Pegcetacoplan controls hemolysis in complement inhibitor–naive patients with paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response to or intolerance of a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for 3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate efficacy and safety of pegcetacoplan versus control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomized and stratified based on their number of transfusions (<4, ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary endpoints were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n=35) or control (n=18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1% [95% CI: 57.2, 89.0]; P <0.0001) and change from baseline in LDH (least-square mean change: pegcetacoplan, -1870.5 U/L; control -400.1 U/L; difference, -1470.4 U/L [95% CI: -2113.4, -827.3]; P <0.0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04085601.

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health‐related quality of life and productivity

“…PEGASUS reported a rise in mean Hb levels from 8.7 g/dL at baseline to 11.5 g/dL after 16 weeks of PEG treatment, 15 and PRINCE a rise from 9.4 g/dL at baseline to 12.8 g/dL after 26 weeks treatment. 16 In our study, fatigue appeared to be ameliorated in patients receiving PEG in real-world clinical settings. This is of clinical importance as fatigue has been identified as one of the most burdensome symptoms of PNH, persisting in patients receiving C5i.…”

“…Patients treated with PEG for ≥6 months had a mean FACIT‐Fatigue total score of 40.3, close to the score of 42.2 at Week 12 of PEG treatment in the PEGASUS trial 15 . In the PRINCE trial, mean FACIT‐Fatigue total score was 45.3 at week 26 of PEG treatment 16 . The scores we report are somewhat lower (suggesting greater fatigue) than those reported for general populations (United States: 43.6 35 ; Germany: 43.5 36 ).…”

“…In the Phase 3 PRINCE trial, which included C5i-naïve patients, results showed PEG was superior to the control group (supportive care only) for the coprimary endpoints of Hb stabilisation and change from baseline in LDH after 26 weeks of treatment. 16 These clinical trial findings demonstrate that PEG provides additional benefits beyond standard of care therapies and highlights the potential for PEG as an effective and targeted treatment for PNH patients. As far as we are aware, except for the observational exploratory outcomes study OPERA, which included 17 patients from a single US centre, there is currently no real-world evidence regarding PEG use in PNH.…”

“…Data from PEGASUS also reported stabilisation in reticulocyte count, normalisation of lactate dehydrogenase (LDH) levels, reduced transfusion requirements and significant improvements in fatigue for patients receiving PEG compared to those receiving eculizumab. In the Phase 3 PRINCE trial, which included C5i‐naïve patients, results showed PEG was superior to the control group (supportive care only) for the coprimary endpoints of Hb stabilisation and change from baseline in LDH after 26 weeks of treatment 16 …”

Efficacy and safety of the C5 inhibitor crovalimab in complement inhibitor‐naive patients with PNH (COMMODORE 3): A multicenter, Phase 3, single‐arm study

“…Terminal complement inhibitors that prevent C5 activation, eculizumab and ravulizumab, 12–14 are the current standard of care for treatment of patients with PNH with symptomatic hemolysis or thrombosis in many countries 15 . Additionally, the C3‐targeting proximal complement inhibitor, pegcetacoplan, 16,17 is approved in some countries 15 . Several complement factor inhibitors are being investigated in ongoing studies 18–21 …”