therapy. A drug’s putative mechanism of action (MOA) in AD was determined from the information on ClinicalTrials.gov or from a comprehensive review of the literature for the specific agent. We grouped the mechanisms into disease-modifying therapies (DMTs) or symptomatic agents. The latter is further divided into cognitive-enhancers or those that address neuropsychiatric and behavioral symptoms. We identified an agent as a DMT when the purpose of the intervention was to modify the underlying disease biology and to delay the onset or slow the progression of the disease. DMTs were divided into those targeting amyloid-related targets, tau-related mechanisms, and those with “other” mechanisms (i.e., neuroprotection, anti-inflammation, metabolic effects). The distinction between symptomatic agents and DMTs can be arbitrary and some agents may have both properties. For the purposes of this study, we chose what appears to be the principal MOA. We retrospectively compare current repurposing trial data with historical data from previous AD pipeline reviews, starting from 2016 onward [ 10 – 14 ]. We used identical methodology to ascertain inclusion of clinical trials as detailed above. Our study analyzes parallel activity between the US and European AD pipelines using trial information reported on the EUCTR. This public register enables access to data from the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, which contains protocols and results of studies conducted in the European Union (EU) or the European Economic Area (EEA). We used EUCTR to query Phase I, Phase II, and Phase III AD trials with ongoing status recorded as of February 27, 2020. We distinguish clinical trials exclusive to the EU/EEA from overlap studies running concurrently in the US.

There are 58 total repurposed drugs in 53 clinical trials as reported on ClinicalTrials.gov. We identified 15 agents in 12 trials in Phase III, 33 agents in 32 trials in Phase II, and 10 agents in nine trials in Phase I. Of these trials, six agents were in Phase II/III trials and two agents were in Phase I/II trial. Several trials have more than one agent; some drugs are being studied across multiple trials. Analysis of the FDA-approved indications of all repurposed drugs in the pipeline showed that 20% are hematologic-oncologic agents, 18% cardiovascular agents, 14% are psychiatric agents, 12% are antidiabetic treatments, 10% are drugs for other neurologic disorders, and the remaining 26% of drugs are derived from other therapeutic area categories. Repurposed psychiatric drugs in Phase III trials represent 50% of all agents being assessed for the treatment of neuropsychiatric symptoms in AD. Half of all cardiovascular agents under study are in Phase III trials. The majority of the pipeline’s hematologic-oncologic, antidiabetic, and neurologic agents are in Phase II trials (70, 67, and 67%, respectively). Phase II has more repurposed agents than Phase I and Phase III combined. Figure  1 shows the classification of all repurposed drugs by FDA-approved indications within their respective clinical phases. Fig. 1 Classification of repurposed agents by their FDA-approved indications ( ClinicalTrials.gov as of February 27, 2020) Classification of repurposed agents by their FDA-approved indications ( ClinicalTrials.gov as of February 27, 2020) Review of the AD-related MOAs of all agents shows that 78% are being developed as DMTs, 16% are symptomatic agents addressing neuropsychiatric and behavioral changes, and 7% are cognitive enhancers (Table  1 ). Escitalopram is being investigated separately as a cognitive enhancer in Phase I and as a neuropsychiatric agent in Phase III. Among DMT trials, the agents are derived primarily from hematologic-oncologic, cardiovascular, and antidiabetic indications (26, 18, and 16%, respectively). In contrast, symptomatic agents are derived mostly from treatments addressing psychiatric illness (50%). Figure  2 shows the repurposed agents’ AD-related MOAs. Table 1 Alzheimer’s disease-related mechanisms of action of repurposed agents in the pipeline (ClinicalTrials.gov as of February 27, 2020) Approved therapeutic area Disease-modifying therapies Cognitive enhancers Behavioral symptoms Behavioral + cognitive symptoms Total # of agents (%) Hematologic-oncologic 10 – – – 10 (20.0) Cardiovascular 7 1 1 – 9 (18.0) Psychiatric 1 1 4 1 7 (14.0) Antidiabetic 6 – – – 6 (12.0) Neurologic 3 – 2 – 5 (10.0) Infectious disease 3 – – – 3 (6.0) Anti-inflammatory 2 – – – 2 (4.0) Genetics 1 – – – 1 (2.0) Cannabinoid – – 1 – 1 (2.0) Hormonal 1 – – – 1 (2.0) Immunologic 1 – – – 1 (2.0) Alkaloid – 1 – – 1 (2.0) Pulmonary 1 – – – 1 (2.0) Nutraceutical 1 – – – 1 (2.0) Vitamin 1 – – – 1 (2.0) TOTAL 38 3 8 1 50 (100.0) Fig. 2 Percentage of repurposed agents currently under study by mechanisms of action ( ClinicalTrials.gov as of February 27, 2020) Alzheimer’s disease-related mechanisms of action of repurposed agents in the pipeline (ClinicalTrials.gov as of February 27, 2020) Percentage of repurposed agents currently under study by mechanisms of action ( ClinicalTrials.gov as of February 27, 2020) There are 50 unique repurposed drugs (defined as drugs represented at least once from the 58 total in the pipeline) that are under study among all AD pipeline trials. Twenty percent are hematologic-oncologic agents, 18% are cardiovascular agents, 14% are psychiatric agents, 12% are antidiabetic agents, 10% are neurologic drugs, and the remaining 26% of treatments were