Early Data Show Promise for Reversible, Fast-Acting, Antiplatelet Drug PZ-128

Much has been said about fine-tuning the balance between ischemic and bleeding risks among PCI patients receiving antiplatelet medications, of which there are legion. Now, findings from a small, phase I study of a novel drug known as PZ-128 hint that it may hold advantages over its predecessors. Namely, it is fast acting, specific, dose dependent, and reversible.

PZ-128 belongs to a new class of drugs known as pepducins, lipidated peptides that penetrate cells to work from within while remaining attached to the cell membrane, said Athan Kuliopulos, MD, PhD, of Tufts Medical Center (Boston, MA), whose lab created the technology. Like vorapaxar (Zonativity; Merck) and atopaxar, it is a PAR-1 inhibitor; however, neither of those 2 drugs is a pepducin.

“The reason why people are interested in PAR-1 is [that its agonist] is thrombin, and thrombin is the most potent activator of platelets” compared with other signaling pathways, he explained to TCTMD. Vorapaxar was FDA approved last year for secondary prevention in patients with PAD or a history of MI, but it failed to get cleared for use during PCI “because of a very high risk of lethal or severe bleeding,” Kuliopulos continued. The main reason why vorapaxar did poorly in that setting, he said, “is that it was essentially irreversible. It had a pharmacodynamic half-life blocking the platelets for over a month with a single dose.”

Dose-Dependent, Reversible Effects

For their study, released online ahead of its print publication, January 2016, in Arteriosclerosis, Thrombosis and Vascular Biology, Kuliopulos and colleagues administered PZ-128 to 31 individuals via continuous IV infusion for 1 to 2 hours at doses ranging from 0.01 to 2 mg/kg. One-fifth had CAD, and all had multiple risk factors such as smoking, hypertension, diabetes, and dyslipidemia.

PZ-128’s inhibitory effects, as measured by platelet aggregation stimulated by the PAR-1 agonist SFLLRN (8 µmol/L) at 30 minutes to 6 hours, were dose dependent: 20-40% inhibition at 0.3 mg/kg, 40-60% at 0.5 mg/kg, and 80-100% at 1-2 mg/kg. Its effects were greater in the 63% of patients also on aspirin therapy.

By 24 hours, the 0.5 mg/kg PZ-128 dose was reversible with 50% recovery of aggregation to SFLLRN. The plasma half-life was 1.3-1.8 hours. Importantly, the drug’s effects seemed specific to PAR-1, and there were no observed changes in bleeding, coagulation, clinical chemistry, or ECG parameters. Nor could the drug be detected in urine.

“The most important adverse events was acute allergic reactions occurring in several subjects receiving the highest doses of PZ-128,” the researchers note. In these cases, they decreased the dose and extended the infusion time from 1 to 2 hours. “This strategy along with premedication mitigated the allergic reaction and resulted in a tolerated and efficacious dose of 0.5 mg/kg,” they say.

TRIP-PCI, a phase II study pitting PZ-128 against placebo in patients undergoing nonemergent PCI, is currently in the planning stages. The drug will be given on top of standard of care, including aspirin and a P2Y12 inhibitor, Kuliopulos said. As with any antiplatelet drug, the question will be any anti-ischemic effects are offset by too much bleeding.

Of broader interest is that PZ-128, as a pepducin, is “the first of its kind to be tested in humans…. It’s not just another antiplatelet tested. It’s really a new class of drugs, and this is why people are very excited about it,” he explained. “If this is successful in the phase II study, maybe we can get interest in developing additional pepducins for other diseases [such as] atherosclerosis, diabetes, obesity, and . . . non-alcoholic steatohepatitis.” 

Source: 
Gurbel PA, Bliden KP, Turner SE, et al. Cell-penetrating pepducin therapy targeting PAR1 in subjects with coronary artery disease. Arterioscler Thromb Vasc Biol. 2016;36:189-197.

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