ABSTRACT
Background: The efficacy of ravulizumab (intravenous [IV] formulation;administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day-1 to day-30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab;all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline;incidence of breakthrough hemolysis;transfusion avoidance;and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84;IV/SC: n = 44;mean [range] duration of SC treatment: 486.4 [37-709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%);no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%);injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image: Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.
ABSTRACT
Background: Pegcetacoplan (PEG), a PEGylated peptide targeting proximal complement protein C3, can control both intravascular and extravascular hemolysis. In the PEGASUS trial (NCT03500549), a phase 3, randomized, open-label, active-comparator controlled study, PEG was shown to be superior to eculizumab (ECU) after 16 weeks in improving hemoglobin levels (Hb) and clinical outcomes in patients with paroxysmal nocturnal hemoglobinuria (PNH) (Hillmen P et al, EHA 2020). Aims: We report on the efficacy and safety of PEG through 48 weeks of treatment. Methods: This study is a continuation of the PEGASUS trial. Eighty patients ≥18 years with PNH, and Hb levels <10.5 g/dL despite stable ECU treatment for ≥3 months, were enrolled. Patients completed a 4-week run-in period with both ECU and PEG before 1:1 randomization to PEG (n=41;1080 mg subcutaneously twice weekly) or ECU monotherapy (n=39;continued dosing regimen). The primary endpoint was the change from baseline (CFB) in Hb levels to Week 16. After the randomized control period (RCP), patients could continue to an open-label period (OLP), which included a 4-week run-in period for ECU patients (ECU-to-PEG), followed by PEG monotherapy (same dosage as in RCP) for all patients for a 48-week total study period. Key secondary endpoints included blood transfusion avoidance, CFB in absolute reticulocyte count (ARC), CFB in lactate dehydrogenase (LDH), CFB in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and adverse events (AEs). Results: Three patients discontinued PEG during the 16-Week RCP due to hemolysis;the remaining 77 patients entered the OLP. PEG demonstrated superiority to ECU with a mean Hb level improvement of 2.7 g/dL at Week 16, which was sustained throughout the OLP in all patients receiving PEG monotherapy. ECU-to-PEG patients demonstrated Hb improvement with mean Hb levels of 11.6 g/dL at Week 48 (CFB: 2.9 g/dL), while PEG-to-PEG patients maintained high Hb levels through the OLP with a mean Hb level of 11.3 g/dL at Week 48 (CFB: 2.6 g/dL) (Figure A). Seventy-three percent of PEG-to-PEG patients remained transfusion free for the 48-week study, and 72% of the ECU-to-PEG patients were transfusion free during the OLP through Week 48. Improvements in ARC (PEG-to- PEG: 80.0×109 cells/L;ECU-to-PEG: 94.0×109 cells/L), LDH (PEG-to-PEG: 222.7U/L;ECU-to-PEG: 224.1 U/L), and FACIT-fatigue score (PEG-to- PEG: 40.6;ECU-to-PEG: 42.5) were also observed at Week 48 (Figure B). The most common AEs by physician-reported preferred term throughout the study for all patients who received PEG were injection site reactions (36%), hemolysis (24%), and diarrhea (21%). Of all study patients, 30% experienced serious AEs with 6% possibly related to PEG. No cases of meningitis were reported. One death was reported due to COVID-19, unrelated to study treatment. Six patients discontinued due to hemolytic events: 5 classified by the treating physician as "hemolysis" and 1 as "hemolytic anemia." Overall, 12 patients (15%) discontinued PEG: 3 in RCP, 8 in OLP due to TEAEs (6 in ECU-to-PEG, 2 in PEG-to-PEG), and one during follow-up;one patient withdrew due to physician decision. Summary/Conclusion: Adult patients with PNH with suboptimal response on prior ECU treatment received PEG in this continuation of the PEGASUS trial and experienced durable treatment effect in all efficacy parameters at Week 48. The safety profile of PEG was consistent with previously reported data. The results suggest that PEG represents a new effective therapeutic option for patients with PNH.
