Compendium of current complement therapeutics

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.