S181: the phase iii, randomized commodore 2 trial: results from a multicenter study of crovalimab vs eculizumab in paroxysmal nocturnal hemoglobinuria (pnh) patients naive to complement inhibitors

Background: COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter Phase III trial evaluating the non-inferiority of the C5 complement inhibitor (C5i) crovalimab (crova) vs eculizumab (ecu) in C5i-naive patients (pts) with PNH. Crova enables rapid and sustained C5 inhibition with subcutaneous (SC) self-administration every 4 weeks (Q4W). Aims: To report the efficacy and safety of crova in COMMODORE 2. Methods: Pts with PNH, age ≥18 years, body weight ≥40 kg, lactate dehydrogenase (LDH) ≥2× upper limit of normal (ULN), and no previous complement inhibitor treatment were randomized 2:1 to crova or ecu. Stratification factors were LDH (≥2 to ≤4×ULN, >4×ULN) and number of packed red blood cell (RBC) units (0, >0 to ≤6, >6) transfused within 6 months (mo) prior to randomization. Pts received a weight-based tiered crova regimen (Liu ASH 2022; #293) or ecu per local prescribing information. Regimens included loading doses, followed by maintenance dosing (SC injection Q4W for crova and intravenous infusion every 2 weeks [Q2W] for ecu). Co-primary efficacy endpoints were proportion of pts with hemolysis control (LDH ≤1.5×ULN) from Week (W)5 through W25 and proportion of pts with transfusion avoidance from baseline (BL) through W25. Non-inferiority was demonstrated if the lower limit of the 95% CI for the odds ratio for hemolysis control between crova and ecu was >0.2 and if the lower limit of the 95% CI for the difference in proportion of pts with transfusion avoidance in crova and ecu arms was >−20% (0.2 and –20% being the pre-defined non-inferiority margins). Secondary efficacy endpoints were breakthrough hemolysis (BTH) and stabilization of hemoglobin (Hb) assessed from BL through W25, and change from BL in FACIT-Fatigue at W25. Safety data were assessed from BL through W25. Pharmacokinetics, pharmacodynamics, and immunogenicity were assessed from BL up to clinical cutoff. Results: At primary analysis (clinical cutoff of Nov 16, 2022), 204 pts were randomized (135 to crova; 69 to ecu). Median age of pts in the crova and ecu arms was 36 and 38 years, respectively. Overall, 64% and 74% of pts were Asian; mean LDH (×ULN) at baseline was 7.57 and 7.77 and mean number of units of RBCs transfused ≤12 mo before enrollment was 6.47 and 6.63, respectively. The study demonstrated that crova was non-inferior to ecu in the co-primary endpoints of hemolysis control and transfusion avoidance as well as in the secondary efficacy endpoints of BTH and Hb stabilization (Table). A clinically meaningful improvement in FACIT-Fatigue score from BL occurred in both arms, with a numerically greater improvement with crova (Table). Complete terminal complement activity inhibition (per liposome immunoassay) and free C5 levels were generally maintained in the crova arm. Adverse events (AEs) occurred in 78% (18% Grade 3–5) of pts treated with crova and 80% (25% Grade 3–5) treated with ecu. Serious infections occurred in 3% of crova-treated pts and 7% of ecu-treated pts, with no meningococcal infections. There were 3 fatal AEs, 2 with crova (myocardial infarction prior to start of treatment [n=1]; respiratory hemorrhage after treatment discontinuation [n=1]) and 1 with ecu (ischemic stroke), all unrelated to treatment. One pt in each arm had an AE leading to treatment discontinuation. Summary/Conclusion: The COMMODORE 2 study demonstrated that crova was non-inferior to ecu in both co-primary efficacy endpoints and had a comparable safety profile. These data highlight the overall favorable benefit–risk profile of crova, including allowing for SC administration with the option to self-administer.Keywords: Randomized, Complement, Paroxysmal nocturnal hemoglobinuria (PNH), Phase III