MDS-135: Injection Site Reactions at Week 48 in the Randomized Phase 3 PEGASUS Trial of Pegcetacoplan Compared with Eculizumab for Individuals with Paroxysmal Nocturnal Hemoglobinuria

Abstract

<h3>Context:</h3> Pegcetacoplan (PEG) is a C3-complement inhibitor recently approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria. PEG was superior to eculizumab (ECU; C5-inhibitor) in improving hemoglobin levels at week 16 in patients with suboptimal response to prior ECU treatment (phase 3 PEGASUS trial NCT03500549). PEG is self-administered twice weekly via two 10-mL subcutaneous injections at two distinct sites, which may lead to injection site reactions (ISRs). <h3>Objective:</h3> To compare ISR safety outcomes from PEGASUS to ISR incidences from similarly administered treatments based on published literature. <h3>Design:</h3> PEGASUS patients completed a 4-week run-in period (RIP) with ECU+PEG before 1:1 randomization to PEG (n=41) or ECU monotherapy (n=39). Primary endpoint was change from baseline in hemoglobin to week 16. Patients receiving ECU during the RCP entered another 4-week RIP (ECU+PEG), followed by an open-label period (OLP), in which all patients received PEG monotherapy. Safety was a secondary endpoint, including monitoring treatment-emergent adverse events (TEAEs) and ISR incidences. Therapies comparable to PEG (subcutaneously administered, having ≥10 mL injection volume or PEGylated) were evaluated from the published literature to establish a context for PEG-associated ISRs. <h3>Results:</h3> Total reported TEAEs were: i) RIP (n=80 [86%]); ii) RCP (PEG arm: n=36 [88%]; ECU arm: n=36 [92%]); iii) OLP (PEG arm: n=38 [87%]; ECU arm: n=39 [95%]). Most ISRs were mild and occurred during treatment initiation: RIP: 58%, RCP: PEG arm: 36.6%, ECU arm: 2.6%; OLP: PEG arm: 18%; ECU arm: 28%. Subjects with moderate ISRs: RIP: 2.5%, RCP: PEG arm: 2.4%, ECU arm: 0%; OLP: PEG arm: 2.6%; ECU arm: 2.6%. No ISRs were severe or led to study drug discontinuation. Five therapies were identified as comparable to PEG; these had ISR incidences of 5-67% and were generally mild. ISR management strategies from literature included injection site rotation and empowering patients to gain confidence and experience in self-administration through training by healthcare providers. <h3>Conclusions:</h3> PEGASUS trial ISRs observed with PEG treatment were mostly mild, decreased over time, and had comparable incidences to other drugs delivered similarly to PEG. Management strategies for ISRs with these drugs may potentially be useful for reactions observed with PEG.