PMID- 28211169
OWN - NLM
STAT- MEDLINE
DCOM- 20180326
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 15
IP  - 5
DP  - 2017 May
TI  - A first-in-human study of DS-1040, an inhibitor of the activated form of 
      thrombin-activatable fibrinolysis inhibitor, in healthy subjects.
PG  - 961-971
LID - 10.1111/jth.13658 [doi]
AB  - Essentials DS-1040 inhibits the activated form of thrombin-activatable 
      fibrinolysis inhibitor (TAFIa). Infusion of DS-1040 was safe and well tolerated 
      in healthy young and elderly subjects. DS-1040 substantially decreased TAFIa 
      activity but had no impact on bleeding time. DS-1040 may provide an option of 
      safer thrombolytic therapy. SUMMARY: Background Current treatments for acute 
      ischemic stroke and venous thromboembolism, such as recombinant tissue-type 
      plasminogen activator and thrombectomy, are limited by a narrow time window and 
      the risk of bleeding. DS-1040 is a novel low molecular weight compound that 
      inhibits the activated form of thrombin-activatable fibrinolysis inhibitor 
      (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of 
      thromboembolic diseases. Objectives This first-in-human, randomized, 
      placebo-controlled, three-part, phase 1 study was conducted to evaluate the 
      safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. 
      Subjects/Methods Young (18-45 years) or elderly (65-75 years) subjects (N = 103) 
      were randomized to receive single ascending doses of DS-1040 ranging from 0.1 mg 
      to 40 mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 
      24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no 
      serious adverse events (AEs) or discontinuations resulting from AEs occurred 
      during the study. Bleeding time remained within the normal range for all doses 
      tested in all subjects. Plasma exposure of DS-1040 increased proportionally with 
      increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged 
      elimination times, probably because of decreased renal clearance. DS-1040 caused 
      a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 
      50% clot lysis time. The levels of D-dimer, indicative of endogenous 
      fibrinolysis, increased in some individuals following DS-1040 treatment. No 
      effects of DS-1040 on coagulation parameters or platelet aggregation were 
      observed. Conclusions The novel fibrinolysis-enhancing agent DS-1040 has 
      favorable pharmacokinetic/pharmacodynamic properties and a favorable safety 
      profile, warranting further clinical development.
CI  - (c) 2017 International Society on Thrombosis and Haemostasis.
FAU - Zhou, J
AU  - Zhou J
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
FAU - Kochan, J
AU  - Kochan J
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
FAU - Yin, O
AU  - Yin O
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
FAU - Warren, V
AU  - Warren V
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
FAU - Zamora, C
AU  - Zamora C
AD  - Worldwide Clinical Trials, San Antonio, TX, USA.
FAU - Atiee, G
AU  - Atiee G
AD  - Worldwide Clinical Trials, San Antonio, TX, USA.
FAU - Pav, J
AU  - Pav J
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
FAU - Orihashi, Y
AU  - Orihashi Y
AD  - Daiichi Sankyo Development Ltd, Gerrards Cross, UK.
FAU - Vashi, V
AU  - Vashi V
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
FAU - Dishy, V
AU  - Dishy V
AD  - Daiichi Sankyo Pharma Development, Edison, NJ, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20170311
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Protease Inhibitors)
RN  - EC 3.4.17.20 (CPB2 protein, human)
RN  - EC 3.4.17.20 (Carboxypeptidase B2)
SB  - IM
CIN - J Thromb Haemost. 2017 Oct;15(10):2080-2081. PMID: 28799246
CIN - J Thromb Haemost. 2017 Oct;15(10):2081-2083. PMID: 28799285
MH  - Adolescent
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Blood Coagulation Tests
MH  - Carboxypeptidase B2/*antagonists & inhibitors/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Fibrinolysis/*drug effects
MH  - Fibrinolytic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Healthy Volunteers
MH  - Hemorrhage/chemically induced
MH  - Humans
MH  - Infusions, Intravenous
MH  - Male
MH  - Middle Aged
MH  - Protease Inhibitors/*administration & dosage/adverse effects/pharmacokinetics
MH  - Risk Factors
MH  - Young Adult
OTO - NOTNLM
OT  - fibrinolysis
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - thrombin-activatable fibrinolysis inhibitor
OT  - thrombosis
EDAT- 2017/02/18 06:00
MHDA- 2018/03/27 06:00
CRDT- 2017/02/18 06:00
PHST- 2016/09/23 00:00 [received]
PHST- 2017/02/18 06:00 [pubmed]
PHST- 2018/03/27 06:00 [medline]
PHST- 2017/02/18 06:00 [entrez]
AID - S1538-7836(22)00883-2 [pii]
AID - 10.1111/jth.13658 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2017 May;15(5):961-971. doi: 10.1111/jth.13658. Epub 2017 Mar 
      11.