PZ-128: Novel Antiplatelet Agent May Provide Rapid, Reversible PAR-1 Inhibition During PCI

Deborah Brauser

December 22, 2015

BOSTON, MA — The "cell-penetrating lipopeptide pepducin" known as PZ-128 may decrease the risk of coronary thrombosis during PCI by targeting and inhibiting the protease-activated receptor-1 (PAR-1), preliminary research suggests[1].

The phase 1 study included 31 patients with documented CAD or multiple risk factors for the disease, all of whom received a continuous IV infusion of the novel antiplatelet agent at doses ranging from 0.01 to 2 mg/kg for 1 to 2 hours.

Between 80% and 100% of the participants who received 1 to 2 mg/kg of PZ-128 had inhibition of platelet aggregation stimulated by the PAR-1 agonist SFLLRN  30 minutes to 6 hours postdosing, report the investigators, led by Dr Paul Gurbel (Sinai Hospital of Baltimore, MD). Inhibition was also achieved by 20% to 40% of those who received the 0.3-mg/kg dose, and by 40% to 60% of those who received the 0.5-mg/kg dose.

In the subgroup receiving concurrent aspirin, inhibition was achieved by 95% to 100% of the participants receiving 0.5 to 1 mg/kg of PZ-128 6 hours after dosing and by 65% to 100% at 30 minutes to 2 hours after dosing.

When examining reversibility of the inhibitory effects, the researchers found that half of the patients receiving 0.5 mg/kg of the novel agent achieved recovery of platelet aggregation within 24 hours of dosing and nearly all had complete recovery by 8 days.

There were no significant treatment-related adverse effects on bleeding, coagulation, or heart rate. However, "transient" tingling or numbing in the skin was commonly reported in the patients receiving doses higher than 0.5 mg/kg. In addition, some patients who received 1- or 2-mg/kg doses had allergic reactions, which stopped when the dose was lowered to 0.5 mg/kg.

"This treatment worked as quickly as 30 minutes, which is exciting because none of the oral drugs generally work in less than 2 hours," principal investigator Dr Athan Kuliopulos (Tufts Medical Center, Boston, MA) told heartwire from Medscape.

"We were able to show, at least in a preliminary study, that we can achieve complete blockade of the receptor quickly; it remained blocked for at least 6 hours; and it starts to recover appreciable function by the next day," added Kuliopulos.

The findings were published online December 17, 2015 in Arteriosclerosis, Thrombosis, and Vascular Biology.

First In-Human Study

"Pepducins are membrane-tethered . . . lipopeptides that target the cytoplasmic surface of their cognate receptor," write the investigators, adding that this is the first-in-human report of benefits from a PAR-1–based pepducin. "PZ-128 is being developed for prevention of acute thrombotic complications of PCI," they add.

Kuliopulos noted that although the PAR-1-inhibiting pill vorapaxar (Zontivity, Merck Sharpe & Dohme) is currently available for patients with peripheral artery disease or a history of MI, it isn't approved for use during cardiac procedures because of the significant risk for increased bleeding. "In other words, there are no drugs approved that target PAR-1 in acute settings," he said.

The goal of this phase 1 study was to examine the safety and tolerability of a variety of doses for PZ-128.

The patients who enrolled (59% men; 50% white, 47% black, 3% other) were between the ages of 43 and 74 years (mean age 57 years). Of these, 22% had CAD and 100% had multiple coronary disease risk factors, such as smoking, diabetes mellitus, and hypertension.

There were three patients in each of the 0.01-, 0.03-, 0.1-, and 0.3- mg/kg PZ-128 dosing groups; six patients in each of the 0.5- and 2-mg/kg groups; and seven patients in the 1-mg/kg group. In addition, all were taking concurrent CVD therapy: 66% were taking antihypertensives, 63% were taking aspirin, and 56% were taking statins or other lipid-lowering medications.

Measures were conducted at baseline and at 30 minutes and 1, 2, 6, and 24 hours after dosing. Follow-ups were also done 7 and 10 days later.

Triple Therapy?

The patients receiving PZ-128 at doses between 0.01 and 0.1 showed no effect on platelet aggregation. However, starting with the 0.5-mg/kg dose, there was a significant, dose-dependent inhibitory effect.

Regardless of whether there was concurrent aspirin use, 80% to 100% of the 1-mg/kg PZ-128 group had inhibition 30 minutes to 6 hours postdosing; 96% to 98% of the 2-mg/kg group achieved inhibition at 1 and 2 hours postdosing and showed the fastest recovery of platelet aggregation.

In addition, "PZ-128 was specific to PAR-1, with no significant effects on aggregation induced by other platelet agonists," report the researchers. Pharmacokinetics analyses showed no trace of the drug in plasma starting at the 24-hour postdosing exam and "little or no" detection in urine.

Kuliopulos noted that a phase 2, multicenter study for PZ-128 is now in the planning stages. It will include 600 PCI and/or ACS patients who will receive one of two doses of the agent or placebo.

"Unlike dual antiplatelet therapy, this is really triple therapy," said Kuliopulos. "We feel that other antiplatelet drugs don't have much effect on PAR-1. But because this one does, we feel that it will be a third drug added onto aspirin and a P2Y12 inhibitor."

He added that "this whole new strategy" is exciting. "It's targeting receptors from the inside surface of cells, which has never been done before. And we think it sets the stage for showing that a pepducin concept can work."

The study was funded by a grant from the National Heart, Lung, and Blood Institute. Gurbel reports serving as a consultant to and/or receiving honoraria from Daiichi Sankyo, Lilly, Bayer, AstraZeneca, Merck, Boehringer, Janssen, and CSL Behring and receiving grants from the National Institutes of Health, Daiichi Sankyo/Lilly, CSL, AstraZeneca, Harvard Clinical Research Institute, Bayer, Haemonetics, Duke Clinical Research Institute, Sinnowa, Coramed, and Accumetrics. Kuliopulos reported serving as a consultant for Eli Lilly as a founder of Oasis Pharmaceuticals. Disclosures for the coauthors are listed in the article.

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