used in other categories. Figure  3 provides a graphical summary of the classifications of all unique repurposed agents represented in the current AD pipeline. Fig. 3 Classification of the therapeutic areas of repurposed agent currently under study ( ClinicalTrials.gov as of February 27, 2020) Classification of the therapeutic areas of repurposed agent currently under study ( ClinicalTrials.gov as of February 27, 2020) The agent most represented among all trials is levetiracetam (four Phase II trials, one Phase III trial). Telmisartan, montelukast, escitalopram, and valacyclovir are each in multiple Phase II and Phase III trials. A propriety low-dose formulation of levetiracetam (AGB101, which is 1/15th of the original dose) is being investigated in Phase II and Phase III trials. In Phase III trials, there are 15 repurposed agents in 12 trials (Table  2 ); this represents one-third of all Phase III trials in the AD pipeline [ 14 ]. These include eight DMTs, one cognitive-enhancer, and six agents addressing behavioral symptoms. Among DMT agents, one had amyloid-related targets, five had anti-inflammatory MOAs, four were considered metabolic, and two were neuroprotective agents. Table 2 Repurposed agents currently in Phase III in the Alzheimer’s disease development pipeline (as of February 27, 2020) Agent name Phase Agent mechanism class Therapeutic purpose under study Drug class FDA-approved indication(s) Therapeutic field ClinicalTrials.gov ID(s) (EudraCT ID) ALZT-OP1a, ALZT-OP1b (cromolyn with and without ibuprofen) III Anti-amyloid, anti-inflammatory Reduce neuronal damage; mast cells may also play a role in amyloid pathology (DMT) Mast cell stabilizer Bronchial asthma; mastocytosis Pulmonary NCT02547818 (2015-002147-34) Amlodipine II/III Anti-inflammatory, metabolic Vascular risk reduction to preserve cognitive function (DMT) Calcium channel blocker Hypertension; coronary artery disease Cardiovascular NCT02913664 Atorvastatin II/III Anti-inflammatory, metabolic Vascular risk reduction to preserve cognitive function (DMT) Statin Adjunct therapy for myocardial infarction, revascularization procedure, angina Cardiovascular NCT02913664 AXS-05 (DM + Bupropion) II/III Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Norepinephrine-dopamine reuptake inhibitor Major depressive disorder; easonal affective disorder; smoking cessation Psychiatric NCT03226522 Escitalopram III Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Selective serotonin reuptake inhibitor Major depressive disorder; generalized anxiety disorder Psychiatric NCT03108846 Guanfacine III Neurotransmitter-based Modulation of noradrenergic deficit (cognitive enhancer) Alpha-receptor agonist Attention deficit hyperactivity disorder Cardiovascular NCT03116126 Icosapent ethyl II/III Neuroprotective Protect neurons from disease pathology (DMT) Purified w-3 fatty acid (eicosapentaenoic acid) Hypertriglyceridemia Cardiovascular NCT02719327 Levetiracetam (AGB101) III Neuroprotective Decrease amyloid-induced neuronal hyperactivity (DMT) Anticonvulsant Adjunct therapy for partial-onset seizures; juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures Neurologic NCT03486938 Losartan II/III Anti-inflammatory, metabolic Vascular risk reduction to preserve cognitive function (DMT) Angiotensin II receptor blocker Hypertension; diabetic neuropathy; risk reduction of stroke Cardiovascular NCT02913664 Masitinib III Anti-inflammatory Activity on mast cells, modulation of inflammatory processes (DMT) Selective tyrosine kinase inhibitor Mast cell tumor (veterinary) Hematologic-oncologic NCT01872598 (2010-021218-50) Metformin II/III Metabolic Improve insulin sensitivity, may improve cognition (DMT) Insulin sensitizer (biguanide) Type 2 diabetes Antidiabetic NCT04098666 Methylphenidate III Neurotransmitter-based Improve neuropsychiatric symptoms (apathy) Stimulant Attention deficit hyperactivity disorder Psychiatric NCT02346201 Mirtazapine III Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Tetracyclic antidepressant Major depressive disorder Psychiatric NCT03031184 Zolpidem III Neurotransmitter-based Improve neuropsychiatric symptoms (sleep disorders) Sedative-Hypnotic Insomnia Neurologic NCT03075241 Zopiclone III Neurotransmitter-based Improve neuropsychiatric symptoms (sleep disorders) Sedative-Hypnotic Insomnia Neurologic NCT03075241 Abbreviations : DMT disease-modifying therapy, DM dextromethorphan Repurposed agents currently in Phase III in the Alzheimer’s disease development pipeline (as of February 27, 2020) Abbreviations : DMT disease-modifying therapy, DM dextromethorphan Therapeutic areas represented among the repurposed agents included five cardiovascular drugs, four with psychiatric indications, three neurological drugs, one hematologic-oncologic agent, one antidiabetic agent, and one pulmonary agent. Among these drugs, sedative-hypnotics were the most common. In Phase III, there were two prevention trials with cognitively normal (preclinical) participants; three trials of patients with prodromal AD/mild cognitive impairment (MCI); five trials of patients with mild to moderate AD; and two trials of patients with mild to moderate/severe AD. Phase II of the AD pipeline has 32 trials involving 33 repurposed agents (Table  3 ); this is 44% of all AD trials in Phase II [ 14 ]. Of the repurposed agents, there were 27 DMTs, one cognitive-enhancing agent, and three drugs for behavioral symptoms. Among the DMTs, three involve amyloid targets, one