A Promising Theory Stumbles in Clinical Trials
MANAGED CARE February 2007. ©MediMedia USA
Going from bench to bedside is not always easy, especially when it comes to halting the inflammatory process after an acute myocardial infarction
Advances in medicine are among the most exciting in all of science, and this column has repeatedly focused on major advances that create hope for patients and challenges for decision makers in managed care.
Many of the advances are giant leaps in technology. Some are simply improvements that supplant older forms of therapy. This month we will look at the failure of a promising hypothesis for heart disease.
The last three decades have produced revolutionary developments in the treatment of hypertension, hyperlipidemia, diabetes, and platelet aggregation. At the same time, there have been reductions in smoking and other encouraging lifestyle modifications, all of which have helped in our fight against heart disease. Imaging, diagnostic, and prognostic testing have advanced and disease management programs, and guidelines-driven care have also become the norm in many managed care markets. Therapy for the complications of acute myocardial infarction (MI) has also progressed rapidly and a variety of reperfusion techniques are now available for acute occlusive disease.
It appears, however, that prevention and acute reperfusion must be accompanied by other therapeutic interventions to control this disease.
Control ongoing damage
One promising approach is to control the ongoing damage to heart tissue in the days to weeks after the acute occlusive event. It has been known for some time that the aftermath of an acute MI is accompanied by an inflammatory reaction in the damaged tissues that may precipitate apoptosis (programmed cell death) of the damaged myocardium in the presence of marginal reperfusion. Inhibiting this immune-mediated damage has been hypothesized to result in a reduced infarct size and improved outcomes. This hypothesis has led to numerous targeted interventions aimed at specific actions of the complex immune system.
Complement protein C5
It has been known for some time that this inflammatory process is somehow involved in the damage to tissue that occurs after a myocardial infarction. Activation of components of the complement system can lead to apoptosis and can promote the production of prothrombotic particles, causing microemboli (small blood clots).
The specific complement protein named C5 has been found to play a key role in the immediate aftermath of acute ST elevation MI (ASTEMI). The ST segment is the interval from the end of ventricular depolarization to the onset of the T wave depicted on an electrocardiogram.
As the complement cascade continues, the C5 molecule is cleaved into a potent anaphylatoxin and proinflammatory substance called C5a and C5b-9, respectively. Endothelial cells and leukocytes are activated by C5b-9; it causes these cells to produce vesicles and creates prothrombotic microparticles. These actions can lead to the additional myocardium death, on top of the anoxia caused by occlusion.
An attractive target
The heavy involvement of C5 suggested an attractive target for researchers hoping to interfere with this process. The expectation was that this would lead to improved outcomes for victims of ASTEMI.
Pexelizumab, a humanized monoclonal antibody that binds specifically to the C5 protein, was developed using recombinant technology by Alexion Pharmaceuticals. After binding, C5 is rendered inactive and cleared. In theory, removing C5 would prevent the myocardium death and anoxia and lead to reduced infarct size.
Trials of pexelizumab
A previously performed phase 2 study involving 960 ASTEMI patients who received a bolus of pexelizumab, followed by a 24-hour infusion, resulted in a favorable improvement in mortality and cardiogenic shock.
Interestingly, this study did not show a reduction in MI size. It was hoped that a follow-up study might demonstrate more favorable results.
These hopes were dashed in an international phase 3 study. Analysis demonstrated no effect of the agent on mortality or morbidity of a randomized population of 5,745 patients who were treated within 6 hours of symptom onset and who also underwent prompt percutaneous transluminal coronary reperfusion.
The dose used was known to produce nearly complete inhibition of C5 for 24 hours. Other attempts to manipulate the immune system have also been disappointing.
Innate and acquired
Operationally, the immune system is divided into two parts: the innate and the acquired. The primitive innate system serves as the first line of defense after the physical barriers fail. This part of the immune system is in a constant state of preparedness and can act instantaneously. The acquired or adaptive immune system is made up of antibodies and the various other activated immune cells that require exposure to a threat or vaccine for their development. These two parts work in tandem.
The immune system is also "structurally" divided into the humoral and cellular components. The humoral component is the serum portion of the immune system. Humoral immunity is made up primarily of antibodies.
The cellular, or complementary, component is made up of more than 35 soluble and cell-bound proteins. This system is involved in both innate and acquired immune functions and acts to bridge these two processes.
The complement system works by creating rapidly developing cascades of actions leading to the attachment of complement components to the invader, as well as production of enzymes that disrupt cell membranes.
The hypothesis that interfering with the inflammatory process will improve the outcome of myocardial infarction is now being questioned. To date, three different approaches and five clinical trials have failed to provide convincing evidence.
These disappointments may reflect the complexities and redundancy of the immune system, limited penetration of the therapeutic agent into the affected site, or just an inadequate understanding of what our immune system is designed to do. Collectively these studies show the challenges of developing Tomorrow's Medicine.