The complement system is found in the blood, tissue fluids, and cell membranes of both humans and animals, consisting of more than 30 proteins. Serving as a bridge between innate and adaptive immunity, the complement system participates in the body's defense responses and immune regulation after activation, including enhancing antibody responses and possessing immune memory, lysing foreign cells, clearing immune complexes, and apoptotic cells, etc.

The complement system can be activated through three pathways: the classical pathway, the alternative pathway, and the lectin pathway.

Classical Pathway: This pathway is initiated by the binding of complement protein C1 to antibodies that are attached to the surface of pathogens. This binding triggers a cascade of reactions leading to the activation of other complement proteins and ultimately resulting in the destruction of the target cell.

Alternative Pathway: The alternative pathway can be activated spontaneously by the hydrolysis of a complement protein called C3. It can also be triggered by certain surface molecules found on pathogens. Once initiated, the alternative pathway also leads to the activation of other complement proteins and the destruction of the target cell.

Lectin Pathway: The lectin pathway is initiated when mannose-binding lectin (MBL), a protein that can recognize specific sugar molecules on the surface of pathogens, binds to its target. This binding triggers a cascade of reactions similar to those in the classical pathway, leading to the activation of other complement proteins and the destruction of the target cell.

Figure 1. Pathways of complement system activation. 

However, besides its ability to play a proactive protective role, once imbalanced or excessively activated, the complement system can also lead to various diseases. These include acute inflammatory conditions such as ocular diseases and periodontal diseases, as well as autoimmune diseases, tumors, kidney diseases, chronic hemolytic diseases, and neurodegenerative diseases.

Given the extensive physiological functions of the complement system, attempts to target various components of the complement system for drug development have gradually become more active, and the development of complement system drugs has received significant attention in recent years.

Development of Complement Inhibitors

Since the discovery of the complement system in the 19th century, researchers have proposed the use of complement inhibitors as therapeutic drugs. However, it wasn't until 2007 that the first C5 complement inhibitor, Sorilis, was approved and brought to market. This was primarily due to the numerous challenges encountered during the development of complement inhibitors.

On one hand, it remains unclear how the complement system mediates diseases and affects the pathogenic mechanisms. On the other hand, due to the complexity of the complement system as a protein network with numerous pathways, even if one complement pathway is blocked, the system can "switch" to another pathway through regulatory mechanisms. Consequently, the anticipated clinical effects of targeting inhibitors may be nullified. Therefore, developing drugs that effectively block complement pathways poses a significant challenge.

Now, there are 14 complement inhibitors are approved by FDA, including C1 inhibitor Berinert, Cinryze, Ruconest and Enjaymo (sutimlimab), C3 inhibitor Empaveli (pegcetacoplan), SYFOVRE™ (pegcetacoplan injection) , and C5 inhibitor, Zilbrysq (Zilucoplan), Veopoz (Pozelimab), Izervay (avacincaptad pegol), Soliris (Eculizumab), Ultomiris (ravulizumab) and Tavneos (avacopan), factor B inhibitor Fabhalta (Iptacopan) and factor D inhibitor Voydeya (Danicopan).

Table 1. FDA approved complement inhibitors

Complement C5 Inhibitors

The complement protein C5, positioned at the cascade reaction's end, regulates complement signals activated by all three pathways, making it a prime target for complement drug development.

The first complement C5 inhibitor Eculizuma (Soliris) can directly inhibit C5, preventing its cleavage into C5a and C5b, thereby inhibiting the formation of the membrane attack complex and hemolysis. Studies have shown that Eculizumab can fundamentally alter the management and clinical course of patients with PNH. However, challenges persist, including polymorphisms at the C5 binding site in certain individuals, which may contribute to resistance development.

The second complement inhibitor, Ravulizumab (Ultomiris), is a long-acting antibody drug derived from Eculizumab. Its structural modifications greatly extend the drug's half-life, allowing for administration every 8 weeks, thus enhancing patient convenience and quality of life. Despite these advantages, concerns remain regarding potential meningococcal infections in treated individuals and its effectiveness in patients with the C5 (Arg885His) polymorphic mutation.

Avacincaptad pegol is an RNA aptamer covalently bound to a branched polyethylene glycol (PEG) molecule. It binds to and inhibits complement protein C5. It was developed to treat an advanced form of age-related macular degeneration (AMD) called geographic atrophy (GA) in August 2023.

