Efficacy matters: broadening complement inhibition in COVID-19 – Authors' reply

We thank Dimitrios C Mastellos and colleagues for their interest in our exploratory, phase 2 randomised controlled trial¹ in 30 patients with severe COVID-19. The authors offer their interpretation of the inefficacy of IFX-1, arguing that upstream inhibition of the complement cascade could be superior to inhibiting C5a. We are surprised that the authors avoid discussing the efficacy signals and group differences generated in our study, and instead argue based on uncontrolled observational data relating to upstream complement C3 inhibitors. We do not think their conclusion is substantiated. As stated by regulatory bodies like the US Food and Drug Administration, in phase 2 studies, researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed to refine research questions and design new phase 3 research protocols. Typically, as in our study, these trials are not large enough to show that the drug is beneficial, but rather suggest efficacy trends and concepts.

In COVID-19, the secondary induction of a systemic hyperinflammatory state with immunothrombosis and endothelial damage in the lungs and other organs, including the kidney, appears to be a main driver of morbidity and mortality. Accumulating evidence points towards a key role for C5a-induced neutrophil activation in disease pathogenesis in critically ill patients with COVID-19.² C5a can be produced by conventional complement activation cascades, but also through direct enzymatic cleavage via proteinases, especially those of the coagulation pathways such as thrombin and plasmin. Because a hypercoagulable state is often observed in patients with severe COVID-19, a large proportion of C5a generated by this enzymatic activation can be expected. C5a made via these enzymes would not be blocked by upstream blockers such as the C5 inhibitor eculizumab.³ Therefore, a targeted blockade of C5a might offer tighter control of C5a in COVID-19 than might an upstream blockade. Thromboinflammation driven by neutrophil extracellular traps has been shown to be a C5a–C5aR-dependent process in COVID-19.⁴ This study provides support to our hypothesis that C5a induces the release of tissue factor by neutrophils, the link between C5a and coagulation, and a potential positive feedback loop for more C5a generation.¹ The observed increase in D-dimer concentrations early after C5a inhibition with IFX-1 should be seen within the context of thromboinflammation driven by neutrophil extracellular traps, C5a generation, and coagulation.

The exploratory phase 2 part of the PANAMO trial showed that C5a inhibition with IFX-1 was safe in patients with severe COVID-19.¹ The observed favourable effects of IFX-1 on mortality, kidney function, lactate dehydrogenase concentrations (a marker of tissue damage), and lymphocytopenia are preliminary because the study was not powered on these endpoints, but they do support investigating C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. The phase 3 part of the PANAMO trial has been initiated (NCT04333420). Importantly, the effects of the C5a inhibitor IFX-1 do not automatically apply to other C5a inhibitors or inhibitors blocking other complement factors in upstream activation pathways. Conclusions on the potential superiority of treatment approaches from very small, non-controlled studies—such as the three patients treated with AMY-101—should be avoided or handled with care. To our knowledge, our data are the first published data of a complement inhibitor from a randomised controlled clinical trial in patients with COVID-19.