{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:21:21Z","timestamp":1790144481939,"version":"4.0.1"},"reference-count":101,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,12]],"date-time":"2019-09-12T00:00:00Z","timestamp":1568246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["No. 2632018YX03"],"award-info":[{"award-number":["No. 2632018YX03"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["No.2632019ZD05"],"award-info":[{"award-number":["No.2632019ZD05"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.81503150"],"award-info":[{"award-number":["No.81503150"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiovascular drug research and development (R&amp;D) has been in active state and continuously attracts attention from the pharmaceutical industry. However, only one individual drug can eventually reach the market from about the 10,000 compounds tested. It would be useful to learn from these failures when developing better strategies for the future. Discontinued drugs were identified from a search performed by Thomson Reuters Integrity. Additional information was sought through PubMed, ClinicalTrials.gov, and pharmaceutical companies search. Twelve compounds discontinued for cardiovascular disease treatment after reaching Phase I\u2013III clinical trials from 2016 to 2018 are detailed in this manuscript, and the reasons for these failures are reported. Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons. In total, three candidates were discontinued in Phase I trials, six in Phase II, and three in Phase III. It was reported that the success rate of drug R&amp;D utilizing selection biomarkers is higher. Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.<\/jats:p>","DOI":"10.3390\/ijms20184513","type":"journal-article","created":{"date-parts":[[2019,9,12]],"date-time":"2019-09-12T10:56:06Z","timestamp":1568285766000},"page":"4513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018"],"prefix":"10.3390","volume":"20","author":[{"given":"Tingting","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sida","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingwei","family":"Ni","sequence":"additional","affiliation":[{"name":"School of Engineering, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuji","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Science, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinan","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Science, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Science, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,12]]},"reference":[{"key":"ref_1","unstructured":"WHO (2018, December 28). Cardiovascular Diseases. Available online: http:\/\/www.who.int\/cardiovascular_diseases\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1517\/13543784.2012.710198","article-title":"Discontinued drugs in 2011: Cardiovascular drugs","volume":"21","author":"Zhao","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1517\/13543784.2013.832198","article-title":"Discontinued drugs in 2012: Cardiovascular drugs","volume":"22","author":"Zhao","year":"2013","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1517\/13543784.2015.1051619","article-title":"Discontinued cardiovascular drugs in 2013 and 2014","volume":"24","author":"Zhao","year":"2015","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1080\/13543784.2016.1212836","article-title":"Discontinued cardiovascular drugs in 2015","volume":"25","author":"Zhao","year":"2016","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1136\/bmj.322.7286.603","article-title":"Premature discontinuation of clinical trial for reasons not related to efficacy, safety, or feasibility","volume":"322","author":"Bruckert","year":"2001","journal-title":"BMJ"},{"key":"ref_7","unstructured":"(2019, June 28). Integrity: Essential Knowledge to Empower Your Drug Discovery and Development. Available online: https:\/\/clarivate.com\/wp-content\/uploads\/2018\/03\/Crv_LS_Integrity_SellSheetShort_A4_FA.pdf."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1124\/dmd.115.067868","article-title":"Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans","volume":"44","author":"Dong","year":"2016","journal-title":"Drug Metab. Dispos."