Use of GMI-1271, an E-selectin antagonist, in healthy subjects and in 2 patients with calf vein thrombosis.
E‐selectin
biomarkers
deep vein thrombosis
therapeutics
venous thromboembolism
Journal
Research and practice in thrombosis and haemostasis
ISSN: 2475-0379
Titre abrégé: Res Pract Thromb Haemost
Pays: United States
ID NLM: 101703775
Informations de publication
Date de publication:
Feb 2020
Feb 2020
Historique:
received:
31
07
2019
revised:
13
09
2019
accepted:
14
10
2019
entrez:
29
2
2020
pubmed:
29
2
2020
medline:
29
2
2020
Statut:
epublish
Résumé
There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI-1271, a potent small-molecule E-selectin antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding. A first-in-human study of GMI-1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf-level deep vein thrombosis (DVT). GMI-1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half-life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E-selectin (sEsel) levels with GMI-1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI-1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution. We demonstrate that GMI-1271 is safe in healthy volunteers and provide proof of concept that an E-selectin antagonist is a potential therapeutic approach to treat venous thrombosis.
Sections du résumé
BACKGROUND
BACKGROUND
There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI-1271, a potent small-molecule E-selectin antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding.
METHODS
METHODS
A first-in-human study of GMI-1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf-level deep vein thrombosis (DVT).
RESULTS
RESULTS
GMI-1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half-life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E-selectin (sEsel) levels with GMI-1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI-1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution.
CONCLUSIONS
CONCLUSIONS
We demonstrate that GMI-1271 is safe in healthy volunteers and provide proof of concept that an E-selectin antagonist is a potential therapeutic approach to treat venous thrombosis.
Identifiants
pubmed: 32110749
doi: 10.1002/rth2.12279
pii: S2475-0379(22)01964-1
pmc: PMC7040550
doi:
Types de publication
Journal Article
Langues
eng
Pagination
193-204Informations de copyright
© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.
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