Phase III COMMODORE 2 and 1 Trials: Characterization of Breakthrough Hemolysis Events in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Crovalimab or Eculizumab

Introduction Crovalimab (crova; PiaSky®), a novel C5 inhibitor (C5i) allowing for maintenance subcutaneous (SC) maintenance dosing (weight-based tiered regimen) every 4 weeks (Q4W) , was assessed vs eculizumab (ecu) in the global, randomized, Phase III COMMODORE 2 and 1 trials (NCT04434092; NCT04432584; primary analysis clinical cutoff date [CCOD]: Nov 16, 2022). In COMMODORE 2, crova showed non-inferior efficacy and a similar safety profile vs ecu in C5i-naive patients (pts; Röth Am J Hematol 2024). In COMMODORE 1, crova was well tolerated in C5i-experienced pts and pts who switched from eculizumab (ecu) to crova had similar efficacy to pts who continued ecu (Scheinberg Am J Hematol 2024). Here, we report a comprehensive characterization of breakthrough hemolysis (BTH) events during the primary treatment periods of COMMODORE 2 and 1 based on data from the updated CCOD. Methods In COMMODORE 2 and 1, self-administration of crova was permitted. BTH was defined as the presence of elevated lactate dehydrogenase (LDH) ≥2×upper limit of normal (ULN) after a prior decrease to <1.5×ULN after study start and a concurrent new or worsening symptom of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event, dysphagia, or erectile dysfunction). BTH events that occurred during the 24-week primary treatment period (baseline to Week 25) were analyzed and categorized as follows: being temporally associated with a complement-activating condition (CAC; such as infection, surgery, or pregnancy);being temporally associated with suboptimal C5 inhibition (i.e. 50% hemolytic complement (CH50) levels >30 U/mL, crova serum concentration <100 µg/mL). If loss of pharmacodynamics/pharmacokinetics was concurrent with a CAC, BTH was attributed to suboptimal C5 inhibition;unrelated to either of the above. Results The updated CCOD was Mar 12, 2024. In COMMODORE 2, 134 C5i-naive pts in the crova arm and 69 in the ecu arm were evaluable for efficacy. In COMMODORE 1, 44 and 42 C5i-experienced pts in the crova and ecu arms, respectively, were evaluable for efficacy. BTH events occurred in 10 of 134 pts (7% [95% CI: 4%, 14%]) in the crova arm and 9 of 69 (13% [7%, 24%]) in the ecu arm of COMMODORE 2, and 4 of 44 (9% [3%, 23%]) and 4 of 42 (10% [3%, 24%]), respectively, in COMMODORE 1. Across both studies, 14 of 178 pts (8% [95% CI: 5%, 13%]) in the crova arms and 13 of 111 pts (12% [7%, 20%]) in the ecu arms had BTH. In COMMODORE 2, 6 pts (4%) had BTH attributed to a CAC, 2 (1%) had BTH attributed to suboptimal C5 inhibition, and 2 (1%) had BTH of unknown cause in the crova arm. The ecu arm had 4 (6%), 3 (4%), and 2 (3%) pts with BTH attributed to a CAC, suboptimal C5 inhibition, and unknown cause, respectively. In the crova arm of COMMODORE 1, 2 pts (5%) had BTH attributed to a CAC, 1 pt (2%) had BTH attributed to suboptimal C5 inhibition, and 1 (2%) had BTH of unknown cause. In the ecu arm BTH occurring in 0 (0%), 3 (7%), and 1 (2%) pts were attributed to a CAC, suboptimal C5 inhibition, and unknown cause, respectively. Of all pts in the crova arms of COMMODORE 2 and 1, 8 pts (4%) had BTH attributed to a CAC, 3 (2%) had BTH attributed to suboptimal C5 inhibition (all due to presence of anti-drug antibodies [ADA]), and 3 (2%) had BTH of unknown cause. In the ecu arms of both studies, 4 pts (4%) had BTH attributed to a CAC, 6 (5%) had BTH attributed to suboptimal C5 inhibition, and 3 (3%) had BTH of unknown cause. Six pts in the crova arm and 2 pts in the ecu arm of COMMODORE 2, and 1 pt in each arm of COMMODORE 1 received red blood cell transfusions. Conclusions Incidence and categorization of BTH events were similar between the crova and ecu arms of both COMMODORE 2 and 1. The majority of BTH cases occurring during the primary treatment periods in the crova arms of COMMODORE 2 and 1 were associated with a CAC while maintaining complete C5 inhibition. A similar trend was seen in the ecu arms. Overall, updated CCOD results show that BTH was infrequent with crova and further support the favorable benefit-risk profile of crova in both C5i-naive and C5i-experienced pts with PNH.