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.2174\/138920021603150812120640","article-title":"Myeloperoxidase Inhibitors as Potential Drugs","volume":"16","author":"Leskovac","year":"2015","journal-title":"Curr. Drug Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8513","DOI":"10.1021\/acs.jmedchem.5b00963","article-title":"Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases","volume":"58","author":"Ruggeri","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1124\/dmd.116.074476","article-title":"Examination of the Human Cytochrome P4503A4 Induction Potential of PF-06282999, an Irreversible Myeloperoxidase Inactivator: Integration of Preclinical, In Silico, and Biomarker Methodologies in the Prediction of the Clinical Outcome","volume":"45","author":"Dong","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1080\/00498254.2017.1353163","article-title":"Induction of human cytochrome P450 3A4 by the irreversible myeloperoxidase inactivator PF-06282999 is mediated by the pregnane X receptor","volume":"48","author":"Moscovitz","year":"2018","journal-title":"Xenobiotica"},{"key":"ref_13","unstructured":"ClinicalTrials (2019, April 10). A Study to Test the Safety, Amount and Effects of PF-06282999 in Healthy Overweight Adults and a Study to Test the Effects of PF-06282999 on the Amount of the Approved Drug, Midazolam, in Healthy Adults, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01707082?term=PF-06282999&rank=2&view=record."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Roth Flach, R.J., Su, C., Bollinger, E., Cortes, C., Robertson, A.W., Opsahl, A.C., Coskran, T.M., Maresca, K.P., Keliher, E.J., and Yates, P.D. (2019). Myeloperoxidase inhibition in mice alters atherosclerotic lesion composition. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214150"},{"key":"ref_15","unstructured":"ClinicalTrials (2019, April 10). A Trial to Determine the Safety, Pharmacokinetics, and Efficacy of OPC-108459 Administered as a Single Intravenous Dose to Patients With Paroxysmal or Persistent Atrial Fibrillation (AF), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT02069119?term=OPC-108459&rank=1."},{"key":"ref_16","first-page":"A15345","article-title":"ONO-4232, an EP4-selective Agonist, Improves Left Ventricular Diastolic Dysfunction and Ameliorates Acute and Chronic Heart Failure in Animal Models","volume":"126","author":"Kanaji","year":"2012","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.clinthera.2016.02.019","article-title":"First Clinical Experience with ONO-4232: A Randomized, Double-blind, Placebo-controlled Healthy Volunteer Study of a Novel Lusitropic Agent for Acutely Decompensated Heart Failure","volume":"38","author":"Ward","year":"2016","journal-title":"Clin. Ther."},{"key":"ref_18","unstructured":"ONO (2018, October 29). Consolidated Financial Statements (Marc 2016). Available online: http:\/\/www.ono.co.jp\/jpnw\/ir\/pdf\/k_tanshin\/2934r\/03.pdf."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s40256-018-00320-6","article-title":"Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class TRPV4 Ion Channel inhibitor, GSK27987445, in Healthy and Heart Failure Subjects","volume":"19","author":"Goyal","year":"2019","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_20","unstructured":"ClinicalTrials (2018, April 21). A Phase I Study to Assess the Pharmacokinetics of GSK2798745 Tablets, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT02925546."},{"key":"ref_21","unstructured":"ClinicalTrials (2017, November 21). A First Time in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Healthy Subjects and Stable Heart Failure Patients, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT02925546."},{"key":"ref_22","unstructured":"ClinicalTrials (2017, November 21). A Study to Evaluate the Effect of the Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Blocker, GSK2798745, on Pulmonary Gas Transfer and Respiration in Patients With Congestive Heart Failure, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02497937."},{"key":"ref_23","unstructured":"GSK (2019, August 28). 2018 Full Year Results. Available online: https:\/\/www.gsk.com\/media\/5293\/fy-2018-results-slides.pdf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/bit.22542","article-title":"Integrated solution to purification challenges in the manufacture of a soluble recombinant protein in E. coli","volume":"105","author":"Caparon","year":"2010","journal-title":"Biotechnol. Bioeng."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1194\/jlr.M033779","article-title":"Effect of repeated apoA-IMilano\/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys","volume":"54","author":"Kempen","year":"2013","journal-title":"J. Lipid. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1161\/ATVBAHA.115.307052","article-title":"High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano\/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients","volume":"36","author":"Kempen","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/ehjcvp\/pvv041","article-title":"A single infusion of MDCO-216 (ApoA-1 Milano\/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease","volume":"2","author":"Kallend","year":"2016","journal-title":"Eur. Heart J. Cardiovas. