Improvements in Fatigue Correlate with Changes in Clinical and Hematological Outcomes: Post Hoc Analyses from the Pegasus Study
Authors: Cella David , Lenderking William R. , Sarda Sujata P. , Baver Scott B. , Hamdani Mohamed , Hsieh Ray , Shaffer Shannon , Röth Alexander 
Published: November 2020

BACKGROUND
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematologic disease characterized by complement-mediated hemolysis resulting in anemia, thrombosis, and bone marrow failure. The PEGASUS phase 3 randomized study demonstrated superiority of pegcetacoplan vs. eculizumab on improvements in hemoglobin, and pegcetacoplan improved clinical and hematological outcomes such as fatigue in patients with partial response to eculizumab after treatment for at least 3 months (Hb &lt;10.5 g/dL). The objectives of these post-hoc analyses were to explore relationships among effect modifiers, including fatigue and hemoglobin, reticulocyte count, indirect bilirubin, and physical functioning. Also, this study assessed further detail on the treatment effects of pegcetacoplan on fatigue in patients.
METHODS
Patients ≥18 years of age with PNH and hemoglobin concentration &lt;10.5 g/dL despite receiving treatment with eculizumab for ≥3 months were eligible for inclusion. Patients entered a 4-week run-in period in which they received eculizumab plus twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously) and were then randomized 1:1 to monotherapy with pegcetacoplan or eculizumab for 16 weeks. Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue scale, and a variety of symptoms (including fatigue and physical functioning) were evaluated with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) scale. Convergent validity was assessed using Spearman correlations and known groups validity was assessed using analysis of covariance (ANCOVA), as suggested by the FDA Guidance on patient-reported outcomes (US Food Drug Administration.Fed Regist. 2009;74(235):65132-65133). Subjects were grouped based on hemoglobin level (&lt;10 g/dL, 10 to ≤12 g/dL, &gt;12 g/dL), and by degree of hemoglobin improvement: &lt;1 g/dL, ≥1 to &lt;2 g/dL, and ≥2 g/dL.
RESULTS
At Week 16, in the overall sample (n = 80; intent-to-treat), the FACIT-Fatigue total score was significantly correlated with hemoglobin (r = 0.47, p &lt; 0.0001; Figure 1), reticulocyte count (r = -0.37, p &lt; 0.01), indirect bilirubin (r = -0.25, p &lt; 0.05), and with multiple EORTC domains including fatigue and physical function (r = -0.88, p &lt; 0.0001 and r = 0.82, p &lt; 0.0001 respectively). In a responsiveness analysis, groups with greater improvement in hemoglobin over 16 weeks showed the most improvement in fatigue (F = 9.03, p &lt; 0.0001), with the largest reduction in fatigue in the group with an increase in hemoglobin of ≥2 g/dL (11.3-point improvement in FACIT-F total score). In contrast, individuals with little to no hemoglobin improvement (&lt;1 g/dL) reported slightly more fatigue (-1.2 worsening in FACIT-F total score). The FACIT-F also distinguished between groups with different levels of hemoglobin (&lt;10 g/dL, 10 to ≤12 g/dL, &gt;12 g/dL) at Week 16 (F = 4.78, p = 0.0019). An analysis of the correlation of change scores indicates a clear separation between pegcetacoplan and eculizumab, showing a greater effect of pegcetacoplan on change in hemoglobin and improvement in fatigue (Figure 2).
CONCLUSION
In PNH, hemoglobin level and positive change in hemoglobin were significantly related to reduced fatigue. Pegcetacoplan resulted in significantly lower fatigue and hemoglobin scores at Week 16 compared to eculizumab.

Disclosures
Cella: Novartis:Consultancy;Kiniksa:Consultancy;IDDI:Consultancy;BMS:Consultancy, Research Funding;Oncoquest:Consultancy;ASAHI KASEI PHARMA CORP.:Consultancy;Mei Pharma:Consultancy;Ipsen:Consultancy, Research Funding;Evidera:Consultancy;DSI:Consultancy, Research Funding;BlueNote:Consultancy;Abbvie:Consultancy, Research Funding;Astellas:Consultancy, Honoraria;FACIT.org:Membership on an entity's Board of Directors or advisory committees, Other: President;PROMIS Health Org:Membership on an entity's Board of Directors or advisory committees, Other;Pled Pharma:Research Funding;Janssen:Research Funding;Clovis:Research Funding;Alexion:Research Funding;Apellis:Consultancy;Pfizer:Consultancy, Research Funding.Lenderking:Evidera:Current Employment.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.Hamdani:Apellis Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Hsieh:Evidera/PPD:Current Employment.Shaffer:Evidera:Current Employment.Röth:Sanofi:Consultancy, Honoraria;Roche:Consultancy, Honoraria, Research Funding;Novartis:Consultancy, Honoraria;Biocryst:Consultancy, Honoraria;Apellis:Consultancy, Honoraria;Alexion Pharmaceuticals Inc.:Consultancy, Honoraria, Research Funding.

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