Each year, approximately 160,000 people in the United States suffer from ST segment-elevated myocardial infarction (STEMI), a severe type of heart attack. Approximately half of all deaths from heart attacks occur before patients reach the hospital. Although emergency medical service providers commonly give heart attack victims aspirin, better pre-hospital therapies are needed. This project’s aim is to test a compound called RUC-4, which blocks a protein receptor on the surface of blood platelet (αIIbβ3) involved in blood clotting, and prepare it for human trials. The investigators hypothesize that injecting RUC-4 into the muscle of STEMI patients before they reach the hospital could help prevent death and heart damage from STEMI.
Scientific Synopsis
There has been relatively little improvement in pre-hospital therapy compared to the dramatic advances in therapy after arriving to the hospital. Our hypothesis is that the addition of a potent αIIbβ3 receptor antagonist administered intramuscularly (IM) via an autoinjector to standard oral aspirin in the pre-hospital therapy of patients with ST segment-elevated myocardial infarction (STEMI) will not only decrease early mortality, but will also decrease the development of congestive heart failure during the next 6-12 months. This hypothesis is based on evidence showing that therapy with other αIIbβ3 antagonists (along with aspirin) soon after symptom onset can abort the progression of thrombotic myocardial ischemia to irreversible cardiac damage and decrease mortality. Moreover, we expect a favorable safety profile since patients will neither be anticoagulated nor undergo arterial access in the pre-hospital setting, and the effects will wear off within 2-4 hours.
Our specific aim is to obtain the pre-Investigational New Drug (IND) data needed to advance RUC-4, a novel αIIbβ3 antagonist, to human studies. RUC-4 was designed to be specific for αIIbβ3 and to have a unique mechanism of action that not only prevents ligand binding, but also prevents the conformational changes in the β3 subunit induced by current αIIbβ3 antagonists that have been implicated in causing thrombocytopenia and paradoxical receptor activation. RUC-4 was also designed to have high solubility so that the likely human dose can be administered by autoinjector. The current αIIbβ3 antagonists all must be administered intravenously, a major disadvantage for pre-hospital therapy.
We currently have support from the NHLBI SMARTT program to produce RUC-4 to support the IND formulation and toxicology studies. The innovative aspects of this project include addressing an urgent unmet medical need, employing a novel compound with theoretical and practical advantages over current agents, proposing an innovative route of administration (IM) and method of delivery (via autoinjector), and proposing administration by Emergency Medical Service personnel in the pre-hospital setting.
Lead Collaborator
The Rockefeller University, New York, New York
Barry Coller, M.D.
Public Health Impact
Annually, approximately 160,000 people in the Unites States experience STEMI according to the American Heart Association. The currently available antiplatelet agents have significant limitations and are challenging to provide in complicated emergency medical service conditions. New therapeutics like RUC-4 that are optimized for delivery in the pre-hospital setting could dramatically reduce the complications associated with STEMI.
Outcomes
BrIDGs program scientists completed formulation and process development, synthesis of Good Manufacturing Practice (GMP) material, and pharmacokinetic and IND-directed toxicology studies. As a result of BrIDGs support, an IND has been cleared by the FDA, allowing clinical trials to proceed. See ClinicalTrials.gov, NCT03844191.