The results of a phase 1 trial that evaluated the safety of RUC-4, a novel subcutaneous GPIIb/IIIa inhibitor, were presented by Dr. Dean Kereiakes at the American Heart Association 2019 meeting. The study showed that in healthy volunteers and subjects on aspirin with stable coronary artery disease (CAD), RUC-4 provided rapid and high-grade platelet inhibition that resolved within 2 hours.
While there was an improvement in the door to balloon time over the past 15 years, this did not translate into an improvement in mortality. However, previous studies demonstrated that reducing the time to GPIIb/IIIa antagonist treatment in STEMI did lead to an improvement in mortality over the next ten years. Developing a GPIIb/IIIa inhibitor that can be easily administered early in the clinical pathway could potentially lead to improved outcomes in patients with a STEMI. In this phase 1 trial, the investigators aimed to assess the safety of various doses of RUC-4 in healthy volunteers and patients on aspirin with stable CAD. The investigators escalated the dose of RUC-4 until they reached the biologically effective dose (BED) or maximum tolerated dose (MTD) as identified. The BED was defined as the dose leading to more than an 80% inhibition of ADP-induced platelet aggregation within 15 minutes of subcutaneous administration with a return towards baseline values of platelet activity within 4 hours.
[perfectpullquote align=”full” bordertop=”false” cite=”” link=”” color=”” class=”” size=””]“Within 20 minutes of a subcutaneous injection, you have got greater than 80% platelet inhibition which we establish is a validated and established benchmark for efficacy with respect to reducing MACE and ischemic events periprocedurally and in ACS. We were able to achieve that within 15 minutes of a subcutaneous injection.” – Dr. Dean Kereiakes, M.D.[/perfectpullquote]
In the final study, a total of 14 healthy volunteers and 28 patients with stable CAD on aspirin were enrolled. In the healthy volunteer group, 6 received an RUC-4 dose of 0.075mg/kg, 6 received a dose of 0.05 mg/kg and 2 received a placebo. In the stable CAD group, 18 received the 0.075mg/kg dose of RUC-4 and 0.050 mg/kg dose of RUC-4 and 4 received a placebo. While aspirin, gender, and BMI did not significantly alter the clearance of RUC-4, the weight did. The investigators found that patients who weighed more had a greater clearance rate. RUC-4 was found to be well tolerated. As for its efficacy profile, patients in both groups who received RUC-4 were able to achieve rapid (within 15 minutes) and high grade (more than 80% platelet inhibition) that resolved within 2 hours. With regard to RUC-4’s safety profile, there were no serious adverse drug events. The majority of adverse events were mild and none led to subject discontinuation. Additionally, the addition of aspirin did not lead to increase bleeding.
In an interview with Dr. C. Michael Gibson, Dr. Kereiakes discussed the findings of this study. He said, “Within 20 minutes of a subcutaneous injection, you have got greater than 80% platelet inhibition which we establish is a validated and established benchmark for efficacy with respect to reducing MACE and ischemic events periprocedurally and in ACS. We were able to achieve that within 15 minutes of a subcutaneous injection”. The results of this phase 1 trial could potentially help identify appropriate doses for a future phase 2 trial for the use of RUC-4 in patients with STEMI.
Click here to view Dr. Gibson’s interview with Dr. Kereiakes.