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.atherosclerosis.2016.10.042","article-title":"Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano\/POPC) in healthy volunteers and stable coronary artery disease patients","volume":"255","author":"Kempen","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_29","unstructured":"ClinicalTrials (2019, April 12). MDCO-216 Infusions Leading to Changes in Atherosclerosis: A Novel Therapy in Development to Improve Cardiovascular Outcomes\u2014Proof of Concept Intravascular Ultrasound (IVUS), Lipids, and Other Surrogate Biomarkers Trial (PILOT), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT02678923?term=MDCO-216&rank=1."},{"key":"ref_30","unstructured":"The Medicines Company (2018, April 03). The Medicines Company Discontinues Development of MDCO-216, its Investigational Cholesterol Efflux Promoter. Available online: http:\/\/www.themedicinescompany.com\/investors\/news\/medicines-company-discontinues-development-mdco-216-its-investigational-cholesterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/eurheartj\/ehv755","article-title":"Agents with vasodilator properties in acute heart failure","volume":"38","author":"Singh","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1124\/jpet.110.173005","article-title":"Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance","volume":"335","author":"Violin","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1161\/CIRCHEARTFAILURE.111.962571","article-title":"Cardiorenal actions of TRV120027, a novel ss-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: A novel therapeutic strategy for acute heart failure","volume":"4","author":"Boerrigter","year":"2011","journal-title":"Circ. Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1161\/CIRCHEARTFAILURE.112.969220","article-title":"TRV120027, a novel beta-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure","volume":"5","author":"Boerrigter","year":"2012","journal-title":"Circ. Heart Fail."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/jcph.111","article-title":"First clinical experience with TRV027: Pharmacokinetics and pharmacodynamics in healthy volunteers","volume":"53","author":"Soergel","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/S0735-1097(13)60683-X","article-title":"TRV027, a \u03b2-arrestin biased ligand at the angiotensin 2 type 1 receptor, produces rapid, reversible changes in hemodynamics in patients with stable systolic heart failure","volume":"61","author":"Soergel","year":"2013","journal-title":"Am. Coll. Cardiol."},{"key":"ref_37","unstructured":"ClinicalTrials (2018, November 10). A Study to Explore the Efficacy of TRV027 in Patients Hospitalized for Acute Decompensated Heart Failure (BLAST-AHF), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/study\/NCT01966601?term=NCT01966601&rank=1."},{"key":"ref_38","unstructured":"Trevena (2018, November 10). TRV027. Available online: http:\/\/www.trevena.com\/TRV027.php."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jchf.2014.09.008","article-title":"Heart failure therapeutics on the basis of a biased ligand of the angiotensin-2 type 1 receptor. Rationale and design of the BLAST-AHF study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure)","volume":"3","author":"Felker","year":"2015","journal-title":"JACC Heart Fail."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1093\/eurheartj\/ehx196","article-title":"Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: A randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF)","volume":"38","author":"Pang","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.exer.2016.06.016","article-title":"Protective effects of bestatin in the retina of streptozotocin-induced diabetic mice","volume":"149","author":"Hossain","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1472-8206.1987.tb00568.x","article-title":"Effects of bestatin and phosphoramidon on the hypertensive response to physostigmine in the rat","volume":"1","year":"1987","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"200ra117","DOI":"10.1126\/scitranslmed.3006674","article-title":"Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension","volume":"5","author":"Tian","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_44","unstructured":"ClinicalTrials (2019, January 25). A Study of Ubenimex in Patients with Pulmonary Arterial Hypertension (WHO Group 1) (LIBERTY), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/study\/NCT02664558?cond=Ubenimex&rank=2."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1161\/HYPERTENSIONAHA.115.06370","article-title":"Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension","volume":"66","author":"Qian","year":"2015","journal-title":"Hypertension"},{"key":"ref_46","unstructured":"ClinicalTrials (2019, January 25). Open-Label Extension Study of Ubenimex in Patients with Pulmonary Arterial Hypertension (WHO Group 1) (LIBERTY2), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT02736149?cond=Ubenimex&rank=3."