Eculizumab

Eculizumab (INN and USAN, trade name Soliris) is a monoclonal antibody directed against the complement protein C5. Eculizumab has been shown to be effective in treating paroxysmal nocturnal hemoglobinuria (PNH), a rare and sometimes life threatening disease of the blood, and is approved for this indication.

Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody that specifically binds to the complement protein C5, inhibiting its cleavage by the C5 convertase which prevents the generation of the terminal complement complex C5b-9. It is this terminal complement complex that causes intravascular hemolysis in people with (PNH).

Eculizumab is a product of Alexion Pharmaceuticals and was approved by the United States Food and Drug Administration (FDA) on March 16, 2007 and the European Medicines Agency on June 20, 2007.

According to Forbes magazine, Soliris, at $409,500 a year, is the world's single most expensive drug.

Biochemistry
Eculizumab is a humanized monoclonal antibody against C5. It contains a human IgG4 heavy chain at constant regions 2 and 3 which eliminates complement activation, a human IgG4 heavy chain at constant region 1 and hinge that eliminates Fc receptor binding and human framework regions and complementary determining regions of murine origin.

Eculizumab binds to the complement protein C5 inhibiting its cleavage to C5a and C5b which then prevents the formation of the membrane attack complex (MAC), C5b-9. This, in turn, inhibits the terminal complement-mediated intravascular hemolysis in PNH patients. The proximal functions of complement remain intact, such as immune complex clearance (upstream from C5 in the complement sequence), microbial opsonization, and weak anaphylatoxin function.

The mechanism of action of eculizumab in PNH can be understood by examining the cell membrane and attached proteins. The underlying defect in PNH is in a gene called PIG-A, which codes for an enzyme, phosphatidylinositol glycan A (PIG-A), that is necessary to form glycosylphosphatidylinositol (GPI) glycolipid, which anchors membrane proteins to the cell surface. Several proteins are normally linked to the GPI anchors on the cell membrane, including proteins that protect the cell membrane from complement-mediated destruction. When a GPI deficit exists, as occurs in PNH, complement can more easily target and lyse the deficient cells. In red blood cells, this results in cell breakdown or hemolysis. The main complement protecting proteins are CD55 which disrupts the formation of CD3 convertase, and CD59, which binds the membrane attack complex and prevents C-9 from binding to the cell, and inducing cell breakdown. Eculizumab targets C5 and thus inhibits the complement system from destroying the otherwise vulnerable CD55 and CD59 deficient blood cells of PNH patients, producing a rapid and substantial reduction in hemolysis in almost all treated patients.

PNH
In a double-blind, randomized, placebo-controlled Phase III trial (TRIUMPH), with 87 patients, eculizumab was found to deliver an 86% reduction of intravascular hemolysis as measured by LDH reduction. It also permitted a 73% reduction in transfusions across all subgroups. Notably, there was a rapid and meaningful improvement in fatigue and quality of life for the treated patients. No serious treatment-related adverse events were encountered.

Significantly, data from three independent parent clinical studies (Phase II pilot study, Phase III TRIUMPH study, and Phase III SHEPHERD study ) demonstrated a greater than 90% reduction in thromboembolic events, the most serious complication and major cause of death in PNH. All PNH patients in clinical trials showed a benefit from eculizumab therapy – many benefits occurred rapidly; others showed improvement over time.

Investigational Uses
There are case reports of eculizumab being used to treat congenital atypical hemolytic uremic syndrome, as well as severe shiga-toxin associated hemolytic uremic syndrome, such as occurred during the May 2011 outbreak of enterohemorrhagic E. coli in Germany. Eculizumab was given in an attempt to block dysregulated complement activation, which is thought to play a role in the pathogenesis of both of these forms of hemolytic uremic syndrome.

There are also reports of eculizumab being used to treat cold agglutinin disease. In one patient cast report, eculizumab led to a sustained reduction of hemolysis, disappearance of further exacerbations, complete elimination of transfusion requirements and improvement of symptoms and quality of life.

Early results from a Mayo Clinic research study demonstrate the effectiveness of a new approach to blocking an important part of the immune system that causes severe damage to some kidney transplants. Results show that eculizumab prevents antibody-mediated kidney transplant rejection by inhibiting the immune system's activation of one of the body's important defense mechanisms — the complement system.

Eculizumab is well tolerated, with headache the most common adverse event on initiation of treatment.

Dosing
The recommended dosage regimen is :
 * 600mg IV weekly x 4 weeks, followed by
 * 900mg IV for the fifth dose 1 week later, followed by
 * 900mg IV every two weeks thereafter.

It is administered by intravenous infusion over 35 minutes. Patients are followed and monitored for response with LDH (measure of intravascular hemolysis), hemoglobin level (transfusion requirement), infection monitoring, and thromboembolism incidence.

Efficacy
A study of 79 patients treated with eculizumab at the Leeds PNH Center, suggests that the agent is effective in preventing new, or evolution of pre-existing thrombosis and appears to remove the need for primary prophylactic anticoagulation. The authors, however, pointed out that anticoagulation was not systematically stopped in patients with a previous history of thrombosis. This landmark study demonstrated that eculizumab was a well tolerated long-term therapy (>8 years), with continued improvement in PNH symptoms, a significant reduction in transfusion requirements, and a significant reduction in thromboembolism. Most importantly, it demonstrated that eculizumab has a major impact on survival, rendering patient survival comparable to an age and sex matched control population, dramatically improved from the pre-eculizumab era.

Safety
Eculizumab inhibits complement activation and therefore makes patients vulnerable to infection with encapsulated organisms. Serious meningococcus infections have been described in patients who received eculizumab. Due to the increased risk of meningococcal infections, meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab. There is concern, however, that current meningococcal vaccines may not be sufficient to protect patients, since commonly available vaccines do not protect against strains of meningococcus with a serogroup B antigen, which is prevalent in countries such as the Netherlands.