Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a biochemical blood cell defect that arises from an acquired genetic mutation in the stem cell lines in the bone marrow. For unknown reasons, the abnormal cell lines become more dominant than the native cells. The abnormal red cells are prone to complement-mediated hemolysis, which leads to leakage of the dark, pigmented hemoglobin into the urine.
Until recently, treatment was based upon relieving the acute complications as well as maintenance transfusions of red blood cells, folic acid and iron supplementation, and glucocorticoids. Red blood cell growth factor (recombinant erythropoietin) is also commonly used. For appropriate patients, stem cell transplantation provided definitive therapy.
But this changed when the FDA approved eculizumab. This monoclonal antibody marketed under the brand name Soliris by Alexion Pharmaceuticals is indicated for the treatment of PNH to reduce hemolysis. Eculizumab binds to the complement protein C5. This prevents C5 from breaking down to form C5a and C5b, effectively preventing this portion of the complement cascade. This prevents the intravascular hemolysis.
In the 87-patient placebo-controlled clinical trial, 600 mg of eculizumab was administered as a 35-minute infusion every seven days for the first four weeks of therapy, followed by a 900 mg dose seven days later. A maintenance dosage regimen followed in which 900 mg was administered every 14 days for 26 weeks. The patient populations were balanced in terms of age, sex, history of thrombosis, use of anticoagulants and corticosteroids, transfusions in the prior year, mean hemoglobin, free hemoglobin, and LDH levels.
The number of packed red blood cell transfusions dropped to zero in the actively-treated group versus 10 units per patient in the placebo group. LDH levels, a measure of hemolysis, dropped significantly in the treated population to a median level of 239, versus 2,167 in the control group. Nearly half of the patients treated with eculizumab had stable hemoglobin levels. None of the recipients who were given a placebo exhibited this stabilization.
Serious adverse reactions were similar for both groups but nonserious reactions were reported as higher in the eculizumab group. These included the following:
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In another study, PNH patients were also treated in a single-arm, 52-week study and a long-term extension study, both of which showed similar results in both efficacy and safety. Immunogenicity does not appear to be problematic, with just 2 percent of all PNH patients ever treated developing antibodies. The presence of antibodies did not appear to correlate with clinical response.
Unfortunately eculizumab use is associated with at least one serious infectious process — meningococcal disease. Meningococcal sepsis developed in 2 of the 196 patients receiving active therapy, both of whom had received the meningococcal vaccine. This has resulted in a black box warning concerning the need to vaccinate all patients at least two weeks prior to beginning eculizumab therapy and to educate them about the risks and early signs of meningococcal infection.
This drug is $4,992/300 mg vial (WAC). Once the patient has reached the 900 mg dose given every two weeks, this amounts to approximately $390,000 per year.
The cause of PNH is a defect in the gene coding for an enzyme called PIG-A. The PIG-A gene is on the X chromosome, but interestingly, there is no sex-linked difference in incidence. PIG-A is required for synthesis of GPA, a cellular protein which allows a number of surface proteins to remain tethered to the cell wall.
The main proteins affected are the complement-regulating surface proteins CD55 (also called decay accelerating factor), CD59 (also called membrane inhibitor of complement lysis), and CD8 (also called homologous restriction factor). All of these proteins are involved in halting the amplification process of the complement cascade.
Several known genetic mutations have been described, including point mutations and deletions. Current understanding is that the defect does not affect just a single cell line (making it a monoclonal disease) but involves numerous cell lines. If these cell lines become a major contributor to the total blood cell volume, the severity of the PNH is increased.
PNH is associated with more than just dark colored urine. PNH can present as aplastic anemia when the cell line involved fails to provide a normal amount of all of the blood cell lines. It can lead to significant anemia (mean hemoglobin of 8 in clinical trials) and severe iron loss. Normally, CD59 prevents platelet aggregation. In a deficient state, the platelets are prone to aggregating, which puts PNH patients at a high risk of thrombosis (30 percent to 50 percent of PNH patients).
Thrombosis of a large vessel — such as the hepatic vein — presents as sudden onset of severe abdominal pain and rapidly enlarging liver and ascites (called Budd-Chiari syndrome). Other abdominal vein thrombosis can result in bowel infarction.
PNH is very uncommon and little is known about the prevalence and incidence. Once present, the disease typically follows a chronic course with a median survival of 10 years. The main causes of death are venous thrombosis, bone marrow failure, and thrombophilia. There are well-documented cases of spontaneous remission as well as leukemic transformation. Thus, if the defective cell line is eliminated, PNH can resolve.
But if the defective line becomes dominant, it forms a type of leukemia.
Of interest, in one study of 35 patients who survived for 10 years or more, 12 had no evidence of PNH-affected cells among the neutrophils or red cells.
For the few patients, perhaps as few as 600 people in the United States, science has provided a new therapy, albeit an expensive one, proving again that Tomorrow's Medicine will continue to offer hope where little existed.