addresses tau-related targets, one has a mechanism relevant to both amyloid- and tau-related targets, and 22 have other MOAs (e.g., neuroprotection, metabolic, or anti-inflammatory). Of the symptomatic agents, all four are neurotransmitter-based. Table 3 Repurposed agents currently in Phase II in the Alzheimer’s disease development pipeline (as of February 27, 2020) Agent name Phase Agent mechanism class Therapeutic purpose under study Drug class FDA-approved indication(s) Therapeutic field ClinicalTrials.gov ID(s) (EudraCT ID) Benfotiamine II Metabolic Improve multiple cellular processes; minimize decline in glucose utilization (DMT) Synthetic thiamine Diabetic nephropathy; type 2 diabetes Antidiabetic NCT02292238 Candesartan II Anti-amyloid, neuroprotective, metabolic Improve vascular function and reduce amyloid (DMT) Angiotensin II Receptor Blocker Hypertension; heart failure Cardiovascular NCT02646982 Cilostazol II Neuroprotective Reduce accumulation of amyloid and reduce tau phosphorylation; improve cerebral circulation (DMT) Antiplatelet Intermittent claudication Hematologic-oncologic NCT02491268 Dapagliflozin I/II Metabolic Improve insulin sensitivity (DMT) Sodium-glucose co-transporter 2 inhibitor Adjunct therapy for type 2 diabetes Antidiabetic NCT03801642 Daratumumab II Anti-inflammatory Broad range immunomodulatory effects; regulate microglia (DMT) Human antibody targeting CD38 Multiple myeloma Hematologic-oncologic NCT04070378 Dasatinib + Quercetin (Combo) I/II Anti-inflammatory Senolytic therapy approach to reduce senescent cells and tau aggregation (DMT) Tyrosine kinase inhibitor + antioxidant/anti-inflammatory (Flavonoid) Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase Hematologic-oncologic NCT04063124 Deferiprone II Anti-Amyloid, neuroprotective Reduce reactive oxygen species that damage neurons; effect on amyloid and BACE pathology (DMT) Iron chelator Iron overload (thalassemia syndromes) Hematologic-oncologic NCT03234686 Dronabinol II Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Cannabinoid Anorexia (associated with AIDS); nausea/vomiting (associated with chemotherapy) Cannabinoid NCT02792257 Insulin glulisine II Metabolic Enhance cell signaling and growth; promote neuronal metabolism (DMT) Insulin Diabetes Antidiabetic NCT02503501 Lenolidomide II Anti-inflammatory Reduce inflammatory cytokines (TNF-a, IL-6, IL-8); reduce inflammatory and AD-associated biomarkers; improve cognition (DMT) Anti-neoplastic Multiple myeloma Hematologic-oncologic NCT04032626 Levetiracetam II Neuroprotective Reduce amyloid induced neuronal hyperactivity (DMT) Anticonvulsant Adjunct therapy for partial-onset seizures; juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures Neurologic NCT03489044 (2016–003109-32) Levetiracetam II Neuroprotective Reduce amyloid induced neuronal hyperactivity (DMT) Anticonvulsant Adjunct therapy for partial-onset seizures; juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures Neurologic NCT02002819 Levetiracetam II Neuroprotective Reduce amyloid induced neuronal hyperactivity (DMT) Anticonvulsant Adjunct therapy for partial-onset seizures; juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures Neurologic NCT03875638 Levetiracetam (AGB101) II Neuroprotective Reduce amyloid induced neuronal hyperactivity (DMT) Anticonvulsant Adjunct therapy for partial-onset seizures; juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures Neurologic NCT03461861 Liraglutide II Metabolic Enhance cell signaling; improve CNS glucose metabolism (DMT) Glucagon-like peptide-1 agonist Adjunct therapy for type 2 diabetes; risk reduction of major cardiovascular events Antidiabetic NCT01843075 (2013-000962-13) Lithium II Neurotransmitter-based Improve neuropsychiatric symptoms (agitation/aggression with or without psychosis) Antimanic Bipolar disorder Psychiatric NCT02129348 Leuprolide depot II Metabolic Alleviates negative effects of elevated GnRH and gonadtropins on the brain (DMT) Gonadotropin-releasing hormone agonist Endometriosis; uterine leiomyomata Hormonal NCT03649724 Montelukast (buccal film) II Anti-inflammatory Reduce inflammatory pathways (neuronal injury, blood-brain barrier integrity, amyloid-ß accumulation); effect on cognition and AD biomarkers (DMT) Leukotriene receptor antagonist Asthma; exercise-induced bronchoconstriction; allergic rhinitis Anti-inflammatory NCT03402503 Montelukast (tablet) II Anti-inflammatory Reduce inflammatory pathways that mediate neuronal injury, blood-brain barrier integrity, amyloid-ß accumulation (DMT) Leukotriene receptor antagonist Asthma; exercise-induced bronchoconstriction; allergic rhinitis Anti-inflammatory NCT03991988 Nicotinamide II Anti-tau, neuroprotective Reduce tau-induced microtubule depolymerization; reduce phosphorylation of tau (DMT) Vitamin B3 Pellagra Vitamin NCT03061474 Nicotine (transdermal patch) II Neurotransmitter-based Enhance acetylcholine signaling (cognitive enhancer) Alkaloid Smoking cessation withdrawal symptoms Alkaloid NCT02720445 Nilotinib II Anti-amyloid, anti-tau Autophagy enhancer; promotes clearance of amyloid and tau proteins (DMT) Tyrosine kinase inhibitor Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase Hematologic-oncologic NCT02947893 Perindopril II Neuroprotective, anti-inflammatory Improves vascular functioning (DMT) Angiotensin-converting-enzyme inhibitor Essential hypertension; stable coronary artery disease Cardiovascular NCT02085265 Prazosin II Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Alpha-receptor antagonist Hypertension Cardiovascular NCT03710642 Rifaximin II Anti-inflammatory Improve cognition and function by lowering blood ammonia; lower circulatory pro-inflammatory cytokines secreted by harmful gut bacteria (DMT) Non-systemic antibiotic Traveler’s diarrhea; overt hepatic encephalopathy; irritable bowel syndrome (diarrhea subtype) Infectious disease NCT03856359 Riluzole II Neuroprotective Reduce glutamate-mediated excitotoxicity (DMT) Benzothiazole Amyotrophic lateral sclerosis Neurologic NCT01703117 Sagramostim II Anti-amyloid, neuroprotective Stimulates innate immune system to remove amyloid pathology; increase neuronal connectivity (DMT) Human granulocyte-macrophage colony-stimulating factor Bone marrow stimulation Hematologic-oncologic NCT01409915 Sodium phenylbutyrate II Neuroprotective Blocks nerve cell death and modulates neuroinflammation (DMT) Anti-hyperammonemia Adjunct for chronic urea cycle disorders Genetics NCT03533257 Tacrolimus II Neuroprotective Prevents amyloid-ß dendritic spine loss; normalizes cranial nerve activity in the brain (DMT) Calcineurin inhibitor Prevent rejection of organ transplants Immunologic NCT04263519 Telmisartan II Neuroprotective, anti-inflammatory Improves vascular functioning (DMT) Angiotensin II Receptor Blocker Hypertension; diabetic neuropathy; risk reduction of stroke Cardiovascular NCT02085265 Thiethylperazine II Anti-amyloid Activates transport protein ABCC1 and enhances transport amyloid-ß peptides from the brain into the blood (DMT) Phenothiazine Nausea/vomiting Neurologic NCT03417986 (2014-000870-20) Valacyclovir II Neuroprotective, anti-inflammatory Reduce amyloid-ß aggregation by preventing overproduction of amyloid in response to infection (DMT) Antiviral (nucleoside analog) Herpes labialis; genital herpes Infectious disease NCT03282916 Valacyclovir II Neuroprotective, anti-inflammatory Reduce amyloid-ß aggregation by preventing overproduction of amyloid in response to infection (DMT) Antiviral (nucleoside analog) Herpes labialis; genital herpes Infectious disease NCT02997982 Abbreviation : DMT disease-modifying therapy Repurposed agents currently in Phase II in the Alzheimer’s disease development pipeline (as of February 27, 2020) NCT03489044 (2016–003109-32) Abbreviation : DMT disease-modifying therapy Therapeutic areas of Phase II repurposed agents comprise hematologic-oncologic agents (seven), neurologic drugs (six), cardiovascular drugs (four), antidiabetic agents (four), and other classes (e.g., cannabinoid, alkaloid; 12 total). Anticonvulsants were the most represented drug class in Phase II. There is one prevention trial; 19 trials of patients with prodromal/MCI or prodromal/mild-AD; 11 trials in mild-moderate AD; and one trial of patients with mild-moderate/severe AD. Among DMT trials, there is one prevention trial with cognitively normal participants, 17 for prodromal/mild AD, and eight for participants with mild-moderate AD. There are ten repurposed agents among nine Phase I trials (Table  4 ), which is 33% of Phase I trials in the pipeline [ 14 ]. Of these, there are eight DMTs and two cognitive enhancers. No agents addressing neuropsychiatric symptoms are represented in the Phase I pipeline. Of the DMTs in Phase I, one agent is directed at amyloid-related targets while seven have other MOAs (e.g., neuroprotection, metabolic, or anti-inflammatory). No tau-related repurposed agents are under investigation in Phase I of the current pipeline. Table 4 Repurposed agents currently in Phase I in the Alzheimer’s disease development pipeline (as of February 27, 2020) Agent name Phase Agent mechanism class Therapeutic purpose under study Drug class FDA-approved indication(s) Therapeutic field ClinicalTrials.gov ID(s) Allopregnanolone (Brexanolone) I Neuroprotective, metabolic Enhanced neurogenesis slow hippocampal atrophy; improve synaptic connectivity (DMT) GABA-A receptor modulator; neuroactive steroid (antidepressant) Postpartum depression Psychiatric NCT03748303 BDPP (Bioactive Dietary Polyphenol Preparation) I Neuroprotective Prevents amyloid and tau aggregation (DMT) Polyphenol Dietary supplement Nutraceutical NCT02502253 Dabigatran I Neuroprotective Reduce neurovascular damage (DMT) Anticoagulant Reduce risk of stroke; embolism associated with atrial fibrillation, deep venous thrombosis, pulmonary embolism Hematologic-oncologic NCT03752294 Efavirenz I Anti-amyloid Increase cholesterol removal and enhance amyloid reduction (DMT) Non-nucleoside reverse-transcriptase inhibitor HIV/AIDS Infectious disease NCT03706885 Escitalopram I Neurotransmitter-based Increase neurotransmission (cognitive enhancer) Selective serotonin reuptake inhibitor Major depressive disorder; generalized anxiety disorder Psychiatric NCT03274817 Empagliflozin I Metabolic Increase ketone levels in the brain; improve neuronal health and delay onset and progression of cognitive impairment (DMT) Sodium-glucose co-transporter 2 inhibitor Adjunct therapy for type 2 diabetes Antidiabetic NCT03852901 Salsalate I Anti-inflammatory Reduce neuronal injury (DMT) Non-steroidal anti-inflammatory drug Rheumatoid arthritis; osteoarthritis Anti-inflammatory NCT03277573 Telmisartan I Neuroprotective, anti-inflammatory Improve vascular functioning and effects on amyloid pathology (DMT) Angiotensin II Receptor Blocker Hypertension; diabetic neuropathy; risk reduction of stroke Cardiovascular NCT02471833 Venlafaxine I Neurotransmitter-based