Targeted Diseases

1. Open-heart surgery

Today challenge

Coronary artery bypass graft (CABG) and valve replacement surgeries are associated with potentially very serious and costly complications, largely as a result from excessive bleeding.

Increasing risk

Performing open-heart surgery on >75 year-old patients has become common and thus 50% or more of all patients are considered at high-risk of complications. For example, severe bleeding occurs in more than 10% of high-risk patients and is directly associated with a high rate of re-intervention, massive transfusions, stroke and death (Fergusson D.A. et al. N. Engl. J. Med. 2008;358:2319-31). The clinical cost of managing these complications is very high and often greater than the initial surgery, which cost ~$40,000 in the US. Therefore, there is a high unmet medical need to improve clinical outcome by reducing the frequency and nature of these adverse events.

Balancing act

Today, the management of extra corporeal circulation (ECC) during cardiac surgery using heparin and its antidote, protamine, is "somewhat of an art". On one hand, they need to use a powerful anticoagulant to avoid clotting in the machine's tubing, but on the other hand they must also avoid using too much heparin that could trigger serious bleeding. The sole product used, heparin, has a short half-life (less than 1 hr) so clinicians need to constantly monitor coagulation markers and inject new doses of heparin as needed throughout the surgery.

Product issues

In addition to managing the no clotting/no bleeding balance, clinicians must address a number of clinical issues specifically associated with heparin and its neutralizing agent, protamine. For example, patients response to a given dose of heparin is quite unpredictable, often forcing physicians to empirically adjust the dose depending on the patient. Also, heparin resistance in patients previously treated with heparin is common and increasing, leading to similar empirical adjustments. In addition, rare but very serious life-threatening reactions, such as Heparin-Induced Thrombocytopenia (HIT), are quite difficult to control. Last, the antidote, protamine, is itself associated with incomplete neutralization (i.e. rebound) that can lead to severe bleeding, as well as mild to severe hypotension, pulmonary hypertension, bronchospasm, vasodilatory shock and cardiac arrest.

Projected clinical benefits of EP217609

By design, EP217609 is projected to provide cardiac surgeons and anaesthesiologists with significantly lower bleeding and complications compared to un-fractionated heparin because of its stable, predictable action and its complete, reliable inactivation by avidin.

The Figure below, based on a number of dog experiments, illustrates the response to EP217609 compared to heparin. EP217609 provides stable and constant anticoagulant throughout cardiac surgery, as opposed to heparin which needs to be frequently monitored and re-dosed.