COMPOSER Part 4: An Optimized Dosing Strategy for Crovalimab in the Treatment of Complement Inhibitor-Naïve or -Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Peffault De Latour Regis , Sica Simona , Ramos Julia , Hernández-Sánchez Jules , Kim Jin Seok , Kiialainen Anna , Yoon Sung-Soo , Sreckovic Sasha , Soubret Antoine , Ninomiya Haruhiko , Sostelly Alexandre , Panse Jens , Buatois Simon , Schrezenmeier Hubert , Paz-Priel Ido , Nishimura Jun-ichi , Röth Alexander 
Published: November 2020

Background
Inhibition of complement C5 is the current standard of care for paroxysmal nocturnal hemoglobinuria (PNH). C5 inhibition reduces transfusion requirements and improves anemia and quality of life by ameliorating intravascular hemolysis. However, current therapies require lifelong intravenous infusions at regular intervals, and breakthrough hemolysis may occur due to inadequate C5 inhibition. Crovalimab is a novel anti-human C5 antibody characterized by pH-dependent target binding, enhanced recycling by the neonatal Fc receptor, and high bioavailability, allowing for small-volume (2 × 2 mL) subcutaneous administration every 4 weeks. Part 3 of the Phase I/II COMPOSER study (Sostelly et al. Blood. 2019; Röth et al. Blood. 2020) demonstrated that in patients switched from eculizumab, enhanced crovalimab clearance occurred during the switching phase due to the formation of drug-target-drug complexes, with a risk of temporary loss of complete complement inhibition. Part 4 of COMPOSER tested a dosing regimen optimized to maintain complete complement inhibition in C5 inhibitor-naive patients and those switched from eculizumab to crovalimab.
Objectives
To evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) effects of an optimized crovalimab regimen.
Study Design and Methods
Crovalimab is being evaluated in the ongoing Phase I/II COMPOSER study (NCT03157635). Parts 1, 2, and 3 of COMPOSER assessed the PK and safety of crovalimab in healthy volunteers, C5 inhibitor-naive patients, and patients switched from eculizumab, respectively. In Part 4, patients received an intravenous loading series of crovalimab 1000 mg on day 1 followed by 340 mg subcutaneous on days 2, 8, 15, and 22. Maintenance dosing of 680 mg subcutaneous every 4 weeks was started on day 29 (week 5). Plasma concentrations of crovalimab, lactate dehydrogenase (LDH), and free and total C5, as well as complement activity were determined at follow-up visits. The primary endpoints were PK and PD effects of the dosing strategy. Patients were followed up for safety and efficacy, including transfusion avoidance, breakthrough hemolysis events, and hemoglobin stabilization.
Results
Data for 15 patients (8 naive, 7 switched) treated with the optimized crovalimab dosing strategy in Part 4 are presented here. The data cutoff was January 29, 2020. The PK profiles showed that crovalimab exposure was maintained above the target concentration (100 µg/mL) for complete complement inhibition in all patients, naive and switched. Complete complement inhibition, as measured by liposome immunoassay &lt; 10 U/mL, was achieved immediately following the initial dose and maintained throughout the study treatment period. Consistent with these results, crovalimab-free C5 levels declined rapidly following the initial dose and remained low throughout the follow-up period. As expected based on the target-disposal properties of crovalimab, limited total C5 accumulation was observed in naive patients and a decline was seen in switched patients. Median LDH rapidly declined to ≤ 1.5-fold the upper limit of normal (ULN) in naive patients, remained ≤ 1.5-fold the ULN in switched patients, and remained below this level throughout the observation period in both patient groups (Figure). Crovalimab was well tolerated, and no serious treatment-related adverse events were observed.
Conclusions
These data showed that the optimized dosing strategy for crovalimab in PNH did not raise any safety concerns and suggest that the strategy results in sustained complete complement inhibition in patients naive to complement inhibitor therapy and those switched from eculizumab. These data support the continued development of crovalimab.

Disclosures
Peffault De Latour: Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Ramos:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.; Genentech, Inc: Current Employment, Other: Fellowship support. Hernández-Sánchez:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Kiialainen:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Yoon:F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Janssen: Consultancy; Novartis: Consultancy, Honoraria; YuhanPharma: Research Funding; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Soubret:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ninomiya:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche., Research Funding; Alexion: Honoraria; Chugai: Membership on an entity's Board of Directors or advisory committees. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Panse:F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buatois:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Nishimura:F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.; Alexion: Honoraria, Research Funding; Chugai: Consultancy. Röth:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria.

OffLabel Disclosure:
Yes. Crovalimab is an anti-C5 monoclonal antibody being evaluated as a therapy for paroxysmal nocturnal hemoglobinuria