Photo by Sakurai Midori
Researchers say they have developed an antiplatelet agent that has demonstrated considerable
antithrombotic activity and low bleeding liability in monkeys.
The agent, known as BMS-986120, is a PAR4 antagonist.
Experiments in cynomolgus monkeys indicated that BMS-986120 can effectively fight thrombosis but poses a lower risk of bleeding than clopidogrel.
The researchers described these experiments in Science Translational Medicine.
The research was supported by Bristol-Myers Squibb but also benefited from funding from the “Fonds pour un Québec Innovant et en Santé” from the Ministry of Economy, Science and Innovation of Québec.
To investigate the effects of PAR4 inhibition, the researchers developed PAR4-targeted antibodies and tested them in guinea pigs. The antibodies exhibited antithrombotic activity in the animals, while posing a low risk of bleeding.
Because of these positive results, the researchers performed a high-throughput screen of more than 1 million molecules to find a PAR4 inhibitor. They identified BMS-986120 as a “highly potent, selective, and reversible” inhibitor of PAR4 in human platelets.
The researchers wanted to test BMS-986120 in cynomolgus monkey models of occlusive arterial thrombosis and provoked bleeding time (BT). But the team first had to validate the translatability of the models (for clinical prediction of efficacy and bleeding liability) by studying clopidogrel in the animals.
When compared to vehicle control, clopidogrel slowed vascular occlusion and reduced thrombus weight in the monkeys in a dose-dependent manner. But clopidogrel also had “strong effects” on hemostasis.
When the researchers tested BMS-986120 (vs vehicle control) in these models, they observed a wider therapeutic window with BMS-986120 than with clopidogrel.
The researchers said BMS-986120 was “highly effective” in preserving vascular patency during the induction of occlusive thrombosis. When given at 1 mg/kg, BMS-986120 prevented vascular occlusion in all monkeys.
BMS-986120 also decreased thrombus weight in a dose-dependent manner. When given at 1 mg/kg, BMS-986120 reduced thrombus formation by 82%.
BMS-986120 had a limited, though still statistically significant, impact on hemostasis. BMS-986120 at 1 mg/kg significantly increased kidney and mesenteric BT when compared to vehicle control (P<0.0001 for both).
The researchers plotted the relative antithrombotic (thrombus weight reduction) and BT effects of clopidogrel and BMS-986120 as a function of the dose of each drug.
They found that, at doses resulting in about 50% to 80% antithrombotic activity, clopidogrel produced about 8- to 9-fold increases in kidney and mesenteric BT. BMS-986120, on the other hand, produced increases of about 2-fold or less in kidney and mesenteric BT.
The researchers said these preclinical findings suggest that targeting PAR4 is an attractive antiplatelet strategy, and BMS-986120 has potential as an antiplatelet agent. The drug is currently being evaluated in clinical trials.
