Ciraparantag Safely and Effectively Reverses Apixaban and Rivaroxaban in Age-Matched Healthy Volunteers As Measured By Whole Blood Clotting Time

Background: Ciraparantag is a small molecule drug candidate in clinical development as a reversal agent for the Xa direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH). In previous clinical trials, ciraparantag has shown complete and sustained reversal of the Xa DOAC, edoxaban, and the LMWH, enoxaparin, following a single intravenous (i.v.) bolus dose, as measured by whole blood clotting time (WBCT) [1-3].

Clinical Design: In the current studies, healthy subjects age-matched to the patient population, 50 to 75 years old, were administered either 10 mg apixaban p.o. BID for 3.5 days or 20 mg rivaroxaban p.o. QD for 3 days to steady-state. At maximal activity, either four hours after the third daily dose of rivaroxaban or three hours after the seventh twice daily dose of apixaban subjects were randomized 3:1::active:placebo in 16 subject dosing cohorts of 50 mg, 100 mg, 200 mg or 300 mg intravenous ciraparantag acetate, or placebo saline. Pharmacodynamic response was measured by WBCT, a modernized and standardized Lee White clotting time, in which the time for freshly drawn venous whole blood to clot after activation in glass test tubes maintained at physiologic temperature is measured by blinded observers.

Results and Discussion: The safety profile of ciraparantag in these studies is consistent with previous trials. The most common potentially related adverse events were transient mild facial flushing and dysgeusia. No pro-coagulant signals were observed in any clinical trials to date. Doses of 100 mg and higher showed complete and sustained reversal of both steady-state apixaban (Figure 1a) and rivaroxaban (Figure 1b). Ciraparantag acetate doses of 100 mg and higher have demonstrated complete and sustained reversal of apixaban, edoxaban, enoxaparin and rivaroxaban potentiating a single reversal dose strategy for the Xa DOACs and LMWH.

Figure 1: Ciraparantag acetate shows complete and sustained reversal of steady-state apixaban (a) and rivaroxaban (b) at doses of 100 mg and greater, as measured by whole blood clotting time (WBCT).

References

1. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso MA, Brown K, Dishy V, Lanz HJ, Mercuri MF, Noveck RJ, Costin JC. "Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban." Thromb Haemost. 2017 Jan 26;117(2):238-245.

2. Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. "Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin." Thromb Res. 2016 Oct;146:113-118.

3. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, Dishy V, Noveck RJ, Costin JC. "Use of PER977 to reverse the anticoagulant effect of edoxaban." N Engl J Med. 2014 Nov 27;371(22):2141-2.

Figure 1

View largeDownload slide

Figure 1

View largeDownload slide

Close modal