Pegcetacoplan shows promise over eculizumab for paroxysmal nocturnal hemoglobinuria
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Pegcetacoplan led to greater improvements in hemoglobin compared with eculizumab among patients with paroxysmal nocturnal hemoglobinuria, according to results of the phase 3 PEGASUS study published in The New England Journal of Medicine.
Researchers said results of this randomized, multicenter trial could lead to pegcetacoplan (APL-2, Apellis Pharmaceuticals) — a pegylated peptide targeting proximal complement protein C3 — becoming a new standard of care for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a chronic life-threatening blood disorder characterized by destruction of oxygen-carrying red blood cells through extravascular and intravascular hemolysis.
“Proximal complement inhibition is extremely effective in PNH, and pegcetacoplan is safe and effective as monotherapy for the majority of patients with a suboptimal response to eculizumab [Soliris, Alexion],” Peter Hillmen, MB, ChB, PhD, professor of experimental hematology at Leeds Teaching Hospitals NHS Trust, told Healio.
C5 inhibition with eculizumab or ravulizumab-cwvz (Ultomiris, Alexion) controls the intravascular hemolysis of PNH, leads to a reduction in thrombosis and improves anemia, but it doesn’t address extravascular hemolysis (EVH) associated with the disease, which can lead to need for continued blood transfusions.
“The current treatment with inhibitors of terminal complement (eculizumab or ravulizumab-cwvz) results in the development of EVH in virtually all patients,” Hillmen said. “EVH leads to a marked reduction in hemoglobin level (median of 4g/dL lower than normal in our experience) and in many patients, significant symptoms. Approximately one-third of patients continue to require transfusions despite terminal complement inhibitor therapy.”
Thus, Hillmen and colleagues sought to evaluate pegcetacoplan, which potentially inhibits intravascular and extravascular hemolysis, for patients with PNH who had a suboptimal response to prior treatment, defined as continued transfusion requirements and/or severe symptoms due to ongoing anemia from EVH.
The analysis included 80 patients enrolled across 44 centers who had hemoglobin levels of less than 10.5 g/dL while they received stable doses of eculizumab for at least 3 months.
The trial treatment consisted of three parts: a 4-week run-in phase, during which all patients continued their current dose of eculizumab with an addition of twice-weekly 1,080 mg subcutaneous pegcetacoplan; a 1:1 randomization phase, during which patients received monotherapy with pegcetacoplan or eculizumab for 16 weeks; and a 32-week period in which all patients received open-label pegcetacoplan.
For the randomization phase — which was stratified according to the number of packed red-cell transfusions patients received over the prior 12 months and baseline platelet count — researchers randomly assigned 41 patients to receive pegcetacoplan (mean age, 50.2 years; 66% women) and 39 to eculizumab (mean age, 47.3 years; 56% women).
Changes in hemoglobin level from baseline to week 16 served as the study’s primary endpoint.
Results showed the adjusted mean change in hemoglobin from baseline to week 16 was 2.37 g/dL with pegcetacoplan compared with –1.47 g/dL with eculizumab, for a mean difference of 3.84 g/dL (95% CI, 2.33-5.34).
Additionally, 35 patients receiving pegcetacoplan no longer required transfusions, compared with only six patients in the eculizumab group (P < .001).
“It is impressive how rapidly the EVH comes under control,” Hillmen said. “The hemoglobin and reticulocyte count normalized within 2 to 4 weeks. The improvement in symptoms [was] very impressive.”
Researchers also reported noninferiority of pegcetacoplan to eculizumab regarding mean change in absolute reticulocyte count — at –136 ± 7 x 109/L with pegcetacoplan and 28 ± 12 x 109/L with eculizumab — but not for the change in lactate dehydrogenase level, with an adjusted mean change from baseline of –15 ± 43 U/L with pegcetacoplan and –10 ± 71 U/L with eculizumab.
Patients assigned pegcetacoplan also showed a 9.2-point improvement in Functional Assessment of Chronic Illness Therapy–Fatigue score from baseline, compared with a 2.7-point decrease with eculizumab (mean difference, 11.9 points; 95% CI, 5.49-18.25).
“The improvements in hemoglobin and fatigue are very impressive and clinically very meaningful,” Hillmen said. “Patients on pegcetacoplan improve to near normality.”
The most common adverse events in the pegcetacoplan vs. eculizumab groups included injection site reaction (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%) and fatigue (5% vs. 15%).
“By the time pegcetacoplan is approved, there will be relatively little safety data compared with eculizumab (only the trial patients for a year or more),” Hillmen said. “The safety profile of pegcetacoplan is reassuring to date. Assuming with more data there are no unexpected safety concerns and that the responses are robust, which they seem to be, then pegcetacoplan could potentially displace eculizumab in the treatment of most patients with PNH.”
Longer follow-up of more patients treated in a real-world setting are important next steps of research, Hillmen said.
“We should consider doing trials in a broader population of patients with PNH to include those with less severe anemia than recruited in PEGASUS,” he told Healio. “The results of front-line therapy in the PRINCE study will be of interest. The main issue before broadening the indication for pegcetacoplan to a wider group of patients with PNH is collecting more safety data. We also need further studies to assess the best way to safely manage breakthrough hemolysis for patients on pegcetacoplan.”
Based on the eligibility criteria used for this study, about one-third of patients on terminal complement inhibitors will need therapy with pegcetacoplan, according to Hillmen.
“When we have more safety data from the real-world use, this proportion might increase as pegcetacoplan is extremely effective and may be better for a greater proportion of patients,” he said.
For more information:
Peter Hillmen, MB, ChB, PhD, can be reached at Bexley Wing, St. James’s University Hospital, Beckett St., Leeds, LS9 7TF, United Kingdom; email: p.hillmen@leeds.ac.uk.
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