What is On-Pump CTS?  |   Why DX-88 in On-Pump CTS?  |   Clinical Trial Status

What is On-Pump CTS?

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.

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Why DX-88 in On-Pump CTS?
DX-88 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.

DX-88 is a specific inhibitor of plasma kallikrein and does not inhibit other blood enzymes against which it has been tested. For this reason, DX-88 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. Since DX-88 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.

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Clinical Trial Status of DX-88 in On-Pump CTS

Phase 1/2 Trial Complete
Dyax completed a Phase 1/2, multicenter, placebo-controlled dose-escalation U.S. study of DX-88 in on-pump CABG. 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 DX-88 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.

Ongoing Clinical Development
In April 2008, Dyax licensed to Cubist Pharmaceuticals the intravenous formulation of DX-88 for the prevention of blood loss during surgery, with rights to North America and Europe. Cubist is responsible for the ongoing development of DX-88 in this indication.

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