ABSTRACT
Background: Pegcetacoplan (PEG), a PEGylated peptide targeting proximal complement protein C3, can control both intravascular and extravascular hemolysis. In the PEGASUS trial (NCT03500549), a phase 3, randomized, open-label, active-comparator controlled study, PEG was shown to be superior to eculizumab (ECU) after 16 weeks in improving hemoglobin (Hb) levels and clinical outcomes in patients with PNH (Hillmen P et al, EHA 2020). Aims: To identify if the prespecified strata (transfusion history and platelet count) of PEGASUS patients showed additional benefit from PEG vs ECU at 48 weeks. Methods: Eighty PNH patients (≥18 years) with Hb levels <10.5 g/ dL and ECU treatment (≥3 months) were enrolled. Patients entered a 4-week run-in period (RIP) with ECU+PEG (1080 mg subcutaneously 2x/week), then were stratified based on baseline platelet count and prior transfusion requirements, and randomized 1:1 to PEG or ECU monotherapy. The primary endpoint was change in Hb level from baseline to Week 16. Patients could continue to an open label period (OLP) of PEG monotherapy, which included a 4-week RIP (ECU+PEG) for ECU patients (ECU-to-PEG) but not for patients continuing PEG (PEG-to- PEG). Key secondary endpoints were transfusion avoidance and adverse events (AEs). Here, primary and key secondary endpoints were analyzed by subgroups (<4 vs ≥4 packed red blood cell transfusions within 12 months prior to baseline;platelet count at screening [<100,000x109/L vs ≥100,000x109/L]). Results: PEG treatment was associated with significantly greater increases in Hb levels from baseline than ECU at Week 16, which were maintained in the PEG-to-PEG arm through Week 48 regardless of baseline subgroup. The ECU-to-PEG arm demonstrated increased Hb levels regardless of prior transfusions (Figure A) or baseline platelet count (Figure B). At Week 48, Hb levels were similar in the <4 (mean [SD];PEG-to-PEG: 11.8 [1.9] g/dL;ECU-to-PEG: 11.8 [2.2] g/dL) and ≥4 transfusion strata (PEG-to-PEG: 10.9 [1.6] g/dL;ECU-to-PEG: 11.4 [2.2] g/dL). Similar Hb levels were also seen for the <100,000x109/L (PEG-to-PEG: 11.5 [2.2] g/dL;ECU-to-PEG: 12.7 [1.4] g/dL) and ≥100,000x109/L platelet strata (PEG-to-PEG: 11.2 [1.6] g/dL;ECU-to-PEG: 11.2 [2.3] g/dL). At Week 48, on PEG monotherapy, both arms had similar proportions of transfusion free patients during the OLP in the <4 (PEG-to-PEG: 80%;ECU-to-PEG: 88%) and ≥4 transfusion strata (PEG-to-PEG: 67%;ECUto- PEG: 61%). Similar trends were seen in the <100,000x109/L (PEGto- PEG: 75%;ECU-to-PEG: 78%) and ≥100,000x109/L platelet strata (PEG-to-PEG: 72%;ECU-to-PEG: 70%). The most common AEs by physician reported preferred term throughout the study for all patients who received PEG were injection site reactions (36%), hemolysis (24%), and diarrhea (21%). Of all study patients, 30% experienced serious AEs, 6% possibly related to PEG. No cases of meningitis were reported. One COVID-19 death was reported, unrelated to study treatment. Six patients discontinued due to hemolytic events: 5 classified by the treating physician as "hemolysis" and 1 as "hemolytic anemia." Overall, 12 patients (15%) discontinued PEG: 3 in RCP, 8 in OLP due to TEAEs (6 in ECU-to-PEG, 2 in PEG-to-PEG), and one during follow-up;one patient withdrew due to physician decision. Summary/Conclusion: In the prespecified stratified analysis of PEGASUS, PEG showed treatment effect durability in Hb level with transfusion avoidance in most PNH patients regardless of prior transfusions or baseline platelet count during the OLP through Week 48. The safety profile of PEG was consistent with previously reported data.