Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers

Current Pharmaceutical Design

Volumn 19, Issue 42, 2013, Pages 7479-7485

  Lyden, Patrick ^a   Levy, Howard ^b   Weymer, Sara ^c   Pryor, Kent ^c   Kramer, William ^d   Griffin, John H ^e   Davis, Thomas P ^f   Zlokovic, Berislav ^g  

^a CEDARS SINAI MEDICAL CENTER   (United States)

^b Howard Levy Consulting LLC   (United States)

^c ZZ Biotech LLC   (United States)

^d Kramer Consulting LLC   (United States)

^e SCRIPPS RESEARCH INSTITUTE   (United States)

^f UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

^g UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Activated protein C; Clinical trials; Coagulation; Humans; PAR1; Pharmaco kinetics; Protein C

Indexed keywords

3K 3A APC; ANTICOAGULANT AGENT; PLACEBO; UNCLASSIFIED DRUG;

ADULT; ANTICOAGULATION; ARTICLE; COHORT ANALYSIS; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG DOSE REDUCTION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; HEADACHE; HUMAN; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NAUSEA AND VOMITING; NORMAL HUMAN; PHASE 1 CLINICAL TRIAL; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RISK ASSESSMENT; SYSTOLIC BLOOD PRESSURE; UNSPECIFIED SIDE EFFECT; YOUNG ADULT;

ADULT; ANTICOAGULANTS; COHORT STUDIES; HEALTHY VOLUNTEERS; HUMANS; PLACEBOS; PROTEIN C; RECOMBINANT PROTEINS;

EID: 84891884106     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612819666131230131454     Document Type: Article

References (32)

1. Mosnier LO, Yang XV, Griffin JH. Activated protein c mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cytoprotective functions. J Biol Chem. 2007;282:33022-33033
2. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein c pathway. Blood. 2007;109:3161-3172
3. Zlokovic BV GJ. Cytoprotective protein c pathways and implications for stroke and neurological disorders. Trends Neurosci. 2011;34:198-209
4. Zlokovic BV. Neurovascular pathways to neurodegeneration in alzheimer's disease and other disorders. Nat Rev Neurosci. 2011; 12: 723-738
5. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein c pathway. Science. 2002;296:1880-1882
6. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, et al. Activated protein c blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9:338-342
7. Domotor E, Benzakour O, Griffin JH, Yule D, Fukudome K, Zlokovic BV. Activated protein c alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein c receptor and activation of protease activated receptor-1. Blood. 2003;101:4797-4801
8. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein c through par1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood. 2005;105:3178-3184
9. Finigan JH, Dudek SM, Singleton PA, Chiang ET, Jacobson JR, Lyden et al. endothelial barrier enhancement: Role of sphingosine 1-phosphate receptor transactivation. J Biol Chem. 2005;280:17286-17293
10. Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernandez JA, et al. Activated protein c prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron. 2004;41:563-572
11. Mosnier LO GA, Yegneswaran S, Griffin JH. Activated protein c variants with normal cytoprotective but reduced anticoagulant activity. Blood. 2004;104:1740-1744
12. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein c for severe sepsis. N Engl J Med. 2001;344:699-709
13. Guo H, Singh I, Wang Y, Deane R, Barrett T, Fernandez JA, et al. Neuroprotective activities of activated protein c mutant with reduced anticoagulant activity. Eur J Neurosci. 2009;29:1119-1130
14. Wang Y, Thiyagarajan M, Chow N, Singh I, Guo H, Davis TP, et al. Differential neuroprotection and risk for bleeding from activated protein c with varying degrees of anticoagulant activity. Stroke. 2009;40:1864-1869
15. Wang Y, Zhang Z, Chow N, Davis TP, Griffin JH, Chopp M, et al. An activated protein c analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents. Stroke. 2012;43:2444-2449
16. Walker CT, Marky AH, Petraglia AL, Ali T, Chow N, Zlokovic BV. Activated protein c analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact. Brain Res. 2010;1347:125-131
17. Zhong Z, Ilieva H, Hallagan L, Bell R, Singh I, Paquette N, et al. Activated protein c therapy slows als-like disease in mice by transcriptionally inhibiting sod1 in motor neurons and microglia cells. J Clin Invest. 2009;119:3437-3449
18. Guo H, Wang Y, Singh I, Liu D, Fernandez JA, Griffin JH, et a Species-dependent neuroprotection by activated protein c mutants with reduced anticoagulant activity. J Neurochem. 2009;109:116-124
19. Soh UJ, Trejo J. Activated protein c promotes protease-activated receptor-1 cytoprotective signaling through beta-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci USA 2011; 108: E1372-1380
20. Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH. Biased agonism of protease-activated receptor 1 by activated protein c caused by noncanonical cleavage at arg46. Blood. 2012;120:5237-5246
21. Williams PD, Zlokovic BV, Griffin JH, Pryor KE, Davis TP Preclinical safety and pharmacokinetic profile of 3k3a-apc, a novel, modified activated protein c for ischemic stroke. Curr Pharm Des. 2012;18:4215-4222
22. Gruber A, Griffin JH. Direct detection of activated protein c in blood from human subjects. Blood. 1992;79:2340-2348
23. Adams HP, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: A report of the trial of org 10172 in acute stroke treatment (toast) Neurology. 1999;53:122
24. The Publications Committee for the Trial of ORGiASTI. Low molecular weight heparinoid org 10172 (danaparoid), and outcome after acute ischemic stroke a randomized controlled trial. Journal of the American Medical Association. 1998;279:1265
25. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467-477
26. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244-2250
27. Lapchak PA, Zhang J, Noble-Haeusslein L. Rigor guidelines: Escalating stair and steps for effective translational research. Transl Stroke Res. 2012
28. Macleod MR, Fisher M, O'Collins V, Sena ES, Dirnagl U, Bath PM, et al. Good laboratory practice: Preventing introduction of bias at the bench. Stroke. 2009;40:e50-52
29. Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, et al. Activated protein c inhibits tissue plasminogen activatorinduced brain hemorrhage. Nat Med. 2006;12:1278-1285
30. Zlokovic BV, Zhang C, Liu D, Fernandez J, Griffin JH, Chopp M. Functional recovery after embolic stroke in rodents by activated protein c. Ann Neurol. 2005;58:474-477.
31. Barreto AD, Alexandrov AA, Lyden P, Lee J, Martin-Schild S, Shen L, et al. The Argatroban and tissue Type Plasminogen Activator Stroke Study; Final Results of a Pilot Safety Study. Stroke 2012; 43: 770-775.
32. Mosnier LO, Fernández JA, Davis TP, Zlokovic BV, Griffin JH. Influence of the 3K3A-activated protein C variant on the plasma clot lysis activity of t-PA and of t-PA on the variant's anticoagulant activity. J Thromb Haemost 2013; 11(11): 2059-2062. doi: 10.1111/jth.12400.