Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors.

Abstract

Drug-target-drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.

• Authors: Jun-Ichi Nishimura, Antoine Soubret, Noriko Arase, Simon Buatois, Masaki Hotta, Jean-Eric Charoin, Yoshikazu Ito, Sasha Sreckovic, Hiroyuki Takamori, Christoph Bucher, Yasutaka Ueda, Jules Hernández-Sánchez, Keisuke Gotanda, Gregor Jordan, Kenji Shinomiya, Julia Ramos, Jin Seok Kim, Jens Panse, Régis Peffault de Latour, Alexander Röth, Eiichi Morii, Hubert Schrezenmeier, Yoshitaka Isaka, Simona Sica, Yuzuru Kanakura, Sung-Soo Yoon, Taroh Kinoshita, Ido Paz-Priel, Alexandre Sostelly
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 113 Issue 4 Pg. 904-915 (04 2023) ISSN: 1532-6535 [Electronic] United States
• PMID: 36660902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 F. Hoffmann-La Roche Ltd and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Antibodies, Monoclonal
• Complement Inactivating Agents
• Complement C5

Topics

• Humans
• Hemoglobinuria, Paroxysmal (drug therapy)
• Antibodies, Monoclonal
• Complement Inactivating Agents (adverse effects)
• Complement C5