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).

Conflict of interest statement

Conflict-of-interest disclosure: A.S., A.D., J.G.-W., J.A.-C., and M.B.-S. are employed by Roche. B.K., and C.B. are employed by and own shares of Roche. J.H. is a former employee of Roche. H.S. has received research support, acted as a consultant for, and received honoraria from Alexion Pharmaceuticals and Novartis and has acted as a consultant for Roche (all to University Hospital Ulm). B.G. is employed by Genentech. A.J. is a former employee of, and owns stock in, Genentech. K.S. is employed by Chugai Pharmaceuticals. A.R. has received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Novartis, and Roche. F.S.d.F. has received research funding and honoraria and has acted as a consultant for Alexion Pharmaceuticals and Novartis. J.N. is a member of the advisory board for Chugai Pharmaceuticals and Alexion Pharmaceuticals and has received research funding and honorarium from Alexion Pharmaceuticals. K.U. has received research funding from Alexion Pharmaceuticals and Chugai Pharmaceuticals and is a member of the speakers bureau for Chugai Pharmaceuticals. J.P. has acted as a consultant for and received honoraria from Novartis, Alexion Pharmaceuticals, Amgen, Roche, Pfizer Inc., and Boehringer Ingelheim. R.P.d.L. has received research funding from Alexion Pharmaceuticals, Pfizer, Novartis, and Amgen, has received honoraria from Alexion Pharmaceuticals, Pfizer, and Novartis, and has acted as a consulted for Alexion Pharmaceuticals, Pfizer, Novartis, and Roche. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Individual (gray lines) PK data and modeled mean (bold blue and red lines) and 95% confidence interval for crovalimab concentration over time in PNH patients.

Figure 2.

PD markers, hemoglobin, and reticulocyte count over time in PNH patients. Mean and 95% CI for complement activity by LIA (A), LDH (normalized) (B), hemoglobin (C), and reticulocytes (D).

Figure 3.

Mean tC5 concentrations over time in PNH patients and HVs.