Each year in the United States, over 500,000 patients undergo on-pump cardiothoracic surgery (CTS), which includes coronary artery bypass grafting (CABG) and heart valve replacement or repair procedures, in order to repair blocked arteries that cannot be opened with stents or other less invasive procedures.
In on-pump CTS procedures, the heart is stopped, and blood is rerouted through a separate cardiopulmonary bypass (CPB) machine. The heart is filled with a solution to keep it still. Throughout the procedure, the pump takes over the function of the heart and lungs and supplies oxygenated blood to the body. Following placement of the grafts, blood flow is restored and the heart restarted.
One of the inherent risks of this surgery is contact activation of the inflammatory cascade. When a patient's blood comes into contact with the artificial surface of the CPB machine and tubing, serious complications can result, including blood loss and the systemic inflammatory response syndrome (SIRS), a whole body inflammatory state that compromises heart and lung function in already fragile patients.
Ecallantide, discovered by Dyax Corp*, was in-licensed by Cubist for surgical indications, to prevent blood loss during on-pump procedures. We are in the clinical stage of evaluating ecallantide as therapy during CTS procedures, and in the future may initiate research for other on-pump surgery indications, such as certain transplant and orthopedic surgery.
Ecallantide is a small protein with high affinity and specificity for plasma kallikrein, a key enzyme in the inflammatory cascade that is thought to be a relevant target during on-pump CTS. Kallikrein liberates bradykinin, a molecule that causes local leakage of fluid from the blood vessels into the tissues.
Ecallantide is a specific inhibitor of plasma kallikrein and does not inhibit other blood enzymes against which it has been tested. For this reason, ecallantide may offer an alternative therapy to help reduce blood transfusion needs associated with on-pump CTS and possibly decrease systemic inflammatory effects.
Current treatments for patients undergoing complicated CABG procedures have been shown to be either less efficacious in reducing blood loss or pose significant safety risks, namely anaphylaxis and renal toxicity. With ecallantide, Cubist aims to advance a safer and equally or more effective therapy for reducing blood loss during CABG, heart valve replacement and other on-pump procedures. Since ecallantide is a recombinant small protein (versus bovine derived) and a highly specific inhibitor of plasma kallikrein (versus broad spectrum enzyme inhibitor), it should have a favorable risk profile and may be more effective in preventing blood loss and SIRS.
A Phase 1/2, multicenter, placebo-controlled dose-escalation U.S. study of ecallantide in on-pump CABG was completed by Dyax Corp. Initial results of the study, which involved 42 first-time CABG patients undergoing CPB, were announced in December 2003. The primary endpoints of this study were to determine the pharmacokinetics and safety of ecallantide compared with placebo. Dose-related pharmacokinetics were consistent across dose groups and no serious adverse drug reactions were reported. There was a strong trend toward efficacy in a secondary endpoint: a ~50% reduction in blood transfusion requirements vs. placebo.
Cubist has assumed responsibility for studies of ecallantide for surgical indications. Our goal is to move ecallantide into a high-quality pivotal Phase 3 randomized controlled clinical trial as soon as possible. To prepare for an end of Phase 2/Phase 3 design meeting with the FDA, we will combine learning from the Phase 2 “Kalahari 1” trial initiated by Dyax with a dose-ranging Phase 2 study Cubist plans to begin as soon as possible. We hope to be ready to meet with the FDA by the end of 2009, or early in 2010.
* Cubist in-licensed the intravenous formulation of ecallantide for the prevention of blood loss during surgery, with rights for North America and Europe, from Dyax Corp., April 24, 2008. Dyax discovered ecallantide using its phage display technology.