Apellis fails to complement severe Covid-19

Snippets

Hitting complement activation looks to follow inhibition of Jak and GM-CSF in being crossed off the list of mechanistic approaches to treat severe Covid-19. Yesterday Apellis said it was canning its complement C3 inhibitor APL-9 in severe Covid-19 after a phase I/II study found no meaningful reduction in mortality. This came on the heels of similar failures from Alexion’s anti-C5 MAb Ultomiris and Inflarx’s C5a-targeting IFX-1. Complement forms part of the innate immune response to viruses and triggers inflammation, so the idea was that inhibiting it could reduce cytokine activation and prevent lung damage, along the lines that have seen anti-IL-6 antibodies tested in Covid-19. This was backed by mouse studies showing that activation of complement C3 exacerbated disease in Sars, and as early as February 2020 Alexion was proposing to use Soliris to manage severe pneumonia associated with Covid-19. Given the successes of antibodies, not to mention vaccine roll-outs, the failure of the complement mechanism probably matters little at this stage, but it does leave up in the air the fate of ongoing complement inhibitor trials being run by UCB, Innate Pharma and Pharming.

Selected complement inhibitors against Covid-19
Project Mechanism Company Status
Soliris Anti-complement factor C5 MAb Alexion Available under expanded access programme
IFX-1 Anti-complement factor C5a MAb Inflarx Failed clinical trial in Dec 2020
Ultomiris Anti-complement factor C5 MAb Alexion Failed clinical trial in Jan 2021
APL-9 Complement factor C3 inhibitor Apellis Failed clinical trial in Mar 2021
Zilucoplan  Complement factor C5 inhibitor UCB Ph2 trial ended Dec 2020; results imminent
Avdoralimab  Anti-complement factor C5a MAb Novo Nordisk/Innate Pharma Ph2 trial ends Mar 2021
Ruconest C1 esterase inhibitor Pharming Ph2 trial ends Aug 2021
AMY-101 Complement factor C3 inhibitor Amyndas Ph2 trial not yet recruiting
Coversin Complement factor C5a & C5b-9 inhibitor Akari Trial cleared in Oct 2020, but not yet begun
Source: clinicaltrials.gov & company statements.

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