The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria

Abstract

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade–naive (part 2) and C5 inhibitor–treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor–pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

“…Pharmacokinetically, crovalimab can be administered subcutaneously with a bioavailability of 90%, which allows for self-administration and reduces treatment burden ( 169 ). In a combined Phase 1/2 study in PNH patients, efficacy and tolerability of subcutaneous dosing regimens of weekly up to once every 4 weeks were assessed and switching from eculizumab to crovalimab was considered safe ( 170 ).…”

Monoclonal Antibodies Capable of Inhibiting Complement Downstream of C5 in Multiple Species

“…This is at least in part because inhibition of C5 has proven to be relatively low risk; the increased risk of Neisserial infections is managed by vaccination before treatment and prophylactic use of antibiotics. There are numerous agents in development that target C5, for example, crovalimab (SKY59), a C5 blocking mAb utilizing a pH-dependent recycling technology to increase drug half-life, and reduce the dose required to block C5 (in phase III clinical trials; (1,6) https://clinicaltrials.gov/ct2/show/ NCT04432584), and ravulizumab, the "next generation" eculizumab that also incorporates recycling technology enabling an increase in dosing interval to eight weeks. Ravulizumab has been FDA approved for PNH (2018) and aHUS (2019) (7).…”

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

“…Two caveats of this otherwise successful treatment are that first, there is a small population of patients (3% of the Japanese population) that have a C5 polymorphism that is not recognized by the anti-C5 antibody eculizumab ( Nishimura et al, 2014 ). Multiple other anti-C5 antibodies, as referred to above, that can provide both improvements on eculizumab and broader patient efficacy are in phase I and II trials at this time ( Mastellos et al, 2019 ; Röth et al, 2020 ). Thus far, a lack of C5a generation and thus C5aR1 signaling have not been harmful for extended clinical use of the C5 inhibitory antibody.…”