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The complement protein C3 inhibitor pegcetacoplan significantly improved hemoglobin levels and reduced the need for transfusion in a randomized comparison with the C5 inhibitor eculizumab (Soliris) for paroxysmal nocturnal hemoglobinuria (PNH).

During 16 weeks of treatment, mean baseline hemoglobin levels increased by 2.37 g/dL with pegcetacoplan and decreased by 1.47 g/dL with eculizumab. Improvement in hemoglobin with pegcetacoplan occurred irrespective of transfusion requirements for the previous 12 months and was evident as early as early as early as 2 weeks the start of randomized treatment.

At the end of the treatment period, 85% of pegcetacoplan-treated patients achieved transfusion independence as compared with 15% of the eculizumab group, reported Peter Hillmen, MD, PhD, of St. James's University Hospital in Leeds, England, and colleagues in the New England Journal of Medicine.

"Despite treatment with eculizumab for an average of 5 years with 30% receiving doses higher than the doses approved for PNH, the trial population remained severely anemic ... continued to be transfusion-dependent ... and reported considerable fatigue," the authors stated. "More than one third of patients treated with pegcetacoplan showed normalized levels of hemoglobin at week 16, and most did so without receiving a transfusion."

"These results show that inhibition of complement C3 was adequate to maintain control of intravascular hemolysis and also prevent extravascular hemolysis," they added.

The overall safety and side-effect profiles of pegcetacoplan and eculizumab were similar.

New Option for PNH

As reported at the 2020 American Society of Hematology virtual meeting, results of the PEGASUS trial showed that C3 inhibition effectively controlled hemolysis in patients who were resistant to, or intolerant of, eculizumab, said Ilene C. Weitz, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles.

"It gives another option to patients who are not having the best response to a C5 inhibitor," she said. "There are questions still out there. Does it continue to suppress thrombosis the way a C5 inhibitor does? Strategies for break through need to be assessed. What are the best patients for this treatment? And we don't have information about patients who have a suboptimal response on C5 but don't have significant anemia or aren't transfusion dependent."

"We did not see a significant number of infections, which you would have expected with a C3 inhibitor, but all the patients were vaccinated for everything and they were all on penicillin prophylaxis," Weitz added.

PNH is a rare, acquired, clonal, nonmalignant blood disorder associated with complement-mediated hemolysis, fatigue, increased susceptibility to thrombosis, and bone marrow dysfunction, according to the authors. The complement dysregulation leads to chronic hemolysis and thrombosis. Hemolytic manifestations arise directly from increased sensitivity of PNH cells to complement.

Development of C5 inhibitors transformed outcomes for PNH by controlling intravascular hemolysis and preventing terminal complement-mediated platelet and white-cell activation and destruction to reduce the risk of thrombosis. C5 inhibition also improves anemia, reduces the need for transfusion, and prevents multiple types of PNH-related complications, the authors continued.

However, PNH red cells lack CD55, leading to which opsonize PNH erythrocytes and are removed by extravascular hemolysis in the liver and spleen. Extravascular hemolysis and associated anemia can occur despite C5 inhibition and may necessitate continued need for transfusions.

By targeting complement C3, pegcetacoplan offers the potential to control intravascular and extravascular hemolysis. The drug was compared with eculizumab in a randomized trial involving patients with PNH and inadequate response or intolerance to eculizumab.

Trial Results

Investigators enrolled patients with PNH associated with hemoglobin levels <10 g/dL despite stable dosing of eculizumab for at least 3 months. Patients were randomized to subcutaneous pegcetacoplan or intravenous eculizumab, and the primary endpoint was mean change in hemoglobin from baseline to 16 weeks.

Data analysis included 80 patients who had median disease duration of 6.0 (pegcetacoplan) and 9.7 (eculizumab) years, median duration of eculizumab therapy of 3 to 4 years, and mean baseline hemoglobin value of about 8.69 g/dL. More than half the patients in each treatment group had received at least four transfusions in the previous 12 months; a fourth had received none.

The primary analysis showed a mean between-group difference in 16-week hemoglobin values of 3.84 g/dL in favor of the pegcetacoplan group (95% CI 2.33-5.34, P<0.001). A supporting analysis that included all available data (not censored for transfusions) yielded similar results favoring the C3 inhibitor. Analysis of data by transfusion history showed a mean hemoglobin improvement of 2.97 g/dL in patients who received fewer than four transfusions and 2.11 g/dL among those who required more transfusions in the previous 12 months before the trial.

During the 16 weeks of randomized therapy, 35 of 41 patients in the pegcetacoplan arm remained transfusion independent as compared with six of 39 in the eculizumab arm (P<0.001). Absolute reticulocyte count decreased by 136 x 10⁹/L with pegcetacoplan and increased 28 x 10⁹/L with eculizumab, demonstrating noninferiority for the C3 inhibitor versus the C5 inhibitor. Lactate dehydrogenase declined by 15 U/L with pegcetacoplan and by 10 U/L in the eculizumab arm, a difference that did not achieve noninferiority.

A clinically meaningful difference in quality-of-life scores occurred among patients treated with pegcetacoplan, but the difference did not achieve prespecified statistical criteria for noninferiority.

Adverse events (AEs) occurred in a similar proportion of patients in both arms. The most common AEs with pegcetacoplan and eculizumab were injection-site reactions (37% vs 3%0, diarrhea (22% vs 3%), breakthrough hemolysis (10% vs 23%), headache (7% vs 23%), and fatigue (5% vs 15%). Infections occurred in 29% of the pegcetacoplan arm and 26% of the eculizumab group.

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