},{"key":"ref_47","unstructured":"ClinicalTrials (2019, January 25). A Dose Finding Study to Assess the Effect of LIK066 Compared to Placebo or Empagliflozin in Patients With Type 2 Diabetes Mellitus and Heart Failure, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT03152552?cond=LIK-066&draw=2&rank=10."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1161\/CIRCULATIONAHA.109.891077","article-title":"Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation","volume":"121","author":"Zuckerbraun","year":"2010","journal-title":"Circulation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/nm1109","article-title":"Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator","volume":"10","author":"Hunter","year":"2004","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s40262-014-0201-y","article-title":"Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects","volume":"54","author":"Rix","year":"2015","journal-title":"Clin. Pharmacokinet."},{"key":"ref_51","unstructured":"ClinicalTrials (2019, February 15). Dose-Finding, Safety, Pharmacodynamic Effect Study of Sodium Nitrite Inhalation Solution in Normal, Healthy Volunteers (AIR001-CS02), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/study\/NCT00814645?cond=sodium+nitrite&draw=5&rank=15."},{"key":"ref_52","unstructured":"ClinicalTrials (2019, February 15). Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01409122?cond=sodium+nitrite&draw=4&rank=8&view=record."},{"key":"ref_53","unstructured":"ClinicalTrials (2019, February 15). Pilot Study of Sodium Nitrite in Resuscitated Cardiac Arrest Patients, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01178359."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.resuscitation.2017.11.055","article-title":"Hemodynamic effects of IV sodium nitrite in hospitalized comatose survivors of out of hospital cardiac arrest","volume":"122","author":"Dezfulian","year":"2018","journal-title":"Resuscitation"},{"key":"ref_55","unstructured":"(2019, February 15). UNITED STATES SECURITIES AND EXCHANGE COMMISSION, Available online: http:\/\/www.sec.gov\/Archives\/edgar\/data\/1160308\/000156459014004815\/mstx-10q_20140930.htm."},{"key":"ref_56","unstructured":"ClinicalTrials (2019, February 15). A Phase 2 Study to Determine the Safety and Efficacy of AIR001 in Subjects with Pulmonary Arterial Hypertension (PAH), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT01725256?cond=sodium+nitrite&draw=3&rank=24."},{"key":"ref_57","unstructured":"ClinicalTrials (2019, February 15). Long-Term Study of AIR001 in Subjects with WHO Group 1 Pulmonary Arterial Hypertension Who Completed AIR001-CS05, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01725269?cond=sodium+nitrite&draw=6&rank=23."},{"key":"ref_58","unstructured":"ClinicalTrials (2019, February 15). Inhaled Sodium Nitrite on Heart Failure with Preserved Ejection Fraction, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/study\/NCT02262078?cond=Sodium+Nitrite+on+Heart+Failure&rank=1."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1161\/CIRCRESAHA.116.309184","article-title":"Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction","volume":"119","author":"Borlaug","year":"2016","journal-title":"Circ. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1001\/jama.2018.14852","article-title":"Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients with Heart Failure with Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial","volume":"320","author":"Borlaug","year":"2018","journal-title":"JAMA"},{"key":"ref_61","unstructured":"ClinicalTrials (2019, February 15). Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02742129."},{"key":"ref_62","unstructured":"Savara Pharmaceuticals (2019, April 19). Press Release. Available online: https:\/\/savarapharma.com\/investors\/press-releases\/release\/?id=2337400."},{"key":"ref_63","unstructured":"Takeda (2019, June 19). Takeda FY2016 Q4 Results Data Book. Available online: https:\/\/www.takeda.com\/siteassets\/system\/investors\/report\/quarterlyannouncements\/fy2016\/fy-2016-q4-announcements-released-on-may-10-2017\/qr2016_q4_d1_en.pdf."},{"key":"ref_64","unstructured":"ClinicalTrials (2018, November 19). A Phase I Food Effect Study of TAK-536TCH Final Formulation Tablet, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT02348658?term=TAK-536TCH&rank=1."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1097\/MBP.0000000000000308","article-title":"Effects of triple combination therapy with azilsartan\/amlodipine\/hydrochlorothiazide on office\/home blood pressure: A randomized-controlled trial in Japanese essential hypertensive patients","volume":"23","author":"Rakugi","year":"2018","journal-title":"Blood Press. Monit."