by The complement system is a collection of over 30 proteins found in the blood and tissues of the human body that work together to eliminate pathogens and trigger inflammation. When activated, complement works as part of the innate immune response to tag foreign invaders like bacteria and viruses for destruction and removal from the body. However, when dysregulated, overactivation of the complement system can lead to excessive inflammation that damages healthy tissues and contributes to the progression of various autoimmune and inflammatory diseases.
Complement activation occurs via three main pathways—the classical, lectin, and alternative pathways—that all converge on a common effector mechanism. The classical and lectin pathways are antibody-dependent and recognize pathogen surfaces directly, while the alternative pathway acts as an amplification loop providing constant low-level activity and priming the system for a swift response. Ultimately, the activation of any of these pathways results in the formation of the membrane attack complex (MAC) that punctures pathogens to directly kill microbes or marks them for destruction by phagocytic cells.
While complement plays an important role in host defense, its dysregulation has been linked to numerous disease states. Excessive or misdirected complement activity damages self-tissues and drives chronic inflammation in diseases like atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, and age-related macular degeneration (AMD). This has made complement an attractive therapeutic target, and complement inhibition a promising new strategy for the treatment of many immunological disorders.
Developing Inhibitors Of The Complement System
The first Global Complement Inhibitors to receive regulatory approval targeted C5, a central protein in terminal complement activation. Eculizumab (Soliris), a monoclonal antibody, was approved in 2007 for the treatment of PNH. By blocking C5 cleavage, eculizumab halts formation of the membrane attack complex (MAC) and the resultant lysis of red blood cells seen in PNH patients. It demonstrated unprecedented efficacy in controlling hemolysis and became the foundation for complement-targeted therapy.
More recently, ravulizumab (Ultomiris)-a long-acting version of eculizumab-was approved in 2018 for PNH and aHUS. Like eculizumab, ravulizumab binds C5 with high affinity but has an extended half-life allowing for less frequent dosing. In clinical studies, ravulizumab maintained hemoglobin levels and reduced transfusion requirements in PNH patients while also preventing thrombotic microangiopathy in aHUS. These C5 inhibitors set the stage for targeting other points in the complement cascade.
Building upon the success of C5 inhibitors, second-generation complement drugs have emerged that act earlier in the pathways. For example, Skyrizi (risankizumab-rzaa) was approved in 2019 for the treatment of plaque psoriasis by blocking interleukin-23, an important signaling cytokine downstream of complement activation. Additionally, pemfevorex (APL-2) completed Phase 3 trials for PNH by blocking C3 and the activation of all three initiation pathways simultaneously at their convergence point. If approved, pemfevorex would be the first oral complement therapy option.
Research is also underway on inhibitors that act even further upstream including compounds targeting C1s in the classical pathway and factors B and D in the alternative pathway amplification loop. By blocking complement at multiple steps, these new drugs aim to more specifically control pathologic inflammation while largely preserving the protective functions of the complement system in host defense. Combined with prognostic biomarkers to identify patients most likely to benefit, this next generation of Global Complement Inhibitors promises more choice and personalized treatment approaches.
Global Progress And Future Outlook
Complement therapies have shown tremendous success clinically and generated substantial interest from pharmaceutical companies and investors. Worldwide sales of the existing C5 inhibitors eclipse $3 billion annually highlighting the significant potential. As the pipeline of novel complement targets continues to mature, this class of biologics appears poised to radically transform treatment outcomes for dozens of rare and common diseases characterized by complement dysregulation.
Regulatory approvals of new Global Complement Inhibitors have kept pace with their clinical development. After initial FDA approval indications for PNH and aHUS, eculizumab gained additional orphan drug designations for generalized myasthenia gravis, neuromyelitis optica, and IgG4-related disease. Pemfevorex’s recommendation for approval in both PNH andautoimmune hemolytic anemia from the CHMP signals expansion into new fields based on early clinical data. Researchers worldwide are actively investigating complement’s roles in postoperative cognitive impairment, chronic obstructive pulmonary disease exacerbations, COVID-19 severity, and more—identifying new prospects for complement-targeted therapeutics.
Supported by substantial financial investment, academia- partnerships like the Complement Alliance aim to advance the rational design of complement modulators through open science collaborations. As our mechanistic understanding of complement signaling grows with the help of -omics technologies and improved animal models, more selective inhibition strategies will continue refining complement’s therapeutic potential. Meanwhile, combination therapies pairing complement drugs with other immunotherapies may unlock new synergies. The future prospects appear bright to realize complement’s full promise in treating currently intractable diseases through the global development and clinical application of complement inhibitors.
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1. Source: Coherent Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author - Vaagisha Singh
Vaagisha brings over three years of expertise as a content editor in the market research domain. Originally a creative writer, she discovered her passion for editing, combining her flair for writing with a meticulous eye for detail. Her ability to craft and refine compelling content makes her an invaluable asset in delivering polished and engaging write-ups. LinkedIn
