Categorized Hematologic Response to Pegcetacoplan and Correlations with Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from Phase 1b, Phase 2a, and Phase 3 Trials

Abstract

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a complement-mediated, hematologic disease characterized by hemolysis, anemia, and fatigue that impairs quality of life. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the Food and Drug Administration for treatment of PNH, controls intravascular hemolysis (IVH) and prevents extravascular hemolysis (EVH). The PADDOCK and PALOMINO trials demonstrated PEG's improvement of key hematologic and clinical parameters, including hemoglobin (Hb) level and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The PEGASUS trial demonstrated that PEG was more effective than eculizumab (ECU) in improving these parameters in PNH patients with suboptimal response to prior ECU treatment. Aims: This post hoc analysis categorized hematologic response to PEG in 3 trials: PADDOCK (phase 1b, open-label, two-cohort [NCT02588833]), PALOMINO (phase 2a, open-label, single-cohort [NCT03593200]), and PEGASUS (phase 3, randomized, open-label, active-comparator controlled [NCT03500549]). Methods: PADDOCK and PALOMINO included adult complement inhibitor-naïve patients, while PEGASUS included adult patients with Hb <10.5 g/dL despite ≥3 months of ECU treatment. PADDOCK was a multiple ascending dose pilot study of 2 cohorts: cohort 1 received a suboptimal PEG dose (180 mg/day subcutaneously [SQ]) for 28 days; cohort 2 received a PEG dose of 270-360 mg/day SQ for up to one year. Patients could be enrolled in both cohorts. PALOMINO patients received a PEG dose of 270-360 mg/day SQ for up to one year. PEGASUS comprised a 4-week run-in period where patients received both ECU (continued dosing regimen) and PEG (1080 mg SQ twice-weekly), 16-week randomized controlled period (PEG or ECU monotherapy), and 32-week open-label period (PEG monotherapy) including a 4-week run-in period for the ECU-to-PEG group. Hematologic response category was assessed at Days 113/337 for patients in the combined PADDOCK/PALOMINO trials (N=24) via manual categorization by two independent, blinded observers. Categorization was assessed at Weeks 16/48 for PEGASUS patients (N=80) using SAS 9.4M5. Statistical significance for hematologic response categories within arms at Week 16 vs. 48, and between arms at Week 48, was evaluated using Wilcoxon-Mann-Whitney and Chi-square testing. FACIT-Fatigue scores for PEGASUS patients, summarized using descriptive statistics, were also correlated to hematologic response category. Response categories were defined per the following criteria (Risitano A, et al., Front Immunol, 2019;10:1157): complete- no transfusions required, stable 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 (<3 units/6 months); minor- regular transfusions required (3-6 units/6 months); no response- regular and frequent transfusions required (>6 units/6 months). PADDOCK/PALOMINO patients missing data at an assessment timepoint, or PEGASUS patients missing data within 6 weeks prior to an assessment timepoint, were not evaluated. Results: Most PADDOCK/PALOMINO patients achieved at least a good hematologic response at Days 113 and 337 (Table 1). At Week 48, most patients in both PEGASUS arms achieved a good/major/complete hematologic response (inter-arm p=0.4390), with a significant increase in the percent of ECU-to-PEG patients achieving at least a good response after switching to PEG at Week 16 (Week 16 vs. 48: intra-arm p<0.0001; Table 1). In PEGASUS, patients with better response categories had higher FACIT-Fatigue scores when compared to the rest of the cohort (Week 16: p<0.001, Week 48: p=0.028; Table 2). Conclusions: In post hoc analyses of PADDOCK, PALOMINO, and PEGASUS trial data, a substantial proportion of patients achieved and maintained good, major, or complete hematologic responses to PEG, suggesting that PEG can lead to sustained improvements in hematologic parameters. PEGASUS data also demonstrated correlation of improved hematologic response category with clinically meaningful improvements in quality of life, as measured by FACIT-Fatigue. Figure 1 Figure 1. Disclosures Risitano: Jazz: Other: Lecture fees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Biocryst: Membership on an entity's Board of Directors or advisory committees; RA Pharma: Research Funding; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Chen: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour: Swedish Orphan Biovitrum AB: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Analysis of Costs per Responder in US Adults with Paroxysmal Nocturnal Hemoglobinuria with a Suboptimal Response to Prior Eculizumab Treatment

