Cardioprotectant - pexelizumab
Heart bypass surgery leads to much higher activation of the complement system than is normal. Ischaemia, post-operative reperfusion and the contact of blood with artificial surfaces can all be a trigger and, once they have been activated, complement components are able to initiate inflammatory responses that are associated with changes in blood pressure and platelet activity, fluid leakage, and blood cell activation.
These can all cause further damage, particularly the destruction of tissues and excessive blood loss. As a result, bypass patients are at a much increased risk of morbidity to organs such as the kidney, heart, brain, lungs and gastrointestinal tract.
Several plasma proteins are involved in the complement system. Most of these require activating by a protease, which cleaves them into two fragments, themselves both proteases, that can activate other complement components, resulting in a cascade of action. The C5 protein on the cascade has been identified by Alexion as a potential target for a drug to reduce the impact of the complement system on heart bypass patients, because upstream components in the cascade from this point are believed to be beneficial, and the damage is more likely to be caused by its cleavage products. It has developed pexelizumab, a humanised single chain monoclonal antibody that selectively binds to the C5 complement protein, and prevents it cleaving. This would stop the cascade into further inflammatory proteins.
A prospective open label, randomised placebo controlled dose escalation study was carried out in 35 heart bypass patients.1 Doses of 0.2, 0.5, 1 or 2mg/kg were given intravenously over 10 minutes, and the desired inhibition of complement products was seen in a dose dependent manner. Those given the highest dose had a 40% reduction in myocardial injury, and no differences in adverse effect profiles was seen between the two groups.
In another trial, 914 patients undergoing bypass surgery were given 2mg/kg as a bolus dose, either alone or followed by a 24 hour infusion of 0.05mg/kg/hr before surgery.2,3 The regimen involving the infusion was found to be more effective than placebo or the bolus dose alone in those undergoing bypass without valve surgery.