Pozelimab, a fully human IgG4 monoclonal antibody, exhibits high-affinity binding to both wild-type and mutant human complement protein C5. In mid-August 2023, it gained FDA approval for treating CD55-deficient protein-losing enteropathy (CHAPLE) in adults and children aged 1 and above. CHAPLE is an exceedingly rare genetic immune disorder caused by mutations in the CD55 gene, leading to overactivation of the complement system. CD55 plays a crucial role in regulating the human complement system; without proper regulation, the complement system may erroneously target normal cells, resulting in damage to the blood vessels and lymphatics of the upper gastrointestinal tract and leading to protein and blood cell loss.

Zilucoplan (Zilbrysq®) is a subcutaneously administered macrocyclic peptide inhibitor of C5 inhibitor being developed by UCB for the treatment of generalised myasthenia gravis (gMG)  who are anti-AChR antibody positive . 

Complement C3 Inhibitors

Pegcetacoplan, a cyclic peptide drug comprising 13 amino acids, inhibits the formation of C3 convertase, effectively targeting both the terminal and proximal ends of the complement system. Phase III clinical trials indicate that compared to Eculizumab, Pegcetacoplan significantly improves hemoglobin (Hb) levels and reduces transfusion dependency, showing promising efficacy in treating bone marrow failure in patients with PNH. In February 2023, the indication was updated to include the treatment of people with geographic atrophy secondary to age-related macular degeneration. However, its short half-life makes patients more susceptible to hemolysis in cases of infection or missed doses.

Complement B Inhibitors

Although C5 complement inhibitors have notably decreased thrombosis risk in PNH patients, many still endure lingering anemia, fatigue, and reliance on transfusions post-treatment, significantly impacting their quality of life.

Iptacopan, a specific complement factor B inhibitor, acts upstream of the C5 terminal pathway, managing both intravascular and extravascular hemolysis concurrently. It addresses the limitations of C5 complement inhibitors and offers a sole oral treatment option. In December 2023, the FDA granted approval to Fabhalta® (iptacopan) as the initial oral monotherapy for PNH. Clinical trials revealed that the majority of Fabhalta-treated patients saw a rise in hemoglobin levels (≥2g/dL increase compared to baseline without RBC transfusions), and nearly all of them no longer needed transfusions.

Complement D Inhibitors

Danicopan is a first-in-class oral proximal, complement alternative pathway factor D inhibitor. Therapeutic factor D inhibition was designed to control intravascular hemolysis and prevent C3-mediated extravascular hemolysis. On 1 April, 2024, The FDA has approved danicopan (Voydeya) as an add-on therapy to ravulizumab-cwvz (Ultomiris) or eculizumab (Soliris) for the treatment of extravascular hemolysis in adult patients with PNH.

Conclusion

Indeed, over 100 diseases are mediated by complement, leading to substantial unmet clinical needs. The development of complement inhibitors is currently advancing swiftly. However, the evaluation of safety and efficacy for complement inhibitors poses challenges due to the limited availability of complement-targeted molecules and preclinical disease research models. Moreover, the development of complement inhibitors has primarily focused on extremely rare diseases with limited cases, resulting in slow expansion into chronic or common diseases. Nevertheless, with ongoing research into the complement system and advancements in related technologies, groundbreaking innovations in the field of complement inhibitors are anticipated in the near future.

Huateng Pharma, as a leading PEG Linker supplier, provides monodispersed, polydispersed and multi-arm PEGs for your drugs developemnt, including complement inhibitors.

References:
1. Pozelimab (C5 antibody) BLA for treatment of children and adults with ultra-rare CHAPLE disease accepted for FDA Priority Review. News release. Regeneron Pharmaceuticals, Inc. Accessed February 21, 2023. 
2. Eye Diseases & Conditions Geographic Atrophy (GA). Prevent Blindness. 
3. https://www.sciencedirect.com/science/article/pii/S0161589019303293#sec0005. 
4. Fritsche L.G. et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016, 48, 134-143.
5. Ostrycharz, E.; Hukowska-Szematowicz, B. New Insights into the Role of the Complement System in Human Viral Diseases. Biomolecules 2022, 12, 226. https://doi.org/10.3390/biom12020226