“…Costs per responder were assessed for pegcetacoplan and eculizumab using data from post hoc EBMT response categorization analyses of the PEGASUS [ 21 , 22 ], PADDOCK and PALOMINO [ 22 ], and PRINCE [ 23 ] clinical trials and a real-world cohort study [ 24 ], plus drug and administration costs from REDBOOK [ 25 , 26 , 27 ]. This analysis was performed in Microsoft Excel 365 (Microsoft Corporation) and followed the best practice recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine [ 28 ].…”

“…Additional scenario analyses were performed using all available data from recent PNH clinical trial response categorization studies (as of July 2022) [ 21 , 22 , 23 , 24 ] to estimate the average costs per treated patient, average costs per good-to-complete responder (i.e., patient with a good, major, or complete response), percentage of total costs for patients with partial-to-no response (i.e., patients with a partial, minor, or no response) or discontinued/missing status, and NNT for pegcetacoplan and eculizumab across a range of PNH patient populations. These additional analyses include the following: Calculation of the average drug costs per responder at Week 48 for patients with a suboptimal response to prior eculizumab treatment with the use of categorized response data for those treated with pegcetacoplan from both the randomized controlled period (Weeks 0–16) and the open-label period (Weeks 16–48) of the PEGASUS trial [ 21 , 22 ] ( Supplementary Materials Section S1 ). Calculation of the average drug costs per responder at Weeks 16 and 48 for C5 inhibitor-naïve patients (i.e., PNH patients who had not previously received treatment with the C5 inhibitors eculizumab or ravulizumab) who initiated pegcetacoplan treatment with the use of nonrandomized, categorized response data from the phase 1b PADDOCK and the phase 2a PALOMINO trials [ 22 ] ( Supplementary Materials Section S2 ).…”

“…These additional analyses include the following: Calculation of the average drug costs per responder at Week 48 for patients with a suboptimal response to prior eculizumab treatment with the use of categorized response data for those treated with pegcetacoplan from both the randomized controlled period (Weeks 0–16) and the open-label period (Weeks 16–48) of the PEGASUS trial [ 21 , 22 ] ( Supplementary Materials Section S1 ). Calculation of the average drug costs per responder at Weeks 16 and 48 for C5 inhibitor-naïve patients (i.e., PNH patients who had not previously received treatment with the C5 inhibitors eculizumab or ravulizumab) who initiated pegcetacoplan treatment with the use of nonrandomized, categorized response data from the phase 1b PADDOCK and the phase 2a PALOMINO trials [ 22 ] ( Supplementary Materials Section S2 ). Calculation of the average drug costs per responder at Week 26 for C5 inhibitor-naïve (i.e., had not received C5 inhibitors within 3 months of screening) patients initiating pegcetacoplan treatment with the use of nonrandomized, categorized response data from the phase 3 PRINCE trial [ 23 ] ( Supplementary Materials Section S2 ).…”

Paroxysmal nocturnal hemoglobinuria: Where we stand

“… 84 These objective criteria are now even more important as eculizumab lost its absolute monopoly and application of response criteria will allow us to better compare therapies with similar or even different modes of action. The advent of proximal complement inhibitors (see below and next chapter) will most likely necessitate a revision of the actual criteria, until then, they can also be applied retrospectively to current study results 101 . In addition to adequate QoL assessment every patient with PNH treated should be assessed semiannually to recognize suboptimal response or evolving marrow failure.…”

“…The advent of proximal complement inhibitors (see below and next chapter) will most likely necessitate a revision of the actual criteria, until then, they can also be applied retrospectively to current study results. 101 In addition to adequate QoL assessment every patient with PNH treated should be assessed semiannually to recognize suboptimal response or evolving marrow failure. 8 weeks was noninferior to eculizumab every 2 weeks for all efficacy endpoints with a comparable safety profile, demonstrating that patients on eculizumab can be safely and effectively switched to ravulizumab.…”