Increase neurotransmission (cognitive enhancer) Serotonin-norepinephrine reuptake inhibitor Major depressive disorder; general anxiety disorder; seasonal affective disorder; panic disorder Psychiatric NCT03274817 Vorinostat I Neuroprotective Multiple cellular processes including tau aggregation and amyloid deposition (DMT) Histone deacetylase inhibitor (anticancer) Cutaneous T-cell lymphoma Hematologic-oncologic NCT03056495 Abbreviations: DMT, disease modifying therapy Repurposed agents currently in Phase I in the Alzheimer’s disease development pipeline (as of February 27, 2020) Abbreviations: DMT, disease modifying therapy In Phase I, repurposed agents include three psychiatric drugs, two hematologic-oncologic agents, one cardiovascular drug, one antidiabetic agent, and three agents in other drug classes (e.g., anti-inflammatory drug, infectious disease agent). Across all trials of repurposed agents, 9% are sponsored by the biopharma industry, 79% by Academic Medical Centers (with funding from the National Institutes of Health, industry, and/or other entities such as a consortium or a philanthropic foundation), and 11% by others. Table  5 shows sponsors for each phase of development. Table 5 Trial sponsor for repurposed agents by phase of drug development (as of February 27, 2020) Sponsor Phase I Phase II Phase III Total (%) Academic Medical Centers 6 14 4 24 (45.3) Biopharma 0 2 3 5 (9.4) NIH 1 0 0 1 (1.9) NIH and Academic Medical Centers 0 4 2 6 (11.3) NIH and consortium 0 1 0 1 (1.9) NIH and Industry 0 0 1 1 (1.9) Academic Medical Centers and Industry 0 2 0 2 (3.8) Academic Medical Centers and Foundation 1 4 0 5 (9.4) Academic Medical Centers, Industry, and NIH 0 0 1 1 (1.9) Other combinations 1 4 0 5 (9.4) Other federal sources 0 1 1 2 (3.8) Total 9 32 12 53 (100.0) Abbreviations : NIH National Institutes of Health Trial sponsor for repurposed agents by phase of drug development (as of February 27, 2020) Abbreviations : NIH National Institutes of Health Table  6 summarizes the number of repurposing trials in previous annual AD pipeline reports [ 10 – 14 ]. Since 2016, the number of trials involving repurposed agents has increased by 89%. The number of trials has grown each year, with the greatest rate of increase occurring between 2019 and 2020 (23% growth). Between 2016 and 2020, repurposed DMT trials have increased 180%; repurposed trials focused on symptom-reduction have decreased by 67%. Table 6 Repurposing agent trials between 2016 and 2020 2016 2017 2018 2019 2020 DMTs Symptomatic agents DMTs Symptomatic agents DMTs Symptomatic agents DMTs Symptomatic agents DMTs Symptomatic agents Phase I 1 3 1 2 3 2 7 1 8 1 Phase II 10 7 11 9 15 10 19 7 28 4 Phase III 4 3 4 4 2 5 3 6 6 6 Total 15 13 16 15 20 17 29 14 42 11 Abbreviations : DMT disease-modifying therapy Repurposing agent trials between 2016 and 2020 Abbreviations : DMT disease-modifying therapy Phase I trials of repurposed agents have increased 125% since 2016; Phase II and Phase III trials have risen 88% and 71%, respectively. DMT trials of repurposed agents currently make up 79% of all repurposed agents in the current pipeline (up from 54% in 2016; Fig.  4 ). Fig. 4 Repurposing trials over time in the Alzheimer’s disease drug development pipeline (2016–2020) Repurposing trials over time in the Alzheimer’s disease drug development pipeline (2016–2020) Out of 138 AD trials with an ongoing status registered with the EUCTR, we identified 14 trials involving 14 FDA-approved drugs (Table  7 ). Eleven of these were dual-registered with the US and EU/EEA databases. Five trials were in Phase III and nine were in Phase II. Six had a completed or terminated status when compared to the information listed on ClinicalTrials.gov . Three trials were registered exclusively with the EUCTR: epoetin alfa, levodopa-carbidopa, and cannabidiol. Table 7 Repurposing agents currently in the European Alzheimer’s Disease development pipeline (as of February 27, 2020) Agent name Phase(s) Agent mechanism class Therapeutic purpose under study Drug class FDA-approved indication(s) Therapeutic field EudraCT ID (Clinicaltrials.gov ID) ALZT-OP1a, ALZT-OP1b (cromolyn with and without ibuprofen) III Anti-amyloid, anti-inflammatory Reduce neuronal damage; mast cells may also play a role in amyloid pathology (DMT) Mast cell stabilizer Bronchial asthma; mastocytosis Pulmonary 2015-002147-34 ( NCT02547818 ) Cannabidiol II Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Cannabinoid Seizures (Lennox-Gastaut syndrome or Dravet syndrome) Neurologic 2019-002106-52 Dronabinol II Neurotransmitter-based Improve neuropsychiatric symptoms (agitation) Synthetic delta-9-THC AIDS-associated anorexia; antiemetic for chemotherapy-induced nausea and vomiting Neurologic 2011-005289-39 * ( NCT01608217 ) 2010-024577-39 * ( NCT01302340 ) Epoetin alfa II Anti-inflammatory, metabolic Reduce neuronal injury (DMT); improve neuropsychiatric symptoms (depression) Erythropoiesis-stimulating agent Anemia (chronic kidney disease, zidovudine treatment, chemotherapy); reduction of red blood cell transfusion Hematologic-oncologic 2008-000453-35 Levetiracetam II Neuroprotective Reduce amyloid induced neuronal hyperactivity (DMT) Anticonvulsant Adjunct therapy for partial-onset seizures; juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures Neurologic 2016-003109-32 ( NCT03489044 ) Levodopa-Carbidopa II Neurotransmitter-based Enhance dopamine neurotransmission (cognitive enhancer) Dopamine prodrug Parkinson’s