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.