(150) Comparative Effectiveness of Pegcetacoplan (PEG) Versus Ravulizumab (RAV) and Eculizumab (ECU) in Complement Inhibitor-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): A Matching-Adjusted Indirect Comparison

Publication Number: 811

Background: Many patients with PNH treated with the complement component 5 (C5) inhibitors RAV and ECU experience persistent symptoms. PEG, an approved C3 inhibitor, is another therapeutic option.

Objectives: In the absence of head-to-head studies, this study compared treatment outcomes with PEG vs. RAV or ECU in complement inhibitor-naïve patients with PNH by matching-adjusted indirect comparison (MAIC).

Methods: Individual patient data from the phase 3 PRINCE trial (NCT04085601; N=34) were compared with aggregate data from the RAV (N=125) and ECU (N=121) arms of the ALXN1210-PNH-301 trial (NCT03056040). Propensity score weighting was used to adjust for cross-study differences in patients’ baseline characteristics. Unanchored comparisons of percent change from baseline in lactate dehydrogenase (LDH) level, LDH normalization, hemoglobin (Hb) stabilization, transfusion avoidance, and transfusion requirements, Functional Assessment of Chronic Illness Therapy Fatigue scores, and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) General Health scores at Week 26 were performed (weighted Wald test with 95% confidence interval [CI]). Bias factor analysis with potential confounders (e.g., age ≥65 years, overweight/obese, history of aplastic anemia, impaired renal function, bone marrow failure, and glycosyl-phosphatidylinositol–deficient granulocyte clone size >70%) was conducted and unanchored indirect comparisons were adjusted for each bias factor by subtracting the factor from the effect estimate and 95% CIs.

Results: The MAIC showed that compared with RAV or ECU, treatment with PEG was associated with significant improvements in absolute and percent (~12%) reductions in LDH level and increases in Hb level (17% vs. RAV, 19% vs. ECU) from baseline; shorter time to first occurrence of LDH normalization; larger proportions of patients achieving Hb stabilization (26% vs. RAV, 28% vs. ECU) and avoiding transfusion (21% vs. RAV, 26% vs. ECU), with fewer packed red blood cell units transfused; and a smaller proportion of patients experiencing breakthrough hemolysis (−4% vs. RAV, −10% vs. ECU) (all P< 0.05). PEG was associated with greater increases in EORTC QLQ-C30 general health status score from baseline than RAV or ECU. The differences between PEG and RAV or ECU remained robust even after adjusting for potential confounders.

Conclusions: PEG is associated with greater improvements in clinical, hematologic, and quality of life outcomes than C5 inhibitors and is a first-line treatment option for complement inhibitor-naïve patients with PNH.