Crovalimab Treatment in the COMMODORE Trial Meets Coprimary End Points

In the phase 3 COMMODORE trial (NCT04654468), crovalimab achieved rapid and stable hemolysis control and transfusion avoidance, with no new safety signals, in Chinese patients with paroxysmal nocturnal hemoglobinuria (PNH), according to findings that were presented during the 2022 ASH Annual Meeting.¹

Results showed that the mean proportion of patients achieving hemolysis control (lactate dehydrogenase [LDH] ≤1.5 x upper limit of normal [ULN]) from weeks 5 through 25 was 78.7% (95% CI, 67.8%-86.6%); the proportion of patients achieving this at week 5 was 72% and remained between 70% and 85% through week 25. Furthermore, the mean LDH (≥1.5 x ULN) was achieved by week 3 and maintained through week 25.

Transfusion avoidance was reached in 51.0% (95% CI, 36.8%-65.1%) of patients post baseline, which was a statistically significant improvement vs 0% (95% CI, 0.0%-8.7%) in the 24 weeks prior to patients being screened (95% CI, 34.3%-65.1%; P <.0001).

The mean packed red blood cell (pRBC) units transfused per patient was 10.8 (standard deviation [SD], 6.6) prior to screening; this was 13.4 (SD, 6.5) among the 25 patients who did not achieve transfusion avoidance. Post baseline, the mean pRBC units transfused per patient was 4.6 (SD, 6.7) and was 9.4 (SD, 6.8) among those who did not have transfusion avoidance.

“These results demonstrate that crovalimab is an efficacious and well-tolerated therapy for patients with PNH,” Camelia Sima, lead medical director of Genentech/Roche, the developer of crovalimab, said in a presentation during the meeting. “Owing to its every-4-week low-volume subcutaneous dosing regimen, with the option for self-administration, crovalimab has the potential to reduce the burden of treatment for this lifelong disease.”

There is an unmet need for patients with PNH, as a lack of access exists for effective treatments, such as C5 inhibitors. Crovalimab is a novel anti-C5 recycling monoclonal antibody with a half-life of 59 days. Because the agent has high solubility and bioavailability, it allows for the development of a high-concentration formulation that enables every-4-week, low-volume subcutaneous (SC) delivery.

Previously, crovalimab showed rapid and sustained terminal complement activity inhibition in patients with PNH who were complement inhibitor–naïve or who had switched from eculizumab (Soliris).2

In the multicenter, single-arm, open-label COMMODORE 3 trial, investigators evaluated crovalimab for 24 weeks in 51 complement inhibitor–naïve patients with PNH in China. To be eligible for enrollment, Chinese patients with PNH had to be at least 12 years of age and weigh at least 40 kg, have an LDH of 2 or higher (x ULN), and 4 or more pRBC transfusions at least 12 months before screening. Patients could not currently be on a C5 inhibitor or have previously received one.

Crovalimab was given on a weight-based, 2-tiered dosing schedule. For patients between 40 kg and 100 kg, crovalimab was given at a loading dose of 1000 mg intravenously (IV) on day 1, followed by 340 mg SC on days 2, 8, 15, and 22, before a maintenance dose of 680 mg SC on day 29 and every 4 weeks thereafter. Patients weighing at least 100 mg had a loading dose of 1500 mg IV on day 1, followed by 340 mg SC on days 2, 8, 15, and 22, which was then followed by a maintenance dose of 1020 mg SC.

The co-primary end points were mean proportion of patients with hemolysis control (LDH ≤1.5 x ULN) and difference in proportion of patients who had transfusion avoidance from baseline through week 25 vs within 24 weeks prior to screening. Secondary end points included breakthrough hemolysis (BTH) from baseline through week 25, hemoglobin stabilization from baseline through week 25, and change in fatigue from baseline through week 25.

Additional outcome measures were safety, immunogenicity, pharmacokinetics, and pharmacodynamics.

Fifty of the 51 patients enrolled had completed 24 weeks of treatment, which they continued through the clinical cutoff date of February 10, 2022. The median age was 31 years (range, 15-58), 43% of patients were male, and the median weight was 60.0 kg (range, 48.9-96.0). Moreover, the median time from PNH diagnosis to enrollment was 7.1 years (range, 0.7-18.2). Regarding history of PNH-relevant conditions, patients had aplastic anemia (37%), myelodysplastic syndrome (2%), renal impairment (4%), or major vascular events (10%). The mean LDH (x ULN) at baseline was 9.3 (SD, 2.8), and the median pRBC units transfused at least 12 months prior to screening was 16 (range, 8.0-50.5).

Two patients (3.9%; 95% CI, 0.7%-14.6%) experienced BTH, and 26 patients (51.0%; 95% CI, 36.8%-65.1%) achieved stabilized hemoglobin. Sima clarified that 1 BTH event was observed, and 1 additional patient died prior to week 25, which was due to subdural hematoma that was found to be unrelated to crovalimab. “As a conservative approach, the patient was assumed to have had a BTH event during the primary treatment period,” she said.

Fatigue was assessed using the FACIT-Fatigue scale. Results showed that rapid and clinically meaningful improvements in fatigue were achieved by week 2 and sustained through week 17 and beyond. At baseline, the mean FACIT-Fatigue score was 31.8 (95% CI, 29.3-34.3), and was 40.5 (95% CI, 38.6-42.5) at week 17; the absolute change from baseline through week 17 was 8.8 (95% CI, 6.0-11.6).

The median duration of treatment was 32.0 weeks (range, 20.1-44.1). Most patients (98%) experienced at least 1 adverse effect (AE), with 24% experiencing grade 3/4 AEs. Eight percent of patients had serious AEs and 2% of patients had serious AEs related to treatment. Two percent of patients had AEs leading to dose modification/interruption of any study treatment.

Clinical AEs included upper respiratory tract infection (47%, all of which were grade 2) and increased weight (12%). The most reported AEs were laboratory abnormalities, some of which included increased bilirubin conjugated (29%), decreased neutrophil count (25%), increased blood bilirubin unconjugated (24%), decreased white blood cell count (24%), and increased alanine aminotransferase (22%).

No patients had to withdraw from crovalimab due to AEs. One treatment-related AE occurred, which was grade 3 bacteremia. Selected AEs, due to the mechanism of action of crovalimab, included infections (61%), infusion-related reactions (4%), and hypersensitivity reactions (2%).

Treatment-emergent antidrug antibodies (ADAs) were identified in 16 patients (31%) post baseline; none of these patients developed neutralizing antibodies. The ADAs were treatment-induced (31%), transient (2%), or persistent (29%). There was no impact of ADA status observed on terminal complement activity inhibition, efficacy, or safety.

_References

_{1. Liu H, Zhang F, Jia J, et al. Results from the first phase 3 crovalimab (C5 inhibitor) study (COMMODORE 3): efficacy and safety in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2022;140(suppl 1):714-716. doi:10.1182/blood-2022-162452}

_{2. Röth A, Nishimura J-I, Nagy Z, et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020;135(12):912-920. doi:10.1182/blood.2019003399}