Elsevier

Molecular Immunology

Volume 114, October 2019, Pages 341-352
Molecular Immunology

Review
Compendium of current complement therapeutics

https://doi.org/10.1016/j.molimm.2019.07.030Get rights and content
Under a Creative Commons license
open access

Highlights

  • Complement plays a key role in pathogenesis of inflammatory and autoimmune disease.

  • Numerous drugs are in clinical development for complement-mediated disease.

  • A small number have been approved by the FDA and EMA.

  • Next generation drugs are in clinical development to address current challenges.

  • We provide a ‘snapshot’ of the complement drug discovery landscape 2019.

Abstract

The complement system is well known for its role in innate immunity and in maintenance of tissue homeostasis, providing a first line of defence against infection and playing a key role in flagging apoptotic cells and debris for disposal. Unfortunately, complement also contributes to pathogenesis of many diseases, in some cases driving pathology, and in others amplifying or exacerbating the inflammatory and damaging impact of non-complement disease triggers. The driving role of complement in a single disease, paroxysmal nocturnal hemoglobinuria (PNH), provoked the development and eventual FDA (US Food and Drug Administration) approval of eculizumab (Soliris™), an anti-C5 antibody, for therapy. Although PNH is very rare, eculizumab provided clinical validation and demonstrated that inhibiting the complement system was not only well-tolerated, but also provided rapid therapy and saved lives. This clinical validation, together with advances in genetic analyses that demonstrated strong associations between complement and common diseases, drove new drug discovery programmes in both academic laboratories and large pharmaceutical companies. Numerous drugs have entered clinical development and several are in phase 3 trials; however, many have fallen by the wayside. Despite this high attrition rate, crucial lessons have been learnt and hurdles to development have become clear. These insights have driven development of next generation anti-complement drugs designed to avoid pitfalls and facilitate patient access. In this article, we do not set out to provide a text-heavy review of complement therapeutics but instead will simply highlight the targets, modalities and current status of the plethora of drugs approved or in clinical development. With such a fast-moving drug development landscape, such a compendium will inevitably become out-dated; however, we provide a snapshot of the current field and illustrate the increased choice that clinicians might enjoy in the future in selecting the best drug for their application, decisions based not only on efficacy but also cost, mechanistic target, modality and route of delivery.

Abbreviations

Ab
antibody
AP
alternative pathway
ASO
antisense oligonucleotide
RNAi
ribonucleic acid interference
CP
classical pathway
LP
lectin pathway
FB
factor B
FD
factor D
FH
factor H
FI
factor I
MASP
mannose-associated serine protease 1
PNS
peripheral nervous system
CNS
central nervous system
MAC
membrane attack complex
FDA
The Food and Drug Administration
EMA
European Medicines Agency
SM
small molecule
IV
intravenous
SC
subcutaneous
IVT
intravitreal
Ph
phase
RoA
route of administration
SoC
standard of care
ULN
upper limit of normal
AQP4
Aquaporin-4

Keywords

Complement
Drug
Therapeutic
Clinical trial
Eculizumab
Disease

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