Key Points

  • Multiple engineering steps led to efficient recycling, antigen disposal, and infrequent low volume s.c. self-administration of crovalimab.

  • PNH patients, treatment-naive or switching from SoC, were stably controlled on up to Q4W s.c. self-administered injections with crovalimab.

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 intravenous (IV) only treatment options. Crovalimab, a Sequential Monoclonal Antibody Recycling Technology (SMART) antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A three-part open label adaptive Phase I/II trial was conducted to assess safety, pharmacokinetics, pharmacodynamics and exploratory efficacy in healthy volunteers (Part 1), complement blockade naive (Part 2) and C5-inhibitor treated PNH patients (Part 3). 29 patients were included in Part 2 (n=10) and Part 3 (n=19). Crovalimab concentrations exceeded the pre-specified 100µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in both PNH treatment naive and C5-inhibitor pretreated patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay: <10U/mL; fC5 <50ng/mL). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes (DTDC) was observed in all 19 patients switching to crovalimab, manifesting in transient mild or moderate vasculitic skin reactions in 2/19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous 680mg (4mL) crovalimab 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.)

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