MDS-126: Categorized Hematologic Response to Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from Phase 1b (PADDOCK) and Phase 2a (PALOMINO) Trials

Context: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated red blood cell hemolysis. Despite treatment with C5-inhibitors to control intravascular hemolysis (IVH), anemia persists in ~70% of patients due to persistent IVH and mostly C3-mediated extravascular hemolysis. Objective: This post hoc analysis categorized the hematologic response to pegcetacoplan (C3-inhibitor recently approved by the FDA) in the PADDOCK (phase 1b, two-cohort [NCT02588833]; n=20) and PALOMINO (phase 2a, single-cohort [NCT03593200]; n=4) open-label trials, which assessed safety/efficacy of pegcetacoplan in complement inhibitor-naive patients. Design: Hematologic response to treatment was categorized at Days 113 and 337 for the combined trials (n=24), per criteria in Risitano AM, et al. Front Immunol. 2019;10:1157: complete- no transfusions required, stable hemoglobin (Hb; normal range), no evidence of hemolysis (lactate dehydrogenase [LDH] ≤1.5×upper limit of normal [ULN] U/L, absolute reticulocyte count [ARC] ≤150,000/µL); major- no transfusion, normal Hb, but with evidence of hemolysis (LDH >1.5×ULN U/L and/or ARC >150,000/µL); good- no transfusions, but with chronic mild anemia or evidence of hemolysis; partial-chronic moderate anemia and/or occasional transfusions ( 6 units/6 months). Patients with missing data at either timepoint for ≥1 parameter were not evaluated. Manual categorization was independently conducted by two blinded observers. Results: Most patients achieved at least a good hematologic response at Days 113 (75.0%; 18/24) and 337 (62.5%; 15/24). Categorized hematologic responses were as follows: Day 113— good-to-complete 75.0%, partial 4.2%, minor 8.3%, no response 4.2%; Day 337— good-to-complete 62.5%, partial 20.8%, minor 4.2%, no response 0.0%. Of patients with evaluable data, 19.0% (4/21) achieved ≥1 category of improvement in hematologic response at Day 337 versus Day 113. In PADDOCK, 2 patients at Day 113 and 3 patients at Day 337 were unevaluable due to missing data. Conclusions: In the PADDOCK and PALOMINO trials, a substantial proportion of patients achieved complete, major, or good hematological responses to pegcetacoplan at Day 113, which was sustained to Day 337, suggesting that pegcetacoplan treatment in complement inhibitor-naive patients can lead to clinical improvements in PNH symptoms.