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1004 First in Human Phase 1 Single Dose Escalation Studies of the E-Selectin Antagonist GMI-1271 Show a Favorable Safety, Pharmacokinetic, and Biomarker ProfileClinically Relevant Abstract

Granulocytes, Monocytes and Macrophages
Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes and Macrophages: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Sumana Devata, MD1, Suman L. Sood, MD1, Martina V Hemmer, MA2*, Henry Flanner, MS2*, William Kramer, PhD3*, Christine Nietubicz2*, Angela Hawley4*, Dana E Angelini, MD1, Daniel Durant Myers, DVM, MPH4*, Susan Blackburn4*, James Froehlich, MD5*, Thomas W. Wakefield, MD4*, John L. Magnani, PhD2 and Helen M. Thackray, MD2

1Department of Medicine; Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI
2GlycoMimetics, Inc., Gaithersburg, MD
3Kramer Consulting, North Potomac, MD
4Section of Vascular Surgery, University of Michigan, Ann Arbor, MI
5Division of Cardiology, University of Michigan, Ann Arbor, MI

Background: GMI-1271 is a potent, specific E-selectin antagonist which targets interactions between cancer cells and the bone marrow niche thereby increasing tumor sensitivity to chemotherapy; avoids HSC mobilization; and inhibits thrombosis without increasing bleeding risk.  Delayed inflammatory cell recruitment into the vein wall post thrombus induction indicates a possible decrease in leukocyte activation, which may be crucial in treating both acute and cancer associated thrombosis.

Here we report first-in-human evaluation of GMI-1271 for safety (including bleeding), PK, and biomarker data for effects on adhesion and mobilization.

Methods: Two Phase I single dose escalation DBRCT in healthy subjects evaluated 2, 5, 10, and 20 mg/kg IV doses of GMI-1271. Study 1 is complete and unblinded (GMI-1271 vs placebo).  Study 2 is ongoing, remains blinded (GMI-1271 vs placebo) with open-label positive control (Lovenox), and is reported in aggregate. In both studies, assessments included safety (adverse events [AEs], clinical labs, bleeding time, PT/PTT, vitals, and exam); PK (drug levels in plasma and urine); and biomarkers (plasma soluble E-selectin [sEsel], sPsel, sICAM-1 levels; and blood CD34+ counts).  Only sEsel and CD34+ are reported for Study 1; sEsel, sPsel, sICAM-1 for Study 2. Comparisons to baseline were made by ANOVA and paired t-test models; PK analyses were for total clearance (CL), volume of distribution (Vz), elimination half-life (t˝), fraction excreted (Fe), and renal clearance (CLr).

Results: Forty-six subjects enrolled; 30 received GMI-1271 (10 each at 2 and 5 mg/kg; 6 at 10 mg/kg; and 4 at 20 mg/kg) and 16 received control (13 placebo, 3 Lovenox). 

Safety: All subjects completed the studies; labs, vitals, and exam were unremarkable.  Bleeding times and PT/PTT were unaffected by E-selectin inhibition.  No serious AEs were seen. For Study 1, AEs were seen in 12/18 (66.7%) of those on GMI-1271 and 5/10 (50%) on placebo. AEs were mostly mild events at the infusion site (i.e. tenderness or erythema), and occurred in both groups. One moderate AE occurred (vasovagal reaction) in the 2 mg/kg GMI-1271 cohort. Three AEs were possibly related to drug: 2 in the 2 mg/kg cohort (infusion site bruise, lightheaded), and 1 in the 5 mg/kg cohort (metallic taste). For Study 2, AEs were seen in 12/15 (80%) of those on GMI‑1271/placebo and 3/3 (100%) on Lovenox.  All AEs were mild. In GMI‑1271/placebo group, all AEs were considered unrelated to study drug; 3 were infusion site bruise (1 per dose level). In the Lovenox group, AEs were bruise at injection site (related) and blood in urine (possibly related). 

PK: Plasma levels, Cmax, and AUC increased in a consistent dose-related manner in both studies (figure).  CL, Vz, and t˝ were not dose dependent; the latter averaged ~2.3 hours.  ~66% of the dose was excreted unchanged in the urine independent of dose level, and CLr averaged 86 mL/min, less than estimated CrCl, suggesting tubular reabsorption is one component of CLr.

Biomarkers: In Study 1, the absolute CD34+ and %CD34+ cell counts were normal across all cohorts. There was no dose-response for changes in peripheral CD34+ counts after administration of GMI‑1271 (doses 2-10 mg/kg).  Plasma concentrations of sEsel were relatively constant in the placebo and GMI‑1271 2 mg/kg cohorts, with significant reduction (vs baseline, p=0.012) at 48hrs post-2mg/kg dose only.  In the 5 and 10 mg/kg cohorts sEsel decreased significantly post-dose (p<0.0001) and returned to baseline by 24 to 48 hours respectively; reductions were greater at high dose.  In Study 2, significant reduction in sEsel was similarly seen after treatment vs baseline (p=0.05), and in sP-sel with treatment vs baseline (p = 0.04), or vs day 2 (p< 0.01). sICAM-1 was also lower after treatment vs baseline (p=0.05).

Conclusion: First-in-human experience with the potent E-selectin antagonist GMI-1271 demonstrated favorable safety and PK at single doses up to 20 mg/kg. These findings are consistent with the glycomimetic class for safety at anticipated therapeutic levels.  Biomarkers of physiologic effect demonstrated clear reductions in sEsel/sPsel; decreased leukocyte adhesion with lower sICAM-1 levels; and no CD34+ rise indicating no mobilization of HSCs. Studies of GMI-1271 are ongoing to evaluate activity in hematologic malignancies and thrombosis.

Figure: Plasma concentrations and Cmax are consistent for GMI-1271 between Phase 1 studies.

image001,image002

 

Disclosures: Sood: Bayer: Research Funding . Hemmer: GlycoMimetics: Employment , Equity Ownership . Flanner: GlycoMimetics: Employment , Equity Ownership . Kramer: GlycoMimetics: Consultancy . Nietubicz: GlycoMimetics: Employment , Equity Ownership . Myers: GlycoMimetics: Research Funding . Wakefield: GlycoMimetics: Research Funding . Magnani: GlycoMimetics: Employment , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees . Thackray: GlycoMimetics: Employment , Equity Ownership .

*signifies non-member of ASH