Efficacy and safety of the <scp>C5</scp> inhibitor crovalimab in complement inhibitor‐naive patients with <scp>PNH</scp> (<scp>COMMODORE</scp> 3): A multicenter, <scp>Phase</scp> 3, single‐arm study

Liu, Hui; Xia, Linghui; Weng, Jianyu; Zhang, Fengkui; He, Chao; Gao, Sujun; Jia, Jinsong; Chang, Alice C.; Lundberg, Pontus; Shi, Jane; Sima, Camelia S.; Sostelly, Alexandre; Sreckovic, Sasha; Xiao, Zhenyu; Fu, Rong

doi:10.1002/ajh.26998

Cited by 13 publications

(4 citation statements)

References 34 publications

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“…SC molecules have variable treatment schedules ranging from multiple times per week, 35 to weekly, 36 or monthly. [37][38][39][40] Oral monotherapies currently being tested must be taken twice a day. 41,42 Assuming commercial approvals, these options would allow patients to deliver their own treatment, but must be weighed against the risk of poor compliance or inability to tolerate oral intake (eg gastroenteritis), which would expose them to worsening IVH and potential complications, such as TE.…”

Section: Conveniencementioning

confidence: 99%

“…47 The frenzy of PNH clinical trials over the past decade has also brought treatment options to countries without prior access to therapies. 37,[48][49][50] We remain hopeful that this will result in wider availability and hopefully global reach of effective PNH therapies.…”

Section: Competitionmentioning

confidence: 99%

“…Both co-primary efficacy endpoints were met, including hemolysis control (LD <1.5× ULN) in 78.7% (95% CI: 67.8-86.6) and transfusion avoidance in 51%. 37 Results from the other phase-3 trials, COMMODORE-1 39 and COMMODORE-2, 38 have recently been reported for patients who were either switched from SOC or were treatmentnaive. Similar control of hemolysis and transfusion needs were seen.…”

Section: Crovalimabmentioning

confidence: 99%

“…With respect to switching treatments, there are further considerations, not least of which is patient preference and willingness to change. As deep and consistent complement blockade is necessary to protect patients from TE and endorgan damage, additional issues such as adherence to oral therapies 41,42,92 or challenges with self-administered delivery mechanisms (eg syringes and infusion pumps) [35][36][37]62,93 need to be carefully considered.…”

Section: Dovepressmentioning

confidence: 99%

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Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations

Oliver,

Patriquin

2023

JBM

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Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired clonal abnormality, which renders hematopoietic cells exquisitely sensitive to complement-mediated destruction. Classical features of PNH include intravascular hemolytic anemia, increased thrombotic risk, and manifestations related to end-organ damage (eg fatigue, chest pain, dyspnea, renal failure, and pulmonary hypertension). With supportive care alone, mortality rate of patients with PNH is approximately 35%. The anti-C5 monoclonal antibody, eculizumab, was the first targeted therapy approved for PNH, and led to improved hemoglobin, quality of life, reduced transfusion need, reduced thrombosis, and greater overall survival. More recently, therapeutics such as longer acting anti-C5 (ravulizumab) and anti-C3 (pegcetacoplan) medications have been approved, along with other novel therapeutics in late-stage clinical trials. Biosimilars of eculizumab are also now available. Proximal inhibitors (against C3, factor B, and factor D) have shown significant improvements in hemoglobin and transfusion-avoidance in patients who remain anemic despite C5 inhibition. Despite these novel therapies, some unmet challenges remain, including management of breakthrough hemolysis, clinically significant iatrogenic extravascular hemolysis, optimal management in pregnancy, and infection risk mitigation as new targets in the complement system are blocked. In addition, the use of self-administered subcutaneous and oral therapies raises concerns around treatment adherence and the risks of uncontrolled terminal complement. Given the ultra-rare nature of PNH, development is underway of a centralized international registry to capture and analyze the data as they mature for various new therapies and characterize the clinical challenges related to PNH management.

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Section: Conveniencementioning

confidence: 99%

Section: Competitionmentioning

confidence: 99%

Section: Crovalimabmentioning

confidence: 99%

Section: Dovepressmentioning

confidence: 99%

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Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations

Oliver,

Patriquin

2023

JBM

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Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition

Röth,

He,

Tong

et al. 2024

American J Hematol

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Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low‐volume self‐administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open‐label, multicenter, phase 3 trial evaluating the non‐inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor‐naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co‐primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT‐Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non‐inferior to eculizumab in the co‐primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, −2.8 [−15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, −3.9 [−14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [−11.4, 16.3]). A clinically meaningful improvement in FACIT‐Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit–risk profile of crovalimab.

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Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor‐experienced patients with paroxysmal nocturnal hemoglobinuria

Scheinberg,

Clé,

Kim

et al. 2024

American J Hematol

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Crovalimab, a novel C5 inhibitor, allows for low‐volume, every‐4‐ week, subcutaneous self‐administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor‐experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight‐based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT‐Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty‐nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24‐week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab‐treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab‐treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor‐naive patients, these data support crovalimab's favorable benefit–risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.

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Efficacy and safety of the C5 inhibitor crovalimab in complement inhibitor‐naive patients with PNH (COMMODORE 3): A multicenter, Phase 3, single‐arm study

Cited by 13 publications

References 34 publications

Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations

Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition

Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor‐experienced patients with paroxysmal nocturnal hemoglobinuria

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