British journal of clinical pharmacology · 2025
Pharmacokinetic characterization and exposure-response relationship of crovalimab in the COMMODORE 1, 2 and 3 and COMPOSER trials of patients with paroxysmal nocturnal haemoglobinuria.
Клиническое исследование III фазыСтатьяНазвание и аннотация: Перевод в очереди
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Cosson Valérie, Fu Rong, Kulasekararaj Austin, Nishimura Jun-Ichi, Panse Jens, Röth Alexander, Scheinberg Phillip, Tong Hongyan, Yoon Sung-Soo, Beveridge Leigh, Gotanda Keisuke, Jaminion Félix, Henrich Andrea, Lundberg Pontus, Shi Dayu, Sreckovic Sasha, Zhang Yuchen, Zhang Zilu, Benkali Khaled, Buatois Simon
Аннотация
AIMS: Crovalimab is a novel C5 inhibitor administered first intravenously and then subcutaneously in patients with paroxysmal nocturnal haemoglobinuria (PNH) naive to complement inhibition or switching from eculizumab or ravulizumab. Crovalimab showed efficacy and safety comparable to eculizumab in the pivotal COMMODORE 2 and supporting studies.
METHODS: We characterized crovalimab pharmacokinetics and the relationship between exposure pharmacokinetic parameters and pharmacodynamic biomarkers, efficacy and safety endpoints using pooled data (healthy volunteers [n = 9], naive [n = 210] and switched [n = 211] patients). Pharmacodynamic biomarkers included 50% complement activity and free C5; normalized lactate dehydrogenase was a marker of haemolysis. Adverse events (AEs) of special interest, related serious AEs, related Grade ≥3 AEs and infections were assessed.
RESULTS: There was no clinically relevant difference in crovalimab concentrations between naive and switch patients. Bodyweight had a statistically significant impact on crovalimab clearances and volumes of distribution. Thus, the recommended dosing regimen used weight-based, two-tiered dosing (100 kg cutoff). Age did not have a clinically meaningful impact on crovalimab exposure. In COMMODORE 2, and the supporting COMMODORE 1 and 3 studies, complete terminal complement activity inhibition was achieved immediately at the end of the initial intravenous infusion and sustained throughout the treatment period in ≥97% of patients. Crovalimab concentrations above ≈100 μg/mL achieved complete inhibition of terminal complement activity, resulting in disease control with normalized lactate dehydrogenase ≤1.5 × upper limit of normal (ULN). There was no increased risk of AEs at higher exposure.
CONCLUSIONS: These data confirm an effective crovalimab-dosing regimen that achieves complete terminal complement activity inhibition and disease control in patients with PNH.
METHODS: We characterized crovalimab pharmacokinetics and the relationship between exposure pharmacokinetic parameters and pharmacodynamic biomarkers, efficacy and safety endpoints using pooled data (healthy volunteers [n = 9], naive [n = 210] and switched [n = 211] patients). Pharmacodynamic biomarkers included 50% complement activity and free C5; normalized lactate dehydrogenase was a marker of haemolysis. Adverse events (AEs) of special interest, related serious AEs, related Grade ≥3 AEs and infections were assessed.
RESULTS: There was no clinically relevant difference in crovalimab concentrations between naive and switch patients. Bodyweight had a statistically significant impact on crovalimab clearances and volumes of distribution. Thus, the recommended dosing regimen used weight-based, two-tiered dosing (100 kg cutoff). Age did not have a clinically meaningful impact on crovalimab exposure. In COMMODORE 2, and the supporting COMMODORE 1 and 3 studies, complete terminal complement activity inhibition was achieved immediately at the end of the initial intravenous infusion and sustained throughout the treatment period in ≥97% of patients. Crovalimab concentrations above ≈100 μg/mL achieved complete inhibition of terminal complement activity, resulting in disease control with normalized lactate dehydrogenase ≤1.5 × upper limit of normal (ULN). There was no increased risk of AEs at higher exposure.
CONCLUSIONS: These data confirm an effective crovalimab-dosing regimen that achieves complete terminal complement activity inhibition and disease control in patients with PNH.