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Atypical hemolytic uremic syndrome (aHUS) is currently treated with the complement C5 antibodies eculizumab and ravulizumab. Although effective at inhibiting complement-mediated thrombotic microangiopathy (TMA) and improving renal function, regular intravenous (IV) infusion dosing regimens can be burdensome, particularly in pediatric patients (pts). Crovalimab (crova) is a novel C5 antibody, engineered for small volume subcutaneous (SC) self‑injection every 4 weeks (Q4W), in a weight-based dosing regimen.
The 4-part, adaptive Phase I/II COMPOSER trial (NCT03157635) evaluated crova in pts with paroxysmal nocturnal hemoglobinuria (PNH), which is a disease driven by uncontrolled complement activation. In COMPOSER, crova maintained disease control and was well tolerated after a median exposure of 3 years.
Crova is currently being evaluated in adult and pediatric pts with aHUS, either treatment-naive or switching from another complement inhibitor, in the ongoing Phase III single-arm COMMUTE-a (NCT04861259) and COMMUTE-p (NCT04958265) trials.
Due to the rapidly progressing nature of aHUS, pts experiencing a TMA require rapid suppression of complement activation upon diagnosis. Data from in vivo models and COMPOSER were used to determine the time to complete complement inhibition after first crova IV dose.
This study assessed the PK and PD of crova in cynomolgus monkeys after a single IV. Four animals per group were evaluated with single 4 mg/kg IV and 20 mg/kg IV doses.
Part 2 (n=10) and Part 4A (n=8) of COMPOSER enrolled pts with PNH who were naive to complement inhibition. Part 2 pts received crova 375 mg IV on Day (D) 1, 500 mg IV on D8, 1000 mg IV on D22, and 170 mg SC weekly from D36 for 20 weeks. Part 4A pts received an optimized crova dosing regimen of 1000 mg IV on D1, 340 mg SC on D2, 8, 15, and 22, and 680 mg SC Q4W from D29 onwards for 20 weeks. Crova concentration, free C5 and complement activity were measured using validated assays.
Compared with baseline values in cynomolgus monkeys, a single crova IV dose of 4 mg/kg reduced mean free C5 concentration by 99.6% and terminal complement activity by 81.4%, within 5 mins of administration.
In treatment-naive pts from COMPOSER Parts 2 and 4, mean free C5 concentration dropped to below 1 µg/ml, indicating a high level of target engagement within 1-6 hours from first IV dose (Fig 1). Also, inhibition of terminal complement activity was reached within 1 hour, with values near or below the lower limit of quantitation (10 U/mL; Fig 2). Complete complement blockade was generally maintained long term, up to Week 20, in both Parts 2 and 4, regardless of dose.
Crova induced a complete, rapid, and sustained blockade of terminal complement activity within hours of first dose. The dosing schedule of crova included an initial IV loading dose, allowing for a rapid onset of action, followed by a convenient long-term SC maintenance regimen.
This abstract was previously presented at the 60th European Renal Association Congress 2023.