Eculizumab is a first-in-class monoclonal antibody developed and marketed as Soliris by Alexion Pharmaceuticals. It binds to the complement protein C5 and prevents its activation, preventing inflammation and cell lysis (disintegration).

Eculizumab is indicated for the treatment of patients with rare diseases such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), some forms of generalized myasthenia gravis, and some forms of neuromyelitis optica spectrum disorder.

Eculizumab also has been investigated for the treatment of hemolytic anemia in cold agglutinin disease (CAD).

How eculizumab works

In CAD, autoantibodies called cold agglutinins bind and clump (agglutinate)  the circulating red blood cells (RBCs) when exposed to cold temperatures. This activates the classical complement pathway and triggers lysis of RBCs.

The excessive lysis of the RBCs causes hemolytic anemia, which leads to symptoms characteristic of the disease such as extreme fatigue, weakness, jaundice, acrocyanosis, and Raynaud’s phenomenon.

Eculizumab binds to the complement protein C5, a downstream protein involved in the complement pathway, which is responsible for triggering cell lysis or other downstream processes of inflammation.

Since C5 is at the crossing point of all three complement pathways, classical, alternative, and lectin pathways, inhibiting it blocks the entire complement pathway. This is one of the major concerns for its use because it increases the risk of infections and related complications.

So, eculizumab is preferred only when other treatments, such as rituximab monotherapy or combined therapy, are not effective in CAD patients.

Eculizumab in clinical trials

The first case study of a CAD patient treated with eculizumab was published in the journal Blood  in 2009. Eculizumab therapy was begun in a 66-year-old male CAD patient who had become unresponsive to prednisone, rituximab, and immunoglobulin therapies.

He was treated with 600 mg of eculizumab injected into the bloodstream every seven days for four weeks, with 900 mg of eculizumab seven days later, and then with 900 mg of eculizumab every 14 days. While cold agglutinins could be detected in his blood throughout the treatment period, he showed a reduction in chronic hemolysis. There was a great improvement in his level of fatigue and his quality of life. He tolerated well the dose of treatment used over the study period.

A Phase 2, prospective, non-randomized multi-center study (NCT01303952) called DECADE, was performed to evaluate the safety and effectivenesss of eculizumab in 13 symptomatic or blood transfusion-dependent patients with untreated or refractory CAD. The patients received 600 mg of eculizumab weekly for four weeks, followed by 900 mg every other week through week 26.

The primary goal of that study was any change in the levels of the lactate dehydrogenase (LDH) enzyme in the blood. LDH levels are generally low in the blood under normal conditions, but in people who have a medical condition in which RBCs are destroyed, it is released into the bloodstream. That’s why it is a good measure of RBC lysis.

The secondary parameters analyzed during the trial included changes in the levels of known indicators of hemolysis in the blood, such as hemoglobin, haptoglobin, and the numbers of reticulocytes. Hemoglobin is the protein in RBCs that carries oxygen. Blood hemoglobin levels are generally greater than 12 g/dL. A hemoglobin level between 8-10 g/dL is considered mild anemia, 6-8 g/dL is severe anemia, and below 6 g/dL is very severe. Haptoglobin is a liver-generated protein that binds to free hemoglobin in the blood. It is significantly reduced in situations where blood cells are lysed; it is the most sensitive marker for hemolysis. Reticulocytes are immature red blood cells that are not found normally in the blood, but are present in conditions of hemolysis as a mechanism to compensate for depleted RBC levels.

The number of blood transfusion-dependent patients and the number of RBC units transfused post-treatment also were analyzed during the trial. Other parameters monitored included thromboembolic events (blood clots that break loose and block blood vessels and cause life-threatening events like a stroke), the six-minute walk test to analyze exercise tolerance , quality of life as assessed by the SF-36v2 health survey questionnaire, fatigue as analyzed by the FACIT (functional assessment of chronic illness therapy) fatigue scale, and pharmacokinetics (how eculizumab moves through the body).

The results were published in the journal Blood Advances and showed a significant decrease in lactate dehydrogenase levels, as well as an accompanying increase in blood hemoglobin levels upon eculizumab treatment. A total of 11 patients did not require blood transfusions, one patient showed a reduced requirement for blood transfusion, while another showed an increased requirement. Patients with cold agglutinins with thermal amplitude (the temperature at which the autoantibody is reactive and can bind to RBCs) of 98.6 degrees Farenheit (37 degrees Celsius) had a lower reduction of lactate dehydrogenase levels compared to those with narrower thermal amplitudes. The researchers concluded these patients may require a higher dose of eculizumab.

 

Last updated: Aug. 10, 2019

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