Tissue factor/activated factor VII (TF/fVIIa) inhibition by recombinant nematode anticoagulant protein c2 (rNAPc2) involves the following steps: 1) rNAPc2 binds tightly to zymogen factor X; 2) docking of the rNAPc2-fX complex to TF/fVIIa assembled on a procoagulant phospholipid surface; and 3) presentation of the reactive loop of rNAPc2 to the active site of fVIIa, resulting in a tightly bound quarternary inhibitory complex. c2 = rNAPc2; TF = tissue factor; VIIa = fVIIa; X = factor X.

The study had 2 phases: (A) a double-blind, randomized, placebo-controlled, ascending dose-ranging phase and (B) a single-arm, unblinded heparin de-escalation phase. In the dose-ranging phase (A), 203 patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS) managed with an early catheterization were randomized 4:1 to recombinant nematode anticoagulant protein c2 (rNAPc2) or matching placebo administered intravenously (IV) every 48 h for 1 to 3 doses in 8 panels of 25 patients each. In the heparin de-escalation phase (B), 26 patients received 10 µg/kg rNAPc2 and half-dose unfractionated heparin (UFH), followed by a second panel of 26 patients treated with 10 µg/kg rNAPc2 and no heparin. *Encouraged per current practice guidelines. 10 µg/kg dose panel repeated. ASA = aspirin; ECG = electrocardiogram; Enox = enoxaparin; GP = glycoprotein.

(A) Increasing doses of recombinant nematode anticoagulant protein c2 (rNAPc2) were associated with increased plasma drug concentrations at 2 to 6 and 48 h. (B) rNAPc2 increased the international normalized ratio (INR) in a dose-related fashion at 2 to 6 and 48 h.

Prothrombin fragment 1.2 (F1.2), a marker of new thrombin generation, was reduced signficantly at 2 to 6 and 48 h with 7.5 µg/kg recombinant nematode anticoagulant protein c2 (rNAPc2) compared with placebo. Lower-dose rNAPc2 (1 to 5 µg/kg) blunted the increase in F1.2 seen at 48 h in the placebo group.

There was no difference between the rates of major plus minor hemorrhage among patients receiving recombinant nematode anticoagulant protein c2 (rNAPc2) versus placebo (3.7% vs. 2.5%, respectively), nor was there a trend across ascending doses (p = NS). All major and minor bleeding events were related to procedures; none were spontaneous. *3/4 major hemorrhages were CABG-related, 2 to 3 days after surgery. CABG = coronary artery bypass graft; Hgb = hemoglobin; ICH = intracranial hemorrhage; TIMI = Thrombolysis In Myocardial Infarction; UFH = unfractionated heparin.