Crovalimab for Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Complement C5 Polymorphism - Experience from the Phase I/II COMPOSER Study
Authors: Nishimura Jun-ichi , Usuki Kensuke , Ramos Julia , Ichikawa Satoshi , Hernández-Sánchez Jules , Kiialainen Anna , Sostelly Alexandre , Peffault De Latour Regis , Paz-Priel Ido , Röth Alexander 
Published: November 2020

Background
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the loss of endogenous complement regulators CD59 and CD55 on hematopoietic cells. Peripheral blood elements are susceptible to destruction by complement, resulting in intravascular hemolysis and thrombosis. Standard therapy is terminal complement inhibition with eculizumab, an anti-C5 monoclonal antibody. However, up to 3.5% of individuals of Asian descent carry polymorphisms in C5 that affect Arg885, which corresponds to the eculizumab and ravulizumab binding site (Nishimura et al. N Engl J Med. 2014). Patients with PNH who have these polymorphisms experience poor control of intravascular hemolysis with eculizumab, thus constituting a group with a high unmet medical need. Crovalimab is a novel anti-C5 monoclonal antibody that binds a distinct epitope on the beta subunit of C5. In vitro studies have demonstrated that crovalimab equally binds and inhibits the activity of wild-type and Arg885-mutant C5 (Fukuzawa et al. Sci Rep. 2017).
Objectives
The aim of the current report is to describe the response to crovalimab of PNH in patients with C5 polymorphism.
Study Design and Methods
Crovalimab is being evaluated in the ongoing Phase I/II COMPOSER study (NCT03157635) to establish its optimal dose, safety, and efficacy (Röth A, et al. Blood 2020). C5 inhibitor-naive or -experienced patients received an initial intravenous loading dose followed by an average subcutaneous maintenance dose of 680 mg every 4 weeks. Plasma concentration of crovalimab, lactate dehydrogenase (LDH), free and total C5, and complement activity were determined at every visit. Patients were followed up for occurrence of blood transfusions, breakthrough hemolytic events, and safety.
Results
Of the 59 patients enrolled in COMPOSER, 4 had the c.2654G-&gt;A nucleotide polymorphism predicting Arg885His substitution. The data cutoff was January 29, 2020. Follow-up ranged from 12.4 to 98.3 weeks. All 4 patients were male and had been diagnosed 44 to 734 weeks before enrollment with PNH granulocyte clone size ranging from 89% to 95%. At enrollment, 1 patient switched from ongoing therapy with eculizumab, while 3 had previously discontinued eculizumab. At enrollment, all patients had LDH &gt; 3-fold the upper limit of normal (ULN), which declined rapidly and was maintained at &lt; 1.5 × ULN throughout the follow-up period (Figure). One patient required transfusions after enrollment (12 red blood cell units over 6 months); this patient had an underlying diagnosis of aplastic anemia and required 198 units of red blood cells in the 12 months prior to enrollment. None of the 4 patients experienced a breakthrough hemolysis event. All 4 patients achieved complete terminal complement inhibition as measured by liposome immunoassay (LIA). LIA levels ranged from 32 to 42 U/mL at study entry, declined to &lt; 10 U/mL (lower level of quantification) by day 2, and were maintained thereafter. Similarly, free C5 levels were maintained at &lt; 0.5 µg/mL after week 6 (day 43). The safety profile in these patients was similar to that in the remainder of the participants. Three serious adverse events (SAEs) were reported, none of which were related to study treatment. One patient had 2 SAEs: bile duct stone and cholelithiasis. A second patient had an SAE of upper respiratory tract infection with admission to the hospital, which occurred after 20 months and resolved during treatment.
Conclusions
Crovalimab achieved complete and sustained terminal complement inhibition in patients with Arg885 polymorphism, consistent with previously reported outcomes for patients in the COMPOSER study. Crovalimab is a promising treatment for these individuals with high unmet medical need.

Disclosures
Nishimura: Chugai: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Alexion: Honoraria, Research Funding. Usuki:Alexion: Consultancy, Research Funding, Speakers Bureau; Chugai: Research Funding; Aperis: Research Funding; F. Hoffmann-La Roche. Ltd.: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. , Research Funding. Ramos: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.; Genentech, Inc: Current Employment, Other: Received fellowship support from Genentech, Inc.. Ichikawa:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. , Research Funding. 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.. 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.. 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.. Peffault De Latour:Pfizer: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paz-Priel: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.; Genentech, Inc: Current Employment. Röth:Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.

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