Targeting prostacyclin: all gain with no pain?

In this issue of Blood, Stanger et al synthesized CS585, a novel analogue of oxylipin 12(S)-hydroxy-eicosatrienoic (12-HETrE) that targets the prostacyclin receptor.¹ Platelets form the 12-HETrE, a metabolite of 12-lipoxygenase. 12-HETrE activates the prostacyclin receptor, increasing cyclic adenosine monophosphate generation and attenuating platelet reactivity. In a comprehensive suite of studies building on a body of prior work,^2-4 these authors demonstrate that CS585 selectively inhibits platelet secretion, aggregation, integrin activation, and adhesion. In addition, both arterial and venous thrombosis in vivo were significantly reduced with CS585. Importantly, CS585 comparably reduced human and murine platelet activation.

The promiscuity of prostaglandin analogs has been a challenge to the development of drug analogs.⁵ Stanger et al demonstrate that CS585 works selectively through the IP receptor, with no apparent off-target signaling through other prostanoid receptors. They also demonstrated that the potency of CS585 for inhibiting platelet aggregation was ∼20× greater than 12-HETrE. CS585 was stable in mice and could be administered intravenously or orally. These features of CS585 could enhance more rapid clinical adoption, if eventually approved, as was observed with the use of direct oral anticoagulants (eg, apixaban, rivaroxaban, dabigatran, end edoxaban) compared with parenteral heparinoids.

Currently available antithrombotic agents remain limited by their propensity to cause bleeding that may be life-threating. These authors assessed the effects of CS585 on tail bleeding times in mice and thromboelastography (TEG) parameters in human whole blood. Encouragingly, even at high concentrations CS585 did not increase tail bleeding times nor significantly prolong initiation of clotting times. Moreover, the addition of CS585 to rivaroxaban (a commonly used, Food and Drug Administration–approved, oral factor Xa-inhibitor) did not alter TEG parameters compared with rivaroxaban alone.

Prior studies have found that the prostacyclin receptor also mediates both pro- and anti-inflammatory host responses, depending on the tissue and/or disease setting (reviewed by Biringer⁶). Although the effects of CS585 on inflammation were not assessed in the current study, it is intriguing to consider whether CS585 might also modulate the injurious inflammatory responses (including inflammatory bleeding⁷) underlying pulmonary fibrosis, arthritis, and atherosclerosis—diseases mediated in part by platelets.

The development of new antithrombotic agents that do not cause bleeding is an unmet clinical need.^8,9 Although current antithrombotic medications, such as antiplatelet and anticoagulant drugs, play a pivotal role in preventing injurious thrombosis and reducing the risk of cardiovascular events, they often come with an inherent trade-off—increased susceptibility to bleeding complications. Striking a delicate balance between preventing thrombosis and maintaining normal hemostasis is challenging. Bleeding events not only undermine the therapeutic benefits of antithrombotic therapy but also limit the use of current agents in many patient populations and for longer periods of time. As such, the quest for novel antithrombotic agents that possess a targeted and selective mechanism of action, tailored to inhibit clot formation without disrupting the delicate equilibrium of hemostasis, is imperative. The development of such agents holds the promise of enhancing patient care by minimizing the detrimental consequences of bleeding complications, thereby optimizing the overall risk-benefit profile of antithrombotic treatment strategies. As such, Stanger and colleagues should be complemented on their efforts to close these knowledge gaps and fill this unmet need.

As is true with all drug development programs, translation of these preclinical and human ex vivo findings into clinical trial programs is necessary. One of many intriguing applications for CS585 might be in patients who require dual antiplatelet therapy or dual antiplatelet therapy plus anticoagulation, which generally increases bleeding risk compared with monotherapy with a single antithrombotic or antiplatelet agent. Although this and other questions are hopefully answered with future clinical trials, the discoveries now reported by Stanger and colleagues mark an important milestone along this pathway.

Conflict-of-interest disclosure: The author declares no competing financial interest.