The complement system is an important part of the innate and adaptive immune system. When activated, it participates in the body’s defense response and immune regulation, including enhancing antibody response, possessing immune memory, lysing foreign cells, and removing immune complexes and apoptotic cells.
The complement system has three different activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. The C5 converting enzyme produced by all three of these pathways cleaves C5, triggering a common end effect. This, in turn, exerts a variety of biological effects such as phagocytosis, lysis of cells, mediation of inflammatory responses, modulation of the immune response, and clearance of immune complexes.
In addition to its positive protective effects, it has been found that an imbalance or over-activation of the complement system can lead to a wide range of diseases, such as acute inflammatory conditions like eye disease, periodontal disease, autoimmune disorders, neoplasms, kidney disease, chronic hemolytic disorders, and neurodegenerative diseases.
Two C5 Targeted Drugs Approved in August
Considering the significant impact of the complement system on the emergence of various diseases, the complement system has gradually become a popular direction for new drug development. Complement protein C5 is at the end of the cascade reaction, and targeting it can regulate complement signaling activated by all three different pathways, making C5 a popular target for complement drug development.
Eculizumab, the world’s first C5-targeted complement drug, was approved by the FDA in 2007 for the treatment of sudden-onset sleep hemoglobinuria (PNH). It was subsequently approved for the treatment of atypical hemolytic uremic syndrome (aHUS), neuromyelitis optica spectrum disorder (NMOSD), and generalized myasthenia gravis (gMG). The drug is a monoclonal antibody that works by binding to complement protein C5 and inhibiting the production of terminal complement components C5a and membrane attack complex C5b-9.
Ravulizumab, the world’s second C5-targeted drug, was approved by the FDA in 2018 for the treatment of PNH, and was subsequently approved for the treatment of aHUS, NMOSD, and gMG. After Ravulizumab binds complement C5 endocytosed into cells, it binds to the neonatal FcRn receptor under acidic conditions, protecting the antibody from lysosomal degradation. The intact antibody then leaves the endothelial cell and is recycled.
In August this year, the world’s third and fourth C5-targeted drugs, Avacincaptad pegol intravitreal injection and Pozelimab were approved by the FDA.
- Avacincaptad pegol
Avacincaptad pegol is a novel complement protein C5 inhibitor, an RNA aptamer covalently bound to a branched polyethylene glycol (PEG) molecule that binds to and inhibits complement protein C5. Earlier in August, the drug was approved by the FDA for the treatment of age-related macular degeneration (AMD)-induced geographic atrophy (GA).
- Pozelimab
Pozelimab, a fully human IgG4 monoclonal antibody with high binding affinity for wild-type and variant human complement protein C5, was approved by the FDA in mid-August for the treatment of CD55-deficient protein-losing enteropathy (CHAPLE) in adults and those over the age of one year. CHAPLE is an extremely rare inherited immune disease caused by a mutation in the CD55 gene leading to overactivation of the complement system. CD55 is a protein that regulates the body’s complement system. Without proper CD55 regulation, the complement system may attack normal cells, causing damage to blood vessels and lymphatic vessels in the upper GI tract and leading to loss of protein and blood cells.
Multiple C5 Targeted Drugs Coming Out of the Gate
In addition, several other investigational C5-targeted drugs are currently in clinical trials around the world.
- Crovalimab is a new generation of C5 circulating antibody, which can remove C5 from the body more efficiently and has a longer half-life and a more convenient way of administration. In August 2022, the drug’s marketing application for the treatment of PNH was accepted by the CDE in China, and the marketing application for this indication was included in the priority review by the CDE.
- Zilucoplan is a novel macrocyclic peptide C5 inhibitor administered subcutaneously and is being developed for the treatment of gMG as well as other rare complement-mediated disorders. In November 2022, a marketing application for the drug for the treatment of gMG entered review in the US and Europe.
- Nomacopan is a recombinant small protein, highly soluble and stable, that acts on complement component C5, preventing the release of C5a and the formation of C5b-9, as well as specifically inhibiting leukotriene B4 (LTB4).
- Cemdisiran is a C5-targeted RNAi therapeutic drug that binds to N-acetylgalactosamine (GalNAc) ligand for the treatment of complement-mediated diseases. Following subcutaneous administration of Cemdisiran, the GalNAc ligand fraction binds specifically to and is taken up by the desialylate glycoprotein receptor (ASGPR) expressed on hepatocytes. Intracellularly, the siRNA binds to C5 mRNA, thereby inhibiting C5 translation and expression.
- Gefurulimab, a third-generation C5 inhibitor developed by Alexion Pharmaceuticals, is a mini-doublet (25kD) containing only the heavy chain variable region (VH) of the antibody targeting C5 and an antibody fragment that binds specifically to albumin. The smaller molecular weight results in better permeability and the binding to albumin extends its half-life.
- KP104 is a world-first complement dual-targeting biologic designed to selectively inhibit both the complement bypass and terminal pathways, providing a powerful and potentially more selective precision therapeutic approach to inhibit complement by modulating two separate rate-limiting steps in the complement activation cascade that are critical for disease progression.
Complement protein C5 is a very successful complement drug target, and the success of drugs already out of the pipeline will give confidence to successors and further accelerate the competition in this track. Overall, the complement protein C5 track has entered the harvest period, and new drugs are expected to be approved in recent years.