Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Keywords: Hemoglobin; LDH; Paroxysmal nocturnal hemoglobinuria (PNH); Phase I/II trials; Quality of life; Safety.

Fig. 1

Study design and disposition for PADDOCK and PALOMINO. A Study design and endpoints investigated; subjects in the PADDOCK trial could participate in cohort 1 and cohort 2. One subject participated in both cohorts. Cohort 1: daily subcutaneous 180 mg pegcetacoplan (n = 3). Cohort 2: daily subcutaneous 270–360 mg pegcetacoplan (n = 20) was initiated after the Safety and Monitoring Committee had determined that pegcetacoplan has an acceptable safety and tolerability profile in cohort 1. Clinical benefit was evaluated throughout the trial and if a patient did not experience PNH symptom improvement, the subject would be withdrawn from the study and entered the follow-up period (Part 3). B CONSORT diagram for PADDOCK and PALOMINO. Asterisk: Subjects who transitioned to either the extension study or Part 2C completed the day 365 visit for Part 3 while continuing to receive pegcetacoplan. For these subjects, the day 365 visit was also the first visit of the open-label extension study or Part 2C and these subjects did not complete Part 3. Dagger: All subjects were offered to enroll in an extension study and the majority of subjects chose to continue

Fig. 2

Primary endpoint findings and hematologic improvements over time in subjects with PNH treated with pegcetacoplan. A Primary endpoints for the PADDOCK and PALOMINO studies; mean (SD) change from baseline at day 365 in hemoglobin, LDH, and haptoglobin levels. B Pegcetacoplan rapidly reduced hemoglobin levels. Mean hemoglobin levels over time are depicted for cohort 2 of the PADDOCK trial and all 4 PALOMINO subjects. The blue shaded area indicates the normal range of hemoglobin levels with the bottom of the shaded area depicting the lower limit of normal (LLN) for female patients [NRR: females 11.9–16]. Smaller dashes on the x-axis indicate additional time points investigated (days 15, 22, 36, 43, and 71), which were left off the x-axis to not overcrowd the axis. N’s for both trials are listed immediately above the x-axis. C Pegcetacoplan dosing rapidly reduced LDH levels. Mean LDH levels over time are depicted for cohort 2 of the PADDOCK trial and all 4 PALOMINO subjects. The y-axis is split to better show differences at lower LDH levels. The blue shaded area depicts the normal range 113–226 U/L for LDH with the ULN, LLN, and 1.5 × ULN (339 U/L) marked. Slight increases in mean LDH levels on day 225 in the PADDOCK trial were due to 3 patients that experienced an increase in LDH levels on this day. One of these patients continued to exhibit elevated LDH levels on day 309 and day 337. These LDH increases most likely result from the patients experiencing adverse events, or serious adverse events such as the abdominal neoplasm and hemolysis during these study days. LDH, lactate dehydrogenase; LLN, lower limit of normal; NRR, normal reference range; SD, standard deviation; SE, standard error, ULN, upper limit of normal

Fig. 3

Other biochemical indicators of hemolysis over time in subjects with PNH treated with pegcetacoplan. A ARC rapidly decreased upon pegcetacoplan dosing. Mean ARC are depicted for cohort 2 of the PADDOCK trial and all 4 PALOMINO subjects. Blue shaded area depicts the normal range: 10–110 × 10.⁹ cells/L with the ULN and LLN marked. B Pegcetacoplan dosing rapidly decreased the total bilirubin levels in both PADDOCK (cohort 2) and PALOMINO (all 4 subjects) trials. Blue shaded area indicates the normal range: 3–20 μmol/L with ULN and LLN marked. Smaller dashes on the x-axis indicate additional time points investigated (days 15, 22, 36, 43, and 71), which were left off the x-axis to not overcrowd the axis. N’s for both trials are listed immediately above the x-axis. ARC, absolute reticulocyte count; LLN, lower limit of normal; SE, standard error; ULN, upper limit of normal

Fig. 4

Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores over time in subjects with PNH treated with pegcetacoplan. Mean FACIT-Fatigue scores are depicted for cohort 2 of the PADDOCK trial and all 4 PALOMINO subjects. Both PADDOCK and PALOMINO mean scores were below the population norm (43.6; gray dotted line) [35] at baseline, but rapidly increased to within or above the population norm. Both trials demonstrate a greater than 3-point increase in the FACIT-Fatigue score, which is considered clinically meaningful [35]. N’s for both trials are listed immediately above the x-axis. FACIT, Functional Assessment of Chronic Illness Therapy; SE, standard error

Fig. 5

Pegcetacoplan improves hemolysis markers in patients with PNH. A The complement cascade and location of pegcetacoplan inhibition at the level of C3 and its downstream effects. B Summarized results from baseline to the 1-year endpoint for specific safety events as well as hemoglobin levels. The thrombosis, red blood cell (RBC) lysis, and hemoglobin icons were created using biorender.com. Footnotes: ¹Adverse event of special interest; ²treatment-emergent adverse event. SAE, serious adverse event; TEAE, treatment-emergent adverse event