Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270–360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90–18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Paroxysmal nocturnal hemoglobinuria: Where we stand

“…Impressive response rates with hemoglobin levels of 12.14 g/dl (PADDOCK trial, N = 23; NCT02588833) and 13 g/dl (PALOMINO trial, N = 4, NCT 03593200) after 85 days of treatment have also been reported for complement inhibitor naïve patients treated with pegcetacoplan. 120 Sixty-five percent of PADDOCK patients and all of the PALOMINO trial patients became transfusion free. The PRINCE (NCT04085601) phase III trial included 53 patients, who were randomized 2:1, evaluates efficacy and safety of pegcetacoplan compared to purely supportive control treatment including transfusion, anticoagulants and supplements in Ci-naive patients is still awaiting full publication; data published so far do show that 91.4% of patients under pegcetacoplan achieved freedom from transfusions with a median hemoglobin level of 12.8 g/dl at 26 weeks.…”

“…While C3‐inhibition results in clinically meaningful blocking of IVH and EVH, we are still lacking evidence that protection from thromboembolic events with proximal complement inhibitions is as effective as terminal inhibition, although preliminary data seem to give some indication that this might be the case 121 . Two cases of thrombosis (one in the setting of diffuse large B‐cell lymphoma and one in the setting of pneumonia) were reported from the 170 patients included into PADOCK, PALOMINO, PEGASUS, and PRINCE 120 …”

“…The PRINCE (NCT04085601) phase III trial included 53 patients, who were randomized 2:1, evaluates efficacy and safety of pegcetacoplan compared to purely supportive control treatment including transfusion, anticoagulants and supplements in Ci-naive patients is still awaiting full publication; data published so far do show that 91.4% of patients under pegcetacoplan achieved freedom from transfusions with a median hemoglobin level of 12.8 g/dl at 26 weeks. 120 While C3-inhibition results in clinically meaningful blocking of IVH and EVH, we are still lacking evidence that protection from thromboembolic events with proximal complement inhibitions is as effective as terminal inhibition, although preliminary data seem to give some indication that this might be the case. 121 Two cases of thrombosis (one in the setting of diffuse large B-cell lymphoma and one in the setting of pneumonia) were reported from the 170 patients included into PADOCK, PALOMINO, PEGASUS, and PRINCE.…”

Case report: Transfusion independence and abolition of extravascular hemolysis in a PNH patient treated with pegcetacoplan

“…Pegcetacoplan appeared generally safe, although drug-related hypersensitivity events occurred in the PADDOCK study. Importantly, there were no thrombotic events or severe infectious complications ( 6 ). Another phase Ib study, the PHAROAH trial (NCT02264639), investigated pegcetacoplan as an add-on therapy in suboptimal responders to eculizumab and demonstrated a hematological improvement, enabling eculizumab discontinuation in 4 subjects ( 7 ).…”

The Importance of C5aR2 in Neutrophil Function and Its Impact on Neutrophil-mediated Diseases

“…The recent FDA approval of several compounds that target the complement system either at the level of the classical pathway (CP) [51,52], the alternative pathway (AP) C3 [53,54], or the terminal pathway C5aR1 [55] and the successful treatment of paroxysmal nocturnal hemoglubinuria (PNH) patients with the terminal pathway inhibiting anti-C5 mAb eculizumab and derivatives [56][57][58] paved the way for an extensive pipeline of new therapeutic inhibitors targeting the complement system at several levels [59][60][61].…”