Antithrombin Aptamer ARC183

Heparin has been used extensively, and almost exclusively, as the anticoagulant during cardiac surgery, including CABG procedures. The reasons for its use are related to low cost, ease of monitoring (by activated clotting time (ACT)), reversibility (using protamine) and lack of a suitable anticoagulant replacement. There are, however, several limitations to the use of heparin, including: a long halflife requiring protamine to be used as an antidote; heparin-induced thrombocytopenia in 2-5% of patients exposed; significant non-specific plasma binding; he-parin cannot inhibit clot bound thrombin; and heparin has been associated with platelet aggregation and dysfunction (Warkentin and Greinacher, 2003; Adler, 2004). Moreover, protamine has been associated with immune-mediated reactions, and its short half-life (~5 min) may result in unopposed heparin effects post operatively (Butterworth et al., 2002). The adverse properties and limitations of heparin with protamine illustrate that this combination of agents is not ideal for anticoagulation during cardiac surgery. Consequently, a number of newer, higher cost anticoagulants, such as low-molecular-weight heparins and Angiomax (Bivalirudin), are being developed for this market. However, these compounds have similar side effects and their anticoagulation activity cannot be reversed rapidly. There is a significant unmet medical need for a safe, moderate-cost anticoagulant that does not require a separate reversing agent.

The antithrombin aptamer drug ARC183 (Archemix Corp) is a thrombin inhibitor in development for use as an anticoagulant during CABG procedures (Bock et al., 1992). ARC183 is an all-DNA molecule, 15 nucleotides in length, and comprised entirely of G and T residues having the following sequence: 5' GGT TGG TGT GGT TGG 3'. NMR studies performed by Wang et al (1993) indicate that ARC183 folds into a stable "chair-like" structure as depicted in Fig. 17.3.

Fig. 17.3 Folded structure of antithrombin aptamer ARC183.

ARC183 exhibits a Kd of 2nmol/L for thrombin, 50nmol/L for prothrombin, and binding to other serum proteins or proteolytic enzymes is essentially undetectable (Bock et al., 1992). It is a strong anticoagulant in vitro, and inhibits throm-bin-catalyzed activation of fibrinogen, and thrombin-induced platelet aggregation. ARC183 has key advantages in that it is a specific inhibitor with rapid onset, is effective at inhibiting clot-bound thrombin and has a short in vivo half-life that allows for rapid reversal of its effects and the avoidance of the dose-adjusting complications of heparin and protamine (Lee et al., 1995). Neither significant toxici-ties nor excessive bleeding intraoperatively have been observed in preclinical studies (DeAnda et al., 1994).

ARC183-dependent anticoagulation occurs within minutes (Griffin et al., 1993; Lee et al., 1995). It is a potent anticoagulant in dog and monkey models of cardiopulmonary bypass, yielding dose-dependent ACT values of 1500 s, at a 0.5 mg/ kg/min dose (DeAnda et al., 1994). ARC183 exhibits a very short functional half-life in vivo of ~2min, thus allowing for rapid reversal of the anticoagulant effects (Lee et al., 1995). It is cleared through the action of serum nucleases (Shaw et al., 1995) and through renal elimination. No acute toxicities have been observed, nor did ARC183 show any evidence of genotoxicity in preclinical testing. These findings indicate that the agent will continue to show an improved efficacy and safety profile over that of heparin. Clinical trials of ARC183 began in 2004.


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