INTRODUCTION

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disease characterized by complement-mediated hemolysis, resulting in anemia, thrombosis, and bone marrow failure. Currently available treatment options for PNH include the C5 inhibitors eculizumab and ravulizumab, which target intravascular hemolysis through terminal complement inhibition. Pegcetacoplan is a targeted C3 inhibitor being developed to control both intravascular and extravascular hemolysis, to improve hematologic and clinical outcomes. There is no head-to-head study of pegcetacoplan vs ravulizumab in patients with PNH. We assessed the comparative effectiveness of pegcetacoplan to ravulizumab through comparison of phase 3 study results, using matching-adjusted indirect comparison (MAIC) methodology, anchoring on the common comparator arm in the studies, eculizumab. We also acknowledge inherent limitations to MAIC (eg, lack of generalizability beyond the analyzed population).

METHODS

Individual patient data from PEGASUS, an ongoing, randomized, phase 3 study comparing pegcetacoplan and eculizumab among patients with PNH previously treated with eculizumab, were used to adjust for baseline differences compared to aggregate, published results from the randomized 302 study (Kulasekararaj AG, et al. Blood. 2019;133(6):540-549), which compared ravulizumab and eculizumab among patients with PNH with previous eculizumab. Both studies had similar eligibility criteria. However, PEGASUS also required hemoglobin <10.5 g/dL and absolute reticulocyte count >1.0× the upper limit of normal; these criteria were not applicable in the 302 study. To adjust for cross-study differences in baseline characteristics, propensity score weighting was used to balance demographic and clinical characteristics. Outcomes assessed included transfusion avoidance, total number of units of packed red blood cells (PRBCs) transfused, hemoglobin stabilization, and change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Outcomes were assessed from PEGASUS at week 16 and from the 302 study at week 26. Unadjusted mean and least-squares mean change in FACIT-Fatigue score were compared for PEGASUS and the 302 study, respectively. Weighted Wald tests and 95% confidence intervals (CIs) were computed for comparisons of categorical and continuous outcomes (ie, chi-square and z tests, respectively).

RESULTS

Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from the 302 study (97 ravulizumab; 98 eculizumab) were included. Among pegcetacoplan and ravulizumab patients, mean age was 46.4 years, 48.5% were female, and 51.5% were white. Overall, 51.5% received ≥4 transfusions in the 12 months before screening in PEGASUS. The adjusted difference in proportion of transfusion avoidance was 71.4% (95% CI, 53.5-89.3%; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 71.4% more transfusion avoidance than ravulizumab. The difference in mean number of units of PRBCs transfused during follow-up was -5.7 units (95% CI, -7.2 to -4.2; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 5.7 fewer units of PRBCs transfused during treatment than ravulizumab. The adjusted difference in proportion of hemoglobin stabilization was 75.5% (95% CI, 56.4-94.6%; P < 0.0001), suggesting that pegcetacoplan is associated with 75.5% more patients who achieved hemoglobin stabilization than ravulizumab. The adjusted difference in mean change from baseline in FACIT-Fatigue score was 8.8 points (95% CI, 4.2-13.3; P < 0.0001), suggesting that pegcetacoplan is associated with an improvement ~3 times greater than the clinically meaningful improvement of 3 points than ravulizumab. See the Figure for additional details.

CONCLUSIONS

MAIC methodology allowed the examination of the comparative effectiveness of pegcetacoplan vs ravulizumab in the absence of a head-to-head trial. Results suggest an improvement in transfusion avoidance, hemoglobin stabilization, and fatigue and a reduction in the total number of units of PRBCs transfused for patients who received pegcetacoplan, a C3 inhibitor, in PEGASUS, vs patients who received ravulizumab, a C5 inhibitor, in the 302 study. As PEGASUS progresses, week 26 data will be used to refresh these analyses.

Disclosures

Bhak:Apellis: Research Funding. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Yee:Apellis: Research Funding. Sundaresan:Apellis: Research Funding. Swartz:Apellis: Research Funding. Duh:Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding; Merck: Research Funding. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company.

OffLabel Disclosure:

Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Author notes

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Asterisk with author names denotes non-ASH members.