Abstract | BACKGROUND: 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:
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: 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.
|
Authors | Sumana Devata, Dana E Angelini, Susan Blackburn, Angela Hawley, Daniel D Myers, Jordan K Schaefer, Martina Hemmer, John L Magnani, Helen M Thackray, Thomas W Wakefield, Suman L Sood |
Journal | Research and practice in thrombosis and haemostasis
(Res Pract Thromb Haemost)
Vol. 4
Issue 2
Pg. 193-204
(Feb 2020)
ISSN: 2475-0379 [Electronic] United States |
PMID | 32110749
(Publication Type: Journal Article)
|
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. |