The complement system is an important part of the innate immune system that helps defend the body against infections and foreign invaders. It is made up of around 30 different plasma and cell surface proteins that work together to eliminate pathogens, immune complexes, and damaged cells. Complement activation occurs through three main pathways - the classical, lectin, and alternative pathways. All three pathways ultimately lead to the cleavage of C3 and C5 proteins, resulting in the formation of the membrane attack complex (MAC) that punctures cell membranes to destroy the target. While complement activation is beneficial for immune defense, inappropriate or uncontrolled activation can cause damage to healthy host cells and tissues, leading to disease.
Paroxysmal Nocturnal Hemoglobinuria
One condition where uncontrolled complement activation causes significant morbidity is paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare, acquired hematopoietic stem cell disorder associated with chronic complement-mediated hemolysis. It is caused by somatic mutations in the PIGA gene resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins like CD55 and CD59 on the surface of blood cells. The lack of these protective proteins makes the cells highly susceptible to complement-mediated lysis. patients experience hemolytic anemia, venous thromboses, and bone marrow failure. Before the development of complement inhibitors, PNH had a mortality rate of approxmiately 50% within 5 years of diagnosis.
Development Of Eculizumab For PNH Treatment
In 2007, eculizumab became the first drug approved by regulatory agencies for the treatment of PNH. Eculizumab is a monoclonal antibody that specifically binds to C5, inhibiting its cleavage and preventing formation of the terminal complement complex C5b-9 (MAC). By blocking terminal complement activation, eculizumab stops uncontrolled complement-mediated hemolysis of blood cells in PNH patients, markedly improving hematologic parameters and overall survival. Post-approval studies have demonstrated that eculizumab results in hematologic remission in over 90% of patients, reduces transfusion requirements, improves quality of life, and increases transplant-free survival. It has become the standard