},{"key":"ref_66","unstructured":"ClinicalTrials (2018, April 19). Study to Evaluate the Efficacy and Safety of Combined Administration of TAK-536CCB and Hydrochlorothiazide in Patients with Grade I or II Essential Hypertension, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT02072330?term=Takeda&cond=Essential+Hypertension&rank=5."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/08037051.2017.1412797","article-title":"A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension","volume":"27","author":"Rakugi","year":"2018","journal-title":"Blood Press."},{"key":"ref_68","unstructured":"ClinicalTrials (2018, April 19). A Phase III Long-term Study of TAK-536TCH in Participants with Essential Hypertension, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT02277691?term=Takeda&cond=Essential+Hypertension&rank=1."},{"key":"ref_69","first-page":"4279","article-title":"Emerging treatment options to improve cardiovascular outcomes in patients with acute coronary syndrome: Focus on losmapimod","volume":"9","author":"Kragholm","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1124\/jpet.109.154443","article-title":"Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease","volume":"330","author":"Willette","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuint.2015.06.010","article-title":"Suppression of mitochondrial fission in experimental cerebral ischemia: The potential neuroprotective target of p38 MAPK inhibition","volume":"90","author":"Zhang","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/cpdd.190","article-title":"Safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod in healthy Japanese volunteers","volume":"4","author":"Ino","year":"2015","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"ClinicalTrials (2018, December 28). Phase I Study of GW856553 (Losmapimod), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/study\/NCT01648192?term=Losmapimod&rank=6.","DOI":"10.1016\/j.ebiom.2018.01.019"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/bcp.12063","article-title":"Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers","volume":"76","author":"Barbour","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_75","unstructured":"ClinicalTrials (2018, December 28). PK Study of IV Formulation of GW856553, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01039961?term=Losmapimod&rank=8."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1007\/s00228-012-1469-1","article-title":"Losmapimod concentration-QT relationship in healthy volunteers: Meta-analysis of data from six clinical trials","volume":"69","author":"Yang","year":"2013","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/S0140-6736(14)60417-7","article-title":"Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: A randomised phase 2 trial","volume":"384","author":"Newby","year":"2014","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.ahj.2012.07.030","article-title":"The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): Design and rationale","volume":"164","author":"Melloni","year":"2012","journal-title":"Am. Heart J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.21037\/jtd.2016.08.53","article-title":"Losmapimod does not reduce cardiovascular events in patients with acute myocardial infarction","volume":"8","author":"Aronow","year":"2016","journal-title":"J. Thorac. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1001\/jama.2016.3609","article-title":"Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial","volume":"315","author":"Glaser","year":"2016","journal-title":"JAMA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.ahj.2015.02.012","article-title":"Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial","volume":"169","author":"Glaser","year":"2015","journal-title":"Am. Heart J."},{"key":"ref_82","unstructured":"ClinicalTrials (2018, April 23). A Phase 3 Clinical Outcomes Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting With Acute Coronary Syndrome Treated with Losmapimod Compared to Placebo (LATITUDE-TIMI 60) (LATITUDE), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02145468?term=GlaxoSmithKline++Losmapimod&cond=Myocardial+Infarction&rank=1."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/jcph.867","article-title":"A Mechanism-Based Pharmacokinetic\/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin\/Kexin Type9, and Its Application in Early Clinical Development","volume":"57","author":"Udata","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1136\/heartjnl-2016-310844","article-title":"PCSK9 inhibition and atherosclerotic cardiovascular disease prevention: Does reality match the hype?","volume":"103","author":"Hadjiphilippou","year":"2017","journal-title":"Heart"},{"key":"ref_85","unstructured":"ClinicalTrials (2018, December 28). A Study to Access the Safety And Tolerability of RN316 (PF-04950615) When Administered to Healthy Adult Subjects, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT00991159?term=NCT00991159&rank=1."