Phase III Randomized COMMODORE 2 Trial: 2-Year Efficacy and Safety of Crovalimab in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Naive to Complement Inhibition

Introduction

Crovalimab (crova; PiaSky®) is a novel C5 inhibitor (C5i) allowing for maintenance subcutaneous (SC) injection every 4 wks (Q4W). Results from the 24-wk primary treatment period of the global, randomized, Phase III COMMODORE 2 (NCT04434092) trial demonstrated the non-inferior efficacy and comparable safety of crova vs eculizumab (ecu) in C5i-naive patients (pts) with PNH (Röth Am J Hematol 2024). These data were supported by the COMMODORE 1 (NCT04432584) trial in C5i-experienced pts (Scheinberg Am J Hematol 2024). Here, we report long-term data from COMMODORE 2, with up to 2 y of follow-up.

Methods

C5i-naive pts with PNH were randomized 2:1 to receive crova (Arm A) or ecu (Arm B) during a 24-wk primary treatment period. Crova was given as a weight-based tiered dosing regimen that included loading doses followed by maintenance doses Q4W via SC injections. Ecu was given via IV infusion at 900 mg every 2 wks. After completing 24 wks of treatment, pts in Arm A continued crova and pts in Arm B switched from ecu to crova if continuing in the extension period (Arm B switch). In the COMMODORE trials, crova self-administration by pts was permitted from Wk (W)9, after training and confirmation of proficiency by a healthcare provider.

Long-term data were only reported in Arm A and Arm B switch pts who received crova up to W97. Efficacy results reported the proportion of pts with hemolysis control (lactate dehydrogenase [LDH] ≤1.5×upper limit of normal [ULN]) at each visit, and proportions of pts with transfusion avoidance (TA), breakthrough hemolysis (BTH), and hemoglobin stabilization over consecutive 24-wk intervals in the extension period from W25–49, W49–73, and W73–97. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score was evaluated at scheduled visits. Long-term safety was evaluated from after the first crova dose up to the clinical cutoff date (CCOD) pooled across both arms.

Results

Of 204 pts enrolled, 135 were randomized to Arm A (crova) and 69 to Arm B (ecu); 129 pts from Arm A continued crova and 68 from Arm B switched to crova in the extension period after W25. At CCOD (Mar 12, 2024), 116 pts in Arm A and 59 pts in Arm B switch were receiving ongoing crova treatment. Median treatment duration was 104.4 wks (range, 0.1–176.1).

In the extension period, all pts received crova. Mean normalized LDH was maintained at ≤1.5×ULN in both arms, with 78%–86% of pts in Arm A and 74%–88% in Arm B switch having LDH≤1.5×ULN at each visit from W25–97. Over consecutive 24-wk intervals in the extension period, TA was achieved by 73%–75% of pts in Arm A and 68%–82% in Arm B switch and hemoglobin stabilization in 70%–73% in Arm A and 62%–72% in Arm B switch. The proportion of pts with BTH events remained low and generally stable (5%–7% in Arm A and 6%–16% in Arm B switch). Mean FACIT-Fatigue score remained stable from W25–97, ranging from 41.9–44.3 in Arm A and 40.3–42.2 in Arm B switch.

In Arm A and Arm B switch, 203 pts (416.6 patient-years [PY]) were evaluated for long-term safety of crova. The incidence of adverse events (AEs) per 100 PY (95% CI) was 344.0 (326.4, 362.3) for any-grade AEs, 68.4 (60.7, 76.8) for treatment-related AEs, 55.9 (49.0, 63.6) for Grade ≥3 AEs, 29.8 (24.8, 35.5) for serious AEs, and 0.5 (0.1, 1.7) for AEs leading to treatment withdrawal. The rate of fatal AEs was 1.9 (0.8, 3.8) per 100 PY; none of the 8 fatal AEs were deemed by investigators to be related to treatment.

Transient immune complex reactions (TICRs; one-time events that some pts may experience when switching between crova and another C5i) occurred in 16% of pts (11/68) in Arm B switch during the extension period. The signs and symptoms of TICRs reported in ≥2 pts were skin and joint abnormalities (arthralgia and rash) and headache, with no renal involvement reported. Most TICRs were mild or moderate, with no life-threatening or fatal events reported, and resolved with no change in crova treatment. No meningococcal infections were reported.

Conclusions

In COMMODORE 2, crova was well tolerated and maintained disease control over a 2-y median treatment duration in C5i-naive pts with PNH treated with crova. The overall safety profile of crova was consistent with that of other C5is, except for the identified risk of usually mild or moderate and manageable TICRs in pts when switching between crova and another C5i. These results support the long-term favorable benefit–risk profile of crova in pts with PNH.