ISIS-FXI_Rx, A Novel and Specific Antisense Inhibitor of Factor XI, Caused Significant Reduction in FXI Antigen and Activity and Increased aPTT without Causing Bleeding in Healthy Volunteers

Factor XI (FXI) deficient subjects (Hemophilia C) have a low incidence of stroke and venous thromboembolism and yet do not exhibit spontaneous bleeding events, suggesting that inhibition of FXI activity (FXI:C) may be an attractive antithrombotic therapeutic strategy. We have previously demonstrated that treatment with FXI antisense oligonucleotides results in robust antithrombotic effects in multiple models of venous and arterial thrombosis without causing bleeding, validating this therapeutic approach preclinically.

To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics (FXI antigen, FXI:C and aPTT) of single and multiple doses of ISIS-FXI_Rx or placebo in healthy volunteers.

In this double blind, single or multiple ascending-dose (SAD or MAD) study, healthy subjects aged 18 to 65 years were randomly assigned in a 3:1 ratio to receive ISIS- FXI_Rx or placebo (normal saline) administered as a single subcutaneous (SC) injection at 50, 100, 200 and 300 mg/kg (n=8/cohort, except 200 mg cohort n=16), or as multiple SC injections (n=12/cohort). In the MAD cohorts, subjects received 8 SC doses over 6-weeks (3 doses in Week 1 followed by once weekly dosing for 5 weeks).

In the SAD cohorts, both FXI antigen and FXI:C in the 200 and 300 mg cohorts were significantly reduced 1-week after dosing. In the MAD cohorts (interim analysis, data for 300 mg not analyzed to date), treatment with ISIS- FXI_Rx demonstrated a robust, sustained and dose-dependent reduction in FXI antigen and FXI:C as compared with placebo group, with maximum reduction observed 1–2 weeks post-dosing (Table). These reductions were accompanied by a concomitant increase in aPTT.

Mean (%) Change From Baseline in the MAD Cohorts

Furthermore, in the 200 mg multiple cohort, FXI:C and FXI antigen were reduced by 92% and 100% respectively in one subject after 6 weeks dosing with no symptoms, including bleeding. Significant correlation between FXI:C reduction and aPTT prolongation was observed (r=-0.8123, p=0.0078). No study drug related bleeding events were reported. ISIS-FXI_Rx did not cause clinically significant changes in vital signs, ECG, hepatic function, renal function or hematology. One serious AE (allergic reaction) was reported in the 200 mg single dose cohort in an ISIS-FXI_Rx treated subject, who recovered completely. Most AEs were mild. SC injections of ISIS-FXI_Rx were well tolerated with mild injection site reactions reported in 33% of the subjects vs. 10.5% in placebo group. Preliminary PK analysis indicates hepatic T_1/2 of ISIS-FXI_Rx across doses to be ∼20 days.

Treatment with ISIS- FXI_Rx in healthy volunteers demonstrated a statistically significant and sustained reduction of FXI:C, FXI antigen and prolonged aPTT with an acceptable safety and tolerability profile. No bleeding events related to ISIS- FXI_Rx were found. These data provide further support for development of ISIS-FXI_Rx as a novel approach for the treatment and prevention of thromboembolic disorders.

Liu:ISIS Pharmaceuticals: Employment. Bethune:ISIS Pharmaceuticals: Employment. Dessouki:ISIS Pharmaceuticals: Consultancy. Grundy:ISIS Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment. Bhanot:ISIS Pharmaceuticals: Employment.