Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition

• Published in: American journal of hematology 2024-09, Vol.99 (9), p.1768-1777
• Main Authors: Röth, Alexander, He, Guangsheng, Tong, Hongyan, Lin, Zenghua, Wang, Xiaoqin, Chai‐Adisaksopha, Chatree, Lee, Je‐Hwan, Brodsky, Andres, Hantaweepant, Chattree, Dumagay, Teresita E., Demichelis‐Gómez, Roberta, Rojnuckarin, Ponlapat, Sun, Jing, Höglund, Martin, Jang, Jun Ho, Gaya, Anna, Silva, Fernando, Obara, Naoshi, Kelly, Richard J., Beveridge, Leigh, Buatois, Simon, Chebon, Sammy, Gentile, Brittany, Lundberg, Pontus, Sreckovic, Sasha, Nishimura, Jun‐ichi, Risitano, Antonio, Han, Bing
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Complement C5 - antagonists & inhibitors; Complement component C5; Complement Inactivating Agents - adverse effects; Complement Inactivating Agents - therapeutic use; Complement inhibitors; Fatigue; Female; Hemoglobin; Hemoglobinuria, Paroxysmal - drug therapy; Hemolysis; Hemolysis - drug effects; Humans; L-Lactate dehydrogenase; Male; Middle Aged; Paroxysmal nocturnal hemoglobinuria
• ISSN: 0361-8609; 1096-8652; 1096-8652
• DOI: 10.1002/ajh.27412

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low‐volume self‐administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open‐label, multicenter, phase 3 trial evaluating the non‐inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor‐naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co‐primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT‐Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non‐inferior to eculizumab in the co‐primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, −2.8 [−15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, −3.9 [−14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [−11.4, 16.3]). A clinically meaningful improvement in FACIT‐Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit–risk profile of crovalimab. The phase 3, randomized COMMODORE 2 trial demonstrated that in patients with PNH not previously treated with C5 inhibitors, crovalimab was non‐inferior to eculizumab for co‐primary efficacy endpoints of hemolysis control and transfusion avoidance and secondary endpoints of breakthrough hemolysis and hemoglobin stabilization with a comparable safety profile. These data, combined with patient preference and health‐related quality of life results, support the positive risk–benefit profile of crovalimab for patients with PNH naive to complement inhibition.