disease Neurologic 2009-011093-15 Liraglutide II Metabolic Enhance cell signaling; improve CNS glucose metabolism (DMT) Glucagon-like peptide-1 agonist Adjunct therapy for type 2 diabetes; risk reduction of major cardiovascular events Antidiabetic 2013-000962-13 ( NCT01843075 ) Masitinib III Anti-inflammatory Activity on mast cells, modulation of inflammatory processes (DMT) Selective tyrosine kinase inhibitor Mast cell tumor (veterinary) Hematologic-oncologic 2010-021218-50 ( NCT01872598 ) Rosiglitazone III Metabolic PPAR-gamma agonist (cognitive enhancer) Thiazolidinedione Adjunct therapy for type 2 diabetes Antidiabetic 2012-002764-27 ** ( NCT00550420 ) 2006-001403-11 * ( NCT00348309 ) 2006-001402-92 * ( NCT00348140 ) Rotigotine II Neurotransmitter-based Enhance dopamine neurotransmission (cognitive enhancer) Non-ergoline dopamine agonist Parkinson’s disease; restless leg syndrome Neurologic 2015-002965-43 * ( NCT03250741 ) Thiethylperazine II Anti-amyloid Activates transport protein ABCC1 and enhances transport amyloid-ß peptides from the brain into the blood (DMT) Phenothiazine Nausea/vomiting Neurologic 2014-000870-20 ( NCT03417986 ) Abbreviations : DMT disease-modifying therapy, THC tetrahydrocannabinol *Trials that have a “Completed” status as reported on CiinicalTrials.gov **Trials that have a “Terminated” status as reported on ClinicalTrials.gov Repurposing agents currently in the European Alzheimer’s Disease development pipeline (as of February 27, 2020) 2011-005289-39 * ( NCT01608217 ) 2010-024577-39 * ( NCT01302340 ) 2012-002764-27 ** ( NCT00550420 ) 2006-001403-11 * ( NCT00348309 ) 2006-001402-92 * ( NCT00348140 ) 2015-002965-43 * ( NCT03250741 ) 2014-000870-20 ( NCT03417986 ) Abbreviations : DMT disease-modifying therapy, THC tetrahydrocannabinol *Trials that have a “Completed” status as reported on CiinicalTrials.gov **Trials that have a “Terminated” status as reported on ClinicalTrials.gov There were six DMTs, five cognitive-enhancing agents, and three drugs addressing neuropsychiatric symptoms among the repurposed agents. Therapeutic areas represented included four neurologic drugs, two hematologic-oncologic agents, one drug with pulmonary indications, and one antidiabetic agent.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a rising prevalence due to the global increase in the aging population [ 1 ]. It is estimated that one in 85 people will be living with an AD diagnosis by 2050 [ 2 ]. An urgent need exists to identify effective interventions that will combat this disabling and ultimately fatal disease. Attempts to find new therapies for AD have been made by academic centers and biopharmaceutical companies: identifying new chemical entities, optimizing them for human use, and investigating their effects in clinical trials. However, the lack of an approved drug for AD by the Food and Drug Administration (FDA) since 2003 demonstrates the complexity of this objective [ 3 ]. Efforts to produce new treatments for AD are focused primarily on identifying new compounds that may improve symptoms, slow disease progression, delay the onset, or ultimately prevent the disease. An alternative approach to advancing new treatments is the development of drugs approved for a non-AD-related indication that may impact the biology of AD through on-target or off-target mechanisms. This repurposing strategy has succeeded in other conditions and has promise for AD since many FDA-approved agents exhibit AD-relevant effects evident through in vitro, animal, epidemiologic, and observational studies [ 4 – 9 ]. To better understand repurposing in the AD drug development process, we conducted an analysis of all ongoing AD clinical trials involving FDA-approved drugs. We analyzed trial data reported on ClinicalTrials.gov, a comprehensive US government database with mandated registration of all clinical trials conducted within the US. We examined all currently ongoing trials that involved repurposed agents and compared this to all drugs in the AD pipeline [ 10 – 14 ]. We also compared ongoing trial activity of repurposed AD drugs as reported on the European Union Clinical Trials Register (EUCTR). Our goal was to examine how repurposing efforts in the AD drug pipeline compares to overall drug development activity in the United States (US) and international pipelines and to provide insight into repurposing as a drug development strategy.

Drug repurposing provides the unique opportunity to significantly shorten the development period of a therapeutic candidate for AD. These agents have been extensively assessed for pharmacokinetic properties and toxicities normally required in nonclinical and Phase 1 stages of development. Over half of all agents fail in development for these two reasons, and repurposing circumvents these challenges [ 18 ]. FDA-approved drugs have already undergone human trials, and safety, efficacy, and adverse event profiles are known. The results of previous trials may suffice to bypass nonclinical stages and earlier clinical phases of study; this has the advantage of foregoing the financial and time-costs associated with a drug development program. Total costs for developing a new agent may be as high as $5.7 billion with $1.66 billion required for non-clinical studies and $1.19 billion for Phase I [ 19 ]. Total development costs may be reduced by 50% compared to the cost of developing a new chemical entity. FDA-approved agents have been optimized for the original indication. Different