Blocking platelet aggregation by inhibiting the protease-activated receptor PAR4 prevented the formation of harmful blood clots, while having less of an effect on blood clots that repaired injury. The results, which were published in the Jan. 4, 2017, issue of Science Translational Medicine, "validate PAR4 as an antithrombotic target with the potential for a favorable safety/efficacy ratio," Michael Burgess, head of cardiovascular, fibrosis, immunoscience and GDD development at Bristol-Myers Squibb Co. (BMS), told BioWorld Today.

In its anniversary publication "50 Years in Hematology: Research That Revolutionized Patient Care," the American Society of Hematology (ASH) highlighted the discovery of clot-busting drugs as one example of transformative research. According to ASH, disorders that arise from blood clots in the vessels, most notably heart attacks and strokes, "collectively are the most common cause of death and disability in the developed world."

The advent of antithrombotic therapy has reduced the risk of deep vein thrombosis, which can lead to pulmonary embolism, by more than 70 percent, and "markedly reduced death from heart attacks, the risk of stroke in people with heart irregularities (atrial fibrillation), and the risk of major stroke in patients with mini-strokes."

To date, all commercially available clotbusters increase the risk of bleeding, because they target both hemostasis, the process by which blood clots form after an injury, and thrombosis, the formation of blood clots in the absence of an injury.

While the clots that are the end products of both hemostasis and thrombosis are indistinguishable from each other, the processes by which those clots form differ to a degree. Researchers are trying to exploit those differences to develop therapies that can affect thrombotic more than hemostatic clots. (See BioWorld Today, Oct. 29, 2013, and Aug. 25, 2016.)

PAR4 is one such target. Along with PAR1, which is the target of Zontivity (vorapaxar, Merck & Co. Inc.), it mediates the activation of platelets by thrombin.

Zontivity illustrates the bind that current antithrombotics are in. While consensus estimates published by Cortellis predict the drug will break $100 million in sales by 2017, it also comes with a black box warning that it increases risk of bleeding, including intracranial hemorrhage and fatal bleeding. It is contraindicated in patients with a history of stroke, transient ischemic attack and intracranial hemorrhage.

In the work now published in Science Translational Medicine, authors from BMS and the University of Montreal focused on PAR4, a less-investigated sibling of PAR1. They first showed that antibodies to PAR4 reduced clot formation in guinea pigs, but did not increase bleeding time.

A high-throughput screen of more than 1 million compounds followed and resulted in BMS-986120, an orally available small-molecule PAR4 blocker.

The team compared BMS-986120 to Plavix (clopidogrel, BMS/Sanofi SA), in cynomolgus monkeys, whose expression pattern of PAR1 and PAR4 is similar to that of humans. "Preclinical species, including mouse, rat, dogs and rabbits, only use PAR4 as a single signaling thrombin receptor. The situation is different in humans and primates, which both express PAR1 and PAR4 on the platelet surface. Whether inhibition of PAR4 in species with a dual PAR1/PAR4 system is antithrombotic was unknown before this work. Also, whether inhibition of PAR4 would lead to bleeding liabilities in a species with a dual PAR1/PAR4 system on platelets was unknown," Burgess said.

The team showed that while Plavix treatment affected both clotting and bleeding in a dose-dependent manner, the effects of BMS-986120 were much stronger on clotting at higher doses, while bleeding times were relatively unaffected, and increased only slightly with higher doses, leading to a larger therapeutic window for BMS-986120.

BMS-986120 has been in two phase I trials in healthy volunteers, but Burgess said that "no studies of this asset are currently ongoing."

However, "BMS has also developed BMS-986141, a second asset targeting PAR4. Based on early study results, this asset has been moved forward to phase II."