Normalization of Hemoglobin, Lactate Dehydrogenase, and Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan

Abstract

Background and objectives: We determined normalization rates for hemoglobin, lactate dehydrogenase (LDH), and fatigue in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan (PEG) in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) phase III trials.

Methods: Enrolled patients had PNH and hemoglobin < 10.5 g/dL despite ≥ 3 months of eculizumab (ECU) [PEGASUS], or were complement component 5 (C5) inhibitor-naive, receiving supportive care only, with hemoglobin less than the lower limits of normal (LLN) [PRINCE]. Hematologic and fatigue normalization endpoints were hemoglobin greater than or equal to the LLN (females: 12 g/dL; males: 13.6 g/dL) in the absence of transfusion; LDH ≤226 U/L in the absence of transfusion; and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue ≥ 43.6, the general population norm. Safety was assessed by investigators using standardized terms and definitions for seriousness and severity.

Results: Hemoglobin normalization occurred in 34.1% (14/41) of PEG-treated patients at Week 16 (randomized controlled period) in PEGASUS (vs. 0% [0/39] of ECU-treated patients) and in 45.7% (16/35) of PEG-treated patients at Week 26 in PRINCE (vs. 0% [0/18] of supportive care-treated patients). At Week 48 (open-label period) in PEGASUS, 24.4% of PEG-treated patients (PEG-to-PEG) and 30.8% of patients treated with ECU through Week 16 who switched to PEG through Week 48 (ECU-to-PEG) had hemoglobin normalization. Rates of LDH normalization in PEGASUS were 70.7% (PEG-treated patients) and 15.4% (ECU-treated patients) at Week 16, and 56.1% (PEG-to-PEG) and 51.3% (ECU-to-PEG) at Week 48. In PRINCE, 67.5% of PEG-treated patients at Week 26 had normalized LDH concentrations. Rates of FACIT-Fatigue score normalization in PEGASUS were 48.8% and 10.3% in PEG- and ECU-treated patients, respectively, at Week 16, and 34.1% and 51.3% in PEG-to-PEG- and ECU-to-PEG-treated patients, respectively, at Week 48. In PRINCE, 68.6% of PEG-treated patients and 11.1% of supportive care patients had FACIT-Fatigue score normalization at Week 26. PEG was safe and well tolerated. Injection site reactions, mostly mild, were the most common adverse event of special interest in PEG-treated patients in the PEGASUS randomized controlled period (36.6%) and in PRINCE (30.4%).

Conclusion: PEG is superior to ECU and supportive care in hemoglobin, LDH, and FACIT-Fatigue score normalization for patients with PNH and persistent anemia despite ≥3 months of treatment with ECU, and in C5 inhibitor-naive patients.

Clinical trial registration: The PEGASUS trial (NCT03500549) was registered on 18 August 2018, and the PRINCE trial (NCT04085601) was registered on 11 September 2019.

Fig. 1

Hemoglobin normalization rates^a. ^aHemoglobin normalization is a hemoglobin concentration at or above the lower limit of the sex-specific normal range (females: 12.0 g/dL; males: 13.6 g/dL). Patients who received a transfusion, withdrew from the study, were lost to follow-up, or switched from control (supportive care only) to pegcetacoplan (PRINCE) were considered not normalized. ^bPEG-to-PEG: pegcetacoplan treatment for 16 weeks during the RCP, then continued on pegcetacoplan through Week 48 of the OLP. ^cECU-to-PEG: eculizumab treatment for 16 weeks during the RCP then switched to pegcetacoplan through Week 48 of the OLP. ^dControl: supportive care only (e.g., transfusions, corticosteroids, anticoagulants, supplements [iron, folate, B₁₂]) in countries where complement inhibitors were not approved or widely available. ECU eculizumab, OLP open-label period, PEG pegcetacoplan, RCP randomized controlled period

Fig. 2

Lactate dehydrogenase normalization rates^a. ^aLDH normalization is an LDH concentration at or below the upper limit of normal (226 U/L). Patients who received a transfusion, withdrew from the study, were lost to follow-up, or switched from control (supportive care only) to pegcetacoplan (PRINCE) were considered not normalized. ^bPEG-to-PEG: pegcetacoplan treatment for 16 weeks during the RCP then continued on pegcetacoplan through Week 48 of the OLP. ^cECU-to-PEG: eculizumab treatment for 16 weeks during the RCP then switched to pegcetacoplan through Week 48 of the OLP. ^dControl: supportive care only (e.g., transfusions, corticosteroids, anticoagulants, supplements [iron, folate, B₁₂] in countries where complement inhibitors were not approved or widely available. ECU eculizumab, LDH lactate dehydrogenase, OLP open-label period, PEG pegcetacoplan, RCP randomized controlled period

Fig. 3

FACIT-fatigue normalization rates^a. ^aFACIT-Fatigue normalization is a score ≥43.6, which is the general population norm.¹⁸ Patients who withdrew from the study, were lost to follow-up, or switched from control (supportive care only) to pegcetacoplan (PRINCE) were considered not normalized. ^bPEG-to-PEG: pegcetacoplan treatment for 16 weeks during the RCP then continued on pegcetacoplan through Week 48 of the OLP. ^cECU-to-PEG: eculizumab treatment for 16 weeks during the RCP then switched to pegcetacoplan through Week 48 of the OLP. ^dControl: supportive care only (e.g., transfusions, corticosteroids, anticoagulants, supplements [iron, folate, B₁₂] in countries where complement inhibitors were not approved or widely available. ECU eculizumab, FACIT-Fatigue Functional Assessment of Chronic Illness Therapy-Fatigue, OLP open-label period, PEG pegcetacoplan, RCP randomized controlled period