Crovalimab non-inferior to eculizumab in patients with paroxysmal nocturnal haemoglobinuria naïve to complement inhibitors

The phase III COMMODORE 2 study demonstrated that the novel anti-C5 recycling monoclonal antibody crovalimab was non-inferior to eculizumab in control of haemolysis and transfusion avoidance and had a comparable safety profile. Results from COMMODORE 2 highlight the overall favourable benefit–risk profile of crovalimab, including allowing for subcutaneous administration with the option to self-administer.

Despite the significant improvements in the treatment of paroxysmal nocturnal haemoglobinuria (PNH) with complement inhibitors, there remains to be a gap in the treatment landscape and additional therapeutic options with a reduced treatment burden are necessary. Crovalimab is a novel anti-C5 recycling monoclonal antibody that allows for low-volume, subcutaneous self-administration every four weeks. Previously, crovalimab has shown to be effective in disease control of patients with PNH who were complement inhibitor naïve and in maintenance of disease control in patients who switched from eculizumab.  The COMMODORE 2 trial is a global, randomised, open-label, multicentre, phase III trial evaluating crovalimab versus eculizumab in C5 inhibitor-naïve patients with PNH.

Study design

Patients with PNH, age ≥18 years, body weight ≥40 kg, lactate dehydrogenase (LDH) at least two times the upper limit of normal (ULN), and no previous complement inhibitor treatment were randomised 2:1 to crovalimab or eculizumab. 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 prior to randomisation. Patients received a weight-based tiered crovalimab regimen or eculizumab per local prescribing information. Regimens included loading doses, followed by maintenance dosing (SC injection Q4W for crovalimab and intravenous infusion every 2 weeks [Q2W] for eculizumab). Co-primary efficacy endpoints were proportion of patients with haemolysis control (LDH ≤1.5×ULN) from Week (W)5 through W25 and proportion of patients with transfusion avoidance from baseline through W25.

Results

In total, 135 patients were randomised to the crovalimab arm and 69 patients to the eculizumab arm. Of them, respectively 95.6% and 98.6% of patients completed 24 weeks of treatment and entered the extension period. Baseline characteristics and PNH history were balanced across both treatment arms. Crovalimab was found to be non-inferior to eculizumab in the co-primary endpoints of haemolysis control and transfusion avoidance. As such, central LDH ≤ 1.5x ULN from week 5 to 25 was obtained in 79.3% of patients in the crovalimab arm and in 79.0% of patients in the eculizumab arm (Odds ratio [95%CI]: 1.02[0.57-1.82]). Furthermore, respectively 65.7% and 68.1% of patients in the crovalimab and eculizumab arms avoided transfusion from baseline to week 25 (weighted difference -2.8%). Breakthrough haemolysis from baseline through week 25 was reported in 10.4% of patients in the crovalimab arm and in 14.5% of patients in the eculizumab arm. A stabilised haemoglobin from baseline to week 25 was obtained in respectively 63.4% and 60.9% of patients.

A clinically meaningful improvement in FACIT-Fatigue score was obtained in both arms. Crovalimab also induced a rapid and sustained inhibition of the terminal complement activity in treatment-naïve patients. The safety profile of crovalimab was comparable to that of eculizumab. Serious infections occurred in 3% of crovalimab-treated and 7% of eculizumab-treated patients, with no meningococcal infections. The most commonly reported adverse event in the crovalimab and eculizumab arm was infusion-related reaction (16% vs. 13%). There were three fatal adverse events but all were unrelated to treatment. Finally, in an exploratory analysis, treatment preference was assessed in patients randomised to the eculizumab arm who switched to crovalimab in the extension period. Approximately 84% of COMMODORE 2 patients who completed the questionnaire preferred crovalimab over eculizumab.

Conclusions

COMMODORE 2 met its co-primary endpoints, demonstrating non-inferiority of crovalimab vs. eculizumab for control of haemolysis and transfusion avoidance. Crovalimab is well tolerated and has a comparable safety profile to eculizumab. These data, in conjunction with phase III COMMODORE 1 results highlight the overall favourable benefit-risk profile of crovalimab in patients with PNH. In an exploratory analysis, the majority of patients who switched from eculizumab to crovalimab and completed a preference survey stated a preference for crovalimab. As such, crovalimab has the potential to offer a new treatment option for people with PNH that allows for subcutaneous self-administration with every four weeks maintenance dosing.

Reference

Röth A, et al. 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. Presented at EHA 2023; Abstract S181.