Treatment with pegcetacoplan led to greater hemoglobin stabilization and lactate dehydrogenase (LDH) reduction than the control therapy in complement inhibitor–naïve patients with paroxysmal nocturnal hemoglobinuria (PNH), according to research findings published in Blood Advances.
While the introduction of C5 complement protein inhibitors (C5is) redefined PNH from a potentially deadly condition to a chronic disease, patients who receive these agents may eventually develop extravascular hemolysis.
The phase III study, led by Raymond S. M. Wong, MD, of the Chinese University of Hong Kong, investigated the efficacy and safety of pegcetacoplan, the first C3-targeting treatment for PNH. According to Dr. Wong and colleagues, the findings that pegcetacoplan results in significant improvements in control of hemolysis in PNH “are an improvement over existing C5i therapies that stabilize but cannot normalize hematologic parameters.”
In the open-label PRINCE study, Dr. Wong and colleagues assessed the efficacy and safety of pegcetacoplan compared with supportive care alone (control), which consisted of anticoagulants, blood transfusions, corticosteroids, and supplements (iron, folate, and vitamin B12).
Eligible complement inhibitor–naïve patients with PNH receiving supportive care were randomly assigned to either pegcetacoplan (n=35) or continued supportive care (n=18), with randomization stratified according to each individual’s number of packed red blood cell transfusions (<4 vs. ≥4) received one year before screening. Assigned treatments included twice weekly subcutaneous pegcetacoplan at 1,080 mg or continued supportive care for a total of 26 weeks.
The study assessed two primary endpoints at week 26 to evaluate efficacy of treatment: hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) and change in LDH.
Over a median 10.2-week period, 11 patients in the control group initiated pegcetacoplan following a qualifying event. These patients completed the remaining portion of the 26-week study on pegcetacoplan.
Although the mean baseline characteristics were comparable between patients in both treatment arms, patients in the pegcetacoplan group were, on average, seven years younger (42.2 vs. 49.1 years), had a lower occurrence of aplastic anemia (14.3% vs. 27.8%), and less frequently had received ≥4 transfusions within 12 months before the study (40.0% vs. 55.6%). In addition, more patients in the control arm were Asian (88.9% vs. 65.7%).
At 26 weeks, nearly all patients treated with pegcetacoplan (85.7%) experienced hemoglobin stabilization compared with none of the patients in the control group (difference = 73.1%; p<0.0001). The mean change in LDH from baseline was also significantly greater in the pegcetacoplan arm (-1,870.5 vs. -400.1 U/L; p<0.0001).
According to analyses of the secondary endpoints, pegcetacoplan therapy significantly improved fatigue and quality of life (QoL) in patients with PNH. For instance, a significantly greater proportion of patients who received pegcetacoplan experienced clinically meaningful improvements in Functional Assessment of Chronic Illness Therapy–Fatigue scores at week 26 compared with patients in the control arm (60.0% vs. 11.1%; p=0.0007). Also, the pegcetacoplan group experienced significant improvements in mean global health status/QoL scores compared with the control group (18.9 vs. -2.9; p=0.0006).
Pegcetacoplan was well tolerated by all patients who received it. There was no difference between the groups with respect to the proportion of patients who experienced adverse events (AEs). Additionally, there were no serious AEs associated with pegcetacoplan, and no new safety signals related to the treatment were observed. The most common AEs reported with pegcetacoplan were arthralgia, dizziness, ecchymosis, fever, headache, and hypokalaemia.
A limitation of the study was the small sample size of the group receiving only supportive care. The researchers also stated that because more than half of patients in the control arm “escaped” to pegcetacoplan, they were unable to conduct proper direct comparisons for safety and some of the efficacy endpoints.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Wong RSM, Navarro-Cabrera JR, Comia NS, et al. Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria [published online, 2023 Feb 27]. Blood Adv. doi: 10.1182/bloodadvances.2022009129.