},{"key":"ref_86","unstructured":"ClinicalTrials (2018, December 28). A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 in Subjects with Hypercholesterolemia, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01435382?term=NCT01435382&rank=1."},{"key":"ref_87","unstructured":"ClinicalTrials (2018, December 28). Safety and Tolerability of Multiple Doses of PF-04950615 (RN316) in Subjects with Hypercholesterolemia, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01243151?term=NCT01243151&rank=1."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1016\/j.clinthera.2017.09.009","article-title":"Effects of Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects","volume":"39","author":"Wan","year":"2017","journal-title":"Clin. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/j.amjcard.2015.02.006","article-title":"Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin\/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia","volume":"115","author":"Ballantyne","year":"2015","journal-title":"Am. J. Cardiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"11090","DOI":"10.1074\/jbc.M111.319764","article-title":"Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCS-K9","volume":"287","author":"Liang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_91","unstructured":"Pfizer (2018, November 24). Pfizer Discontinues Global Development of Bococizumab, Its Investigational PCSK9 Inhibitor. Available online: https:\/\/www.pfizer.com\/news\/press-release\/press-release detail\/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor."},{"key":"ref_92","unstructured":"ClinicalTrials (2018, November 24). Pharmacokinetic and Pharmacodynamic Study of Bococizumab Alone and When Combined with Recombinant Human Hyaluronidase, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02667223?term=Pfizer+Bococizumab&cond=Hypercholesterolaemia&rank=2."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1056\/NEJMoa1614062","article-title":"Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab","volume":"376","author":"Ridker","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.jacl.2018.03.088","article-title":"Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab","volume":"12","author":"Ridker","year":"2018","journal-title":"J. Clin. Lipidol."},{"key":"ref_95","unstructured":"ClinicalTrials (2018, November 24). A 52 Week Study to Assess the Use of Bococizumab (PF-04950615; RN316) in Subjects with Heterozygous Familial Hypercholesterolemia (SPIRE-FH), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01968980?term=Pfizer+Bococizumab&rank=8."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1056\/NEJMoa1701488","article-title":"Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients","volume":"376","author":"Ridker","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_97","unstructured":"ClinicalTrials (2019, June 29). The Evaluation of Bococizumab (PF-04950615; RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01975389?term=NCT01975389&rank=1."},{"key":"ref_98","unstructured":"FDA (2018, April 23). FDA Approves Praluent to Treat Certain Patients with High Cholesterol, Available online: https:\/\/www.fda.gov\/newsevents\/newsroom\/pressannouncements\/ucm455883.htm."},{"key":"ref_99","unstructured":"Amgen (2019, January 24). FDA Approves Amgen\u2019s Repatha (evolocumab) To Prevent Heart Attack and Stroke. Available online: http:\/\/www.amgen.com\/media\/news-releases\/2017\/12\/fda-approves-amgens-repatha-evolocumab-to-prevent-heart-attack-and-stroke\/."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/nrd1470","article-title":"Can the pharmaceutical industry reduce attrition rates?","volume":"3","author":"Kola","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_101","unstructured":"BIO, Biomedtracker, Amplion (2019, March 18). Clinical Development Success Rates 2006\u20132015. 25 May 2016. Available online: https:\/\/www.bio.org\/sites\/default\/files\/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4513\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:19:12Z","timestamp":1760188752000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4513"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,12]]},"references-count":101,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijms20184513"],"URL":"https:\/\/doi.org\/10.3390\/ijms20184513","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,12]]}}}