key: cord-0894954-23joybbd
authors: Mastellos, Dimitrios C; Skendros, Panagiotis; Calado, Rodrigo T; Risitano, Antonio M; Lambris, John D
title: Efficacy matters: broadening complement inhibition in COVID-19
date: 2020-12-14
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30423-9
sha: 446e90778a9db7ab161a350f2f44c555e69f0b81
doc_id: 894954
cord_uid: 23joybbd

nan

We and others have proposed the use of anti-complement agents for the treatment of COVID-19; 1 thus, we read with great interest the Article by Alexander P J Vlaar and colleagues 2 reporting the results of an exploratory, randomised phase 2 trial of IFX-1, an anti-human C5a monoclonal antibody, in patients with severe COVID-19.

Here, we discuss plausible explana tions for IFX-1's inefficacy in this study. One major concern is the choice of the primary endpoint, the percentage change in PaO 2 /FiO 2 from baseline to day 5, which was assessed well before the anticipated pharmacodynamic window of IFX-1. In addition, as acknowledged by the authors, the trial was not powered to show statistically significant differ ences in clinical endpoints, eventually jeopardising any conclusion, even on secondary end points. The possible biological efficacy of IFX-1 was not adequately investigated by exten sive assessment of key inflamma tory mark ers (eg, C-reactive protein) related to the effect of C5a blockade on hyperinflammation. In fact, upstream comple ment inhibition at the C3 or C5 level leads to a rapid decline in the con centration of serum inflammatory markers in patients with COVID-19. 3, 4 Monitoring plasma C5a concentra tions would enable a reliable assess ment of the drug's effective thera peutic concentration. Inclu sion of pharmacokinetic and pharmacodynamic measurements would have also been informative (eg, the ability of IFX-1-treated plasma to block C5aR1dependent responses in appropriate assays), helping to resolve issues related to drug plasma residence, target saturation, dosing, and efficacy.

We believe that the selection of a complement target with a narrow therapeutic scope, such as C5a, is contradictory to mounting evidence indicating that COVID-19 thromboinflammation is fuelled by multiple elements of the comple ment cascade that remain operative during anti-C5a treatment (eg, C3, C3a-C3aR1, and C5b-9). 4,5 For instance, C3 inhi bi tion offers broader control of thromboinflammation driven by neutro phil extracellular traps in patients with COVID-19 than does C5 inhibition, partly explaining the small impact of IFX-1 on coagulation and indicating that D-dimer analysis might not be a uniformly predictive or reliable marker of coagulation in patients with COVID-19. 4 Considering that high neutrophil numbers are associated with poor prognosis in COVID-19, the projected non-interference of IFX-1 on neutrophil counts might signify that anti-C5a treatment is not the optimal way to treat COVID-19-associated neutrophilia. In fact, blockade of other complement components, acting upstream of C5a, might be a more robust and favourable clinical approach (eg, blockade of C3-mediated signalling with therapeutics like AMY-101). Thus, even if apparently disappointing, the results of this trial indicate that broader, rather than narrower, complement inhibition might be more beneficial for the treatment of COVID-19. JDL reports that he is the founder of Amyndas Pharmaceuticals, which develops complement inhibitors for therapeutic purposes, inventor of a broad patent portfolio that describes the therapeutic use of complement inhibitors, some of which are developed by Amyndas Pharmaceuticals, inventor of the compstatin technology licensed to Apellis Pharmaceuticals (ie, 4(1MeW)7W/POT-4/APL-1 and pegylated derivatives such as APL-2/pegcetacoplan and APL-9), and has received consulting fees from Achillion, Baxter, LipimetiX, Ra Pharma, Sanofi, and Viropharma. RTC has acted as a speaker for Alexion Pharma Brazil. AMR has received research support from Alexion Pharmaceuticals, Novartis, Alnylam, and Ra Pharma, lecture fees from Alexion, Novartis, Pfizer, and Apellis, and has served as a member of advisory investigator boards for Alexion, Roche, Achillion, Novartis, Apellis, and Samsung, and as a consultant for Amyndas. All other authors declare no competing interests.

Complement as a target in COVID-19?

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial

Complement C5 inhibition in patients with COVID-19-a promising target

Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy

Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis