Among patients with paroxysmal nocturnal hemoglobinuria, does the anti-complement monoclonal antibody eculizumab stabilize hemoglobin levels and decrease RBC transfusion requirements when compared to placebo?
Eculizumab improves anemia and decreases RBC transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria without increasing serious treatment-related side effects.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by complement-mediated intravascular hemolysis. PNH classically results from a mutation of the PIGA gene, resulting in deficiency of glycosylphosphatidylinositol (GPI), a glycolipid responsible for anchoring >100 different proteins to the cell membrane. Complement inhibitory proteins CD55 and CD59 are two such proteins anchored on the RBC membrane, preventing the formation of the terminal complement complex on RBCs. In patients with PNH, CD55 and CD59 are lacking, and RBCs undergo excessive complement-mediated hemolysis leading to hemolytic anemia, thrombosis, renal dysfunction, and pulmonary hypertension. The name of the disease derives from a perceived increase in hemolysis with subsequent hemoglobinuria at night. Historically, therapy relied on stem cell transplant for eligible patients as well as palliative RBC transfusions.
Published in 2006, the Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (TRIUMPH) trial by Hillmen and colleagues randomized 87 patients with transfusion-dependent PNH to the complement C5 inhibitor eculizumab or placebo for a 26-week period. The eculizumab group showed statistically significant improvement in hemoglobin stabilization (49% vs. 0%) and number of RBC units transfused (131 vs. 482). There was also significant improvement in multiple secondary outcomes including transfusion independence (51% vs. 0%), fatigue, and quality of life. All 85 patients who completed 26 weeks of therapy entered long-term extension for up to 3 years, and these patients were included in an analysis of 195 patients with long-term follow-up. With a median treatment duration of 30 months (range 10-66 months), intravascular hemolysis was decreased in patients receiving eculizumab, transfusion independence was achieved more frequently (82.1% vs. 8.2%), and thrombotic events decreased (2.1 vs. 11.1 events per 100 patient-years).
A feared complication of eculizumab is meningococcal sepsis, arising from the impairment in complement activation necessary for clearance of meningococcus. All patients receiving eculizumab therapy are therefore vaccinated against N. meningitidis at least 14 days prior to their first dose of eculizumab, and then periodically thereafter. There were no patients with meningococcal disease in the original 26-week report from the TRIUMPH study. However, in the larger cohort of patients with long-term follow-up, two patients developed meningococcal sepsis which was successfully treated with antibiotics (infection rate 0.42 per 100 patient-years). Both of these patients had received appropriate meningococcal vaccination, but developed a strain of meningococcus to which they had not been immunized.
The cost of eculizumab is estimated at over US$400,000 per year. A Canadian cost-effectiveness analysis estimates the incremental cost per quality adjusted life-year (QALY) gained is CAN$2.13 million, and estimated that the cost of the medication would need to be reduced by 98.5% in order to be cost-effective.
- Multicenter, double-blind, placebo-controlled, stratified randomized, phase 3 trial
- Stratification based on number of units transfused in past year
- N=87 patients with transfusion-dependent PNH
- Eculizumab (n=43)
- Placebo (n=44)
- Setting: 34 centers across the United States, Canada, Europe, and Australia
- Enrollment: October 2004 to June 2005
- Mean follow-up: 26 weeks
- Analysis: Intention-to-treat
- Primary outcome:
- Stabilization of hemoglobin levels
- Number of units of packed red cells transfused
- Diagnosis of PNH
- Age 18 years or older
- At least 4 transfusions in the previous 12 months
- PNH Type III Erythrocyte (No CD59 present on cell) > 10%
- Platelet count > 100,000
- Lactate dehydrogenase > 1.5 times the upper limit of normal
- Concomitant use of erythropoietin, immunosuppressants, steroids, anti-coagulation, iron, and folic acid were allowed provided doses did not change throughout the study
- Hemoglobin level > 10.5 g/dL and requiring transfusions
- Another investigational drug used within 30 days of first visit
- Complement deficiency
- Active bacterial infection
- History of meningococcal disease
- History of bone marrow transplant
- Did not require a transfusion during the 3 month observation period
Placebo group vs. eculizumab group.
- Median age: 35 vs. 41 years
- Median Duration of PNH: 9.2 vs. 4.3 years
- Median Reticulocyte Count: 204,400 vs. 206,600
- History of Aplastic Anemia: 27% vs. 14%
- Use of Anticoagulants: 25% vs. 49%
There was no statistically significant difference in any of the baseline characteristics
- Prospectively determined hemoglobin set point and transfusion algorithm created for each patient during 3 month observation period
- Disease-modifying (immunosuppressants, steroids, etc.) or symptom-related (Coumadin, etc.) medications were continued at pre-study doses
- All patients vaccinated against Neiserria meningitidis
- Randomized to Eculizumab or placebo
- Dosing schedule was 600 mg ever week for 4 weeks, followed one week later by 900 mg, and then maintenance dose of 900 mg every 2 weeks through week 26
- Adverse events assessed at each of 17 study visits, blood counts checked at 9 study visits
Comparisons are Eculizumab vs. Placebo.
- Stabilization of hemoglobin levels
- 49% vs. 0% (P<0.001)
- Median number of transfused units (total transfused)
- 0 (131) vs. 10 (482) (P<0.001)
- Transfusion independence
- 51% vs. 0% (P<0.001)
- Median area under the curve for LDH
- 58,587 vs. 411,822 Units/L (P<0.001)
- Quality of Life
- FACIT-Fatigue: +6.4 vs. -4.0 points (P<0.001)
- EORTC QLQ-C30: P<0.01 for each scale and measure except for nausea and vomiting, financial difficulties, constipation, and diarrhea
- 4 vs. 9 events (no P value given)
- Non-serious adverse events
- Headache: 19 vs. 12 events
- Nasopharyngitis: 10 vs. 8 events
- Upper respiratory tract infection: 6 vs. 10 events
- Back pain: 8 vs. 4 events
- More patients with aplastic anemia in the placebo group (27% vs. 14%).
- Patients in the placebo group had PNH for a longer duration (9.2 vs. 4.3 years).
- Information on the ethnic background of patients would be helpful since the disease course is known to differ among races. 
- Funded by Alexion Pharmaceuticals
- Authors with multiple financial disclosures mainly relating to Alexion Pharmaceuticals
- Hillmen P et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 2004. 350:552-9.
- Brodsky RA & Paroxysmal nocturnal hemoglobinuria. Blood 2014. 124:2804-11.
- Memon AR, et al. "Paroxysmal nocturnal hemoglobinuria presenting as cerebral venous sinus thrombosis: a case report." International archives of medicine 7.1 (2014): 39.
- Hillmen P et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 2013. 162:62-73.
- Matthew Herper. Forbes. "The World's Most Expensive Drugs." February 22, 2016.
- Coyle D et al. Opportunity cost of funding drugs for rare diseases: the cost-effectiveness of eculizumab in paroxysmal nocturnal hemoglobinuria. Med Decis Making 2014. 34:1016-29.
- Multiple authors. "Correspondence: Eculizumab in Paroxysmal Nocturnal Hemoglobinura." The New England Journal of Medicine. 2006; 355:1233-1243.