Pexelizumab Overview

Introduction of Pexelizumab

Pexelizumab is a single-chain fragment of a humanized monoclonal antibody developed by Alexion Pharmaceuticals, Inc. Pexelizumab binds to the C5 component of the complement cascade, preventing its cleavage into C5a and C5b-9, which are proinflammatory and activate endothelial cells and leucocytes. Myocardial injury and dysfunction in myocardial infarction and cardiac surgery with cardiopulmonary bypass (CPB) are accompanied by an undesirable systemic inflammatory response, in which the complement cascade plays an essential part. Research has shown that C5 inhibition has been found to significantly reduce myocardial infarct size and decrease cellular necrosis and apoptosis. Prospective, randomized, double-blind, placebo-controlled trials using pexelizumab during percutaneous coronary intervention following acute myocardial infarction (AMI), or in patients undergoing coronary artery bypass graft (CABG) with CPB, have demonstrated a reduction in morbidity and mortality. Thus, pexelizumab represents a promising therapeutic option with sustained benefit both in AMl and during CABG with CPB.

The Mechanism of Action of Pexelizumab

Inflammation is a normal response, while persistent exposure to foreign surfaces, toxic antigens, and tissue injury leads to pathologic local and systemic inflammation (SIRS). Numerous humoral and cellular elements play a role in this response, such as leukocytes, monocytes, adhesion molecules (ICAM-1), endothelial cells, cytokines (TNF-alpha, interleukins), coagulation (Factor XII, thrombin, proteins C and S, platelets), and complement systems. When active, the complement system produces C3-convertase, which converts C3 to C3a and C3b. C3a cleaves C5 into C5a and C5b. C5b, along with C6, C7, C8, and C9, form the membrane attack or terminal complement complex (TCC) C5b-9. Both C5a and C5b-9 activate, promote, and amplify inflammatory components and are thought to play important roles in the development of SIRS, tissue injury, reperfusion injury, and apoptosis. Two activation pathways are involved in the complement system: the classical pathway involves the binding of an antibody to its antigen, and the alternative pathway involves activation by a variety of antigens and pathogens. Both pathways have a similar terminal sequence which creates the membrane attack complex (MAC), an enzyme complex that causes the lysis of the target cell. The cleavage of complement C5 protein into C5a and C5b is the key step in the formation of MAC, which ultimately leads to the promotion of host immunity via the induction of an inflammatory response.

Cardiopulmonary bypass surgery (CPB) and myocardial infarction are two conditions that significantly increase complement activation. Once complement components are engaged, they can cause tissue damage through inflammatory reactions. Pexelizumab, a recombinant humanized single-chain monoclonal antibody to C5, inhibits the conversion of C5 to C5a and C5b-9 and is a potential therapeutic for reducing cardiac damage, mortality reduction, and other related sequelae associated with CPB and myocardial infarction.

Clinical Trials

Phase I–III Trials

Early-phase clinical trials focused on the safety, pharmacokinetics, and pharmacodynamics of pexelizumab. These studies demonstrated that pexelizumab was well-tolerated and effectively inhibited complement activation. Phase II trials provided preliminary evidence suggesting that pexelizumab could reduce myocardial damage in patients undergoing CABG surgery. Despite the promising results from earlier trials, Phase III trials yielded mixed outcomes. The PRIMO-CABG II trial, which involved over 3,000 patients undergoing CABG surgery, did not show a significant reduction in the primary endpoint of death or myocardial infarction at 30 days. Similarly, the APEX-AMI trial, which tested pexelizumab in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention, failed to meet its primary endpoint of reducing 90-day mortality.

Safety and Efficacy

Pexelizumab has been generally well-tolerated in clinical trials, with adverse events similar to those seen with a placebo. The most common side effects included hypotension, anemia, and infections. However, the lack of significant clinical efficacy in reducing mortality and myocardial infarction has raised questions about its future development and application.

Potential and Future Directions

Pexelizumab did not meet its primary endpoints in large-scale clinical trials, but the concept of complement inhibition in myocardial ischemia-reperfusion injury remains valid. Future research may focus on identifying subpopulations of patients who could benefit from complement inhibition or developing combination therapies that enhance the efficacy of pexelizumab. Additionally, advancements in biomarkers could help identify patients at high risk of complement-mediated damage, thus guiding more personalized therapeutic approaches.

For research use only. Not intended for any clinical use.