FDA Approval Sought for Crovalimab for Paroxysmal Nocturnal Hemoglobinuria

The FDA has accepted a biologics license application (BLA) seeking the approval of crovalimab for use in patients with paroxysmal nocturnal hemoglobinuria (PNH).¹ The application was supported by findings from the phase 3 COMMODORE 2 trial (NCT04434092) and the phase 3 COMMODORE 1 trial (NCT04432584).

Data from COMMODORE 2 presented at the 2023 EHA Congress showed that when crovalimab was given as subcutaneous injections every 4 weeks, it provided disease control and proved to be noninferior to eculizumab.²

Specifically, 79.3% (95% CI, 72.9%-84.5%) of patients who received crovalimab achieved hemolysis control from week 5 to week 25 vs 79.0% (95% CI, 69.7%-86.0%) with eculizumab (odds ratio [OR], 1.02; 95% CI, 0.57-1.82). Moreover, transfusion avoidance from baseline to week 25 was achieved in 65.7% (95% CI, 56.9%-73.5%) of patients given crovalimab vs 68.1% (95% CI, 55.7%-78.5%) with eculizumab (difference, –2.8; 95% CI, –15.7 to 11.1). Additionally, those in the crovalimab arm (adjusted mean change, 7.8 [95% CI, 6.5-9.1]) experienced a numerically greater improvement in FACIT-Fatigue score from baseline to week 25 vs those in the eculizumab arm (adjusted mean change, 5.2 [95% CI, 3.4-6.9]).

Findings from COMMODORE 1 showed that crovalimab maintained disease control in patients with PNH who switched over from currently approved complement inhibitors.³ The agent had a risk-benefit profile that was consistent with what was observed in COMMODORE 2.

“The filing acceptance reinforces the value of crovalimab, which was engineered to be recycled in the bloodstream with the goal of offering a sustained response while reducing treatment burden,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, stated in a press release.¹ “Crovalimab could provide an option to self-administer as infrequently as every 4 weeks, thereby reducing clinic visits for people with this lifelong condition.”

COMMODORE 2: Design, Key Objectives, and Safety Findings

The global, randomized, open-label, multicenter, phase 3 COMMODORE 2 trial enrolled patients with PNH aged 18 years or older who had a body weight of at least 40 kg and a lactate dehydrogenase (LDH) level of at least 2 × the upper limit of normal (ULN).²

Participants were randomly assigned 2:1 to receive crovalimab or eculizumab. Those in the investigative arm received a weight-based tiered regimen and those in the control arm received eculizumab in accordance with local prescribing information. Patients received loading doses, followed by maintenance dosing.

Stratification factors included LDH (≥2 to ≤4 × ULN vs >4 × ULN) and number of packed red blood cell (RBC) units () vs >0 to ≤6 vs >6) transfused within 6 months before study randomization.

The co-primary end points of the trial included the proportion of patients who achieved hemolysis control, defined as a LDH of 1.5 × ULN or less, from week 5 to week 25 and the proportion of patients with transfusion avoidance from baseline to week 25. If the lower limit of 95% CI for the odds ratio for hemolysis control between crovalimab and eculizumab was greater than 0.2, noninferiority was achieved; moreover, if the lower limit of the 95% CI for the difference in proportion of patients with transfusion avoidance in the investigative and control arms was greater than or equal to 20%, noninferiority was demonstrated.

The primary analysis of the trial had a data cutoff date of November 16, 2022. A total of 204 patients underwent randomization, with 135 assigned to the crovalimab arm and 69 assigned to the eculizumab arm. The median age of patients in the investigative arm was 36 years vs 38 years in the control arm. Additionally, more than half of patients were Asian (64% vs 74%).

The mean LDH at baseline was 7.57 × ULN with crovalimab vs 7.77 × ULN with eculizumab, and the mean number of units of RBC transfused at 12 months or less before enrollment was 6.47 and 6.63, respectively.

Safety findings showed that 78% of patients who received crovalimab experienced adverse effects (AEs) compared with 80% of those given eculizumab; 18% and 25% of patients, respectively, experienced grade 3 to 5 AEs. Serious infections were experienced by 3% of those in the investigative arm and 7% of those in the control arm.