doses might be needed, and different adverse event profiles may occur in an AD population compared to other populations for which the agent was originally developed. Some steps in the development process might be repeated to account for these contingencies. Repurposed agents are often generic and have limitations on intellectual property rights that compromise attracting investments that could propel their development [ 20 ]. Examination of the repurposed agents in the current AD pipeline revealed that DMT trials were chiefly based on agents derived from hematologic-oncologic (tyrosine kinase inhibitors), cardiovascular (angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors), and neurologic indications (anticonvulsants), as well as diabetes. Growing evidence supports the association between the key pathologic changes these drugs target and the underlying biology of AD [ 21 – 24 ]. The links between dementia-related symptoms and the abnormal activation of tyrosine kinase pathways, cardiovascular disease, and impaired insulin sensitivity are reflected by the presence of these agents in the pipeline of repurposed drugs. With increasing knowledge of these processes in AD, repurposing may comprise a precision medicine approach to AD therapeutics [ 25 ]. A preponderance of psychiatric compounds comprise the symptomatic agent class, and the vast majority (including some non-antipsychotics) are aimed at alleviating AD-associated agitation. This may show a priority in the field to identify treatments for a distressing aspect of AD for patients and caregivers. These trials were facilitated by the development of new diagnostic criteria for agitation that assist in patient identification and outcome determination [ 26 ]. Certain repurposed candidates may offer therapeutic benefits without directly engaging AD targets. Reduced cerebral blood flow correlates with AD pathology [ 27 ]. A pilot study has suggested that the antiplatelet agent, cilostazol ( NCT02491268 ), may slow cognitive decline through pleiotropic effects, including regional enhancement of cerebral perfusion [ 28 – 30 ]. Some drugs target the role of neuroinflammation in AD: inflammation affecting the function of the blood-brain barrier is a component of interest in two trials of montelukast ( NCT03402503 , NCT03991988 , [ 31 , 32 ]). Trialists studying rifaximin ( NCT03856359 ) posit an improvement in cognitive function by reduction in pro-inflammatory cytokines and ammonia levels [ 32 ]. Repurposing agent trials make up 39% of the total AD pipeline in 2020 (compared to 24% in 2016). Phase II has the largest number of trials—in both repurposing trials and in the overall pipeline (60 and 55%, respectively). This likely results from entry of repurposed agents directly into Phase II or Phase I/II. DMT trials comprise approximately 79% of the 2020 AD pipeline, compared to 75% when looking at the subset of repurposed agents. Although amyloid is the most common specific target in Phase II and Phase III DMT trials overall, the majority of repurposed DMTs involve tau targets. Forty-six percent of all AD trials are funded at least in part by biopharmaceutical industry sources. In contrast, the majority of repurposed trials (79%) receive partial or complete funding from Academic Medical Centers and only 9% are sponsored by the biopharmaceutical industry. This reflects the challenges of obtaining intellectual property protection for repurposed agents that discourage for-profit enterprises from exercising this development pathway. The observation emphasizes the importance of Academic Medical Centers and federal and philanthropic funding in the AD drug development ecosystem. A variety of strategies are being assessed to try to secure intellectual property positions for repurposed agents. Using different doses relative to an agent’s original indication is one approach and depends on the drug exposure required for each indication. This strategy is exemplified by the HOPE4MCI study ( NCT03486938 ), which is using one-tenth of the dose of levetiracetam used for anticonvulsant purposes. Another approach is the use of novel formulations of an agent. Insulin glulisine ( NCT02503501 ) is a rapid-acting version of the insulin; a long-acting form ( NCT01595646 ) was developed for trials in AD [ 33 ]. Montelukast is being investigated as a cognitive enhancer in two separate trials ( NCT03991988 , NCT03402503 ) using an oral tablet and a buccal film patch, respectively. This highlights the opportunity to develop novel delivery mechanisms for repurposed agents as a means of enhancing efficacy and securing intellectual property rights. The marked increase in repurposing may reflect the recent efforts aimed at elucidating the benefits of repurposing as a strategy in AD drug development [ 7 , 34 ]. Funding from federal, advocacy, and philanthropic sources disproportionately support trials of repurposed agents and this may have driven the increase in repurposing. Repurposing may have been accelerated by advances in methodologies that are being used to identify AD-efficacious pharmaceuticals that include phenotypic or high content screening, in silico techniques, bioinformatic or computational strategies, and medical genetic-based approaches [ 9 , 35 – 39 ]. Electronic health records may provide evidence of beneficial effects on AD or other neurodegenerative disorders by therapies approved for other indications and represent another means for discovering repurposing agents [ 39 , 40 ]. The effects of long-term exposure to these agents, however, may not be recapitulated in the 18–24 months of most current AD trials. Between 2016 and 2020, 20 trials of repurposed agents reached a “completed” status while four were “terminated” for various reasons. Post hoc analysis of a pilot Phase II Metformin study ( NCT01965756 ) found the agent to be safe and well-tolerated, with improvements in executive function [ 41 ]. In another study, a short course of NewGam 10% IVIG (intravenous immunoglobulin; NCT01300728 ) given during the mild cognitive impairment (MCI) stage of AD decreased brain atrophy and ameliorated cognitive decline, but beneficial effects did not persist after 2 years [ 42 ]. A phase I study ( NCT01780519 ) found that lorazepam may unmask pre-symptomatic cognitive dysfunction in individuals with underlying genetic risk for AD [ 43 ]. Primary outcome analyses of the NILVAD study ( NCT02017340 ) failed to show any treatment benefit with nilvadipine when compared to the matched placebo population, though the drug was found to be safe and well-tolerated [ 44 ]. The AMBAR study by Grifols ( NCT01561053 ) offers a novel approach to potential AD treatment via therapeutic albumin replacement with or without immunoglobulin [ 45 ]. Outcome analyses revealed a statistically significant 61% decrease in progression of moderate AD who received treatment. None of the trial “failures” results from problems associated with safety or tolerability, which may be indicative of the extensive studies repurposed agents have already undergone. A single repurposed compound may target different outcomes; escitalopram is being studied simultaneously in trials for agitation and for improvements in cognition ( NCT03108846 , NCT03274817 ). Combinations of FDA-approved drugs represent another approach to repurposing; ALZT-OP1 ( NCT02482324 ) uses a two-part combination of repurposed agents—a mast-cell stabilizer (cromolyn) and the non-steroidal anti-inflammatory agent ibuprofen. A combination of losartan, amlodipine, and atorvastatin is a combination trial ( NCT02913664 ) involving repurposed agents to address the vascular dimensions of AD. We assessed repurposing in the EUCTR and compared it to the analyses of ClinicalTrials.gov . Using the same criteria used to query the US governmental database, we found that repurposing trials make up approximately 10% of all ongoing EU/EEA AD trials (in contrast to 39% in the US AD pipeline). Similar to the US pipeline, the majority of trials (64%) are in Phase II and involve DMT agents (43%). The majority of agents identified in the EU/EEA trials were among the agents identified in ClinicalTrials.gov ; only three trials were unique to the EUCTR. Some major discrepancies were encountered when comparing both trial registers. Six of the 14 EUCTR trials, or 43%, were found to have a “completed” or “terminated” status on ClinicalTrials.gov (Table  7 ). Inaccurate reporting of dual-registered trials on EUCTR is a prevalent issue [ 46 ], which may in part reflect the register’s reliance on sponsors to manually enter study results onto the EudraCT database. Suboptimal completion of RCT protocols and results may lead to overestimates of trial activity [ 47 – 50 ]. Repurposing is to be distinguished from developing extended indications for a proprietary agent as part of life-cycle management. Pimavanserin, for example, is approved for the treatment of hallucinations and delusions in Parkinson’s disease psychosis; an extended application for dementia-related psychosis is currently being developed for several dementia syndromes [ 51 , 52 ]. Likewise, suvorexant is approved for insomnia and completed a successful trial for insomnia in AD and the labeling of the compound has been adjusted to include this information. Brexpiprazole is approved for the treatment of schizophrenia and as adjunctive therapy for major depressive disorder; it is being assessed in the AD pipeline as a therapy for agitation [ 53 ]. These programs represent extensions of indications and not repurposing. Repurposing can be distinguished from repositioning in which a non-approved agent in a sponsor’s development program changes from one indication to another because disease-related, compound-related, or commercial circumstances suggest that success in further development may be more likely in one condition than another [ 54 , 55 ]. There are limitations of the current analyses. Because not all Phase I trial activity may be recorded in the clinicaltrials.gov database, our data may underestimate the actual number of trials in this phase. Estimates of drugs designated as DMT versus symptomatic agents may be equivocal depending on what is perceived as an agent’s principle MOA. We stopped entering new data into our database at a time that allowed submission, peer review, and publication (final data collection stopped on February 27, 2020) and there may be newer trials or changes to current trials not reflected in this document.

In summary, repurposing is a promising avenue for AD drug development, comprises a substantial part of the current AD pipeline, and is increasing in absolute numbers of agents and as a proportion of the pipeline. Repurposing may reduce drug development costs by up to 50% and accelerate times lines for progression in the pipeline. Repurposing draws on development programs from numerous other indications. Repurposing is an important part of the current AD drug development ecosystem.