A total of 3 AEs proved to be fatal; 2 of these occurred in the crovalimab arm. One patient experienced myocardial infarction before treatment initiation and the other had respiratory hemorrhage after treatment was discontinued. One patient in the eculizumab arm died; this patient had ischemic stroke. None of these fatal AEs were determined to be related to study treatment. One patient in each arm experienced a toxicity that resulted in discontinued treatment.

COMMODORE 1: Eligibility Criteria, End Points, and Profile Insights

The global, randomized, open-label, multicenter phase 3 COMMODORE 1 trial enrolled patients with complement inhibitor–experienced PNH who weighed at least 40 kg and who had an LDH of 1.5 × ULN or less.³

Study participants were administered 900 mg of eculizumab every 2 weeks for 24 weeks or longer and were then randomly assigned 1:1 to receive crovalimab or eculizumab. Patients received loading doses followed by maintenance treatment. They were stratified by whether they had a history of packed RBC transfusion within 12 months before randomization (yes vs no).

The primary end point of the study was safety, which was examined in all patients who had received at least 1 dose of study treatment. Exploratory end points comprised the proportion of patients who achieved transfusion avoidance, hemolysis control, breakthrough hemolysis, and hemoglobin stabilization. Investigators also evaluated FACIT-Fatigue score changes from baseline to week 25.

The primary analysis of the trial had a data cutoff date of November 16, 2022. A total of 89 patients were randomized, with 45 in the crovalimab arm and 44 in the eculizumab arm. The median age in the investigative and control arms was 42 years (range, 21-81) and 49 years (range, 22-85), respectively. The mean LDH at baseline in these groups was 1.1 × ULN and 1.0 × ULN, respectively. Moreover, 23% and 25% of patients, respectively, had packed RBC transfusions within a year before screening; the mean number of units transfused were 1.6 and 2.3, respectively.

Additional data showed that in 39 crovalimab-treated patients and 37 eculizumab-treated patients, mean hemolysis control was achieved in 93% (95% CI, 87%-96%) and 94% (95% CI, 87%-97%) of patients, respectively. Transfusion avoidance was achieved in 80% (95% CI, 63%-90%) of those in the crovalimab arm and 78% (95% CI, 61%-90%) of those in the eculizumab arm. Breakthrough hemolysis was observed in 10% (95% CI, 3%-25%) of those in the investigative arm and 14% (95% CI, 5%-30%) of those in the control arm.

Moreover, stabilized hemoglobin was observed in 59% (95% CI, 42%-74%) and 70% (95% CI, 53%-84%) of patients, respectively. The mean adjusted change in FACIT-Fatigue in the investigative arm was 1.1 (95% CI, –1.5 to 3.7) and –2.6 (95% CI, –5.4 to 0.1%) in the control arm.

In terms of safety, 77% of patients in the crovalimab arm experienced AEs vs 67% of those in the eculizumab arm; grade 3 or 4 AEs were experienced by 18% and 2% of patients, respectively. Moreover, 14% of those in the investigative arm experienced serious toxicities vs 2% of those in the control arm, and none of these effects were treatment related. Serious infections were observed in 7% and 2% of patients, respectively, but no patients reported meningococcal infections. No patients experienced AEs that resulted in death or withdrawal.

Looking Ahead

Data from the phase 3 COMMODORE 1 and 2 trials have been submitted to additional regulatory authorities on a global scale, and submissions are ongoing.

References

1. FDA accepts application for Genentech’s crovalimab for the treatment of PNH, a rare life-threatening blood condition. News release. Genentech. September 4, 2023. Accessed September 6, 2023. https://www.gene.com/media/press-releases/15000/2023-09-04/fda-accepts-application-for-genentechs-c
2. S181: 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. Hemasphere. Published online August 8, 2023. doi:10.1097/01.HS9.0000967636.72750.f1
3. S183: Phase III randomized, multicenter, open-label COMMODORE 1 trial: comparison of crovalimab vs eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Hemasphere. Published online August 8, 2023. doi:10.1097/01.HS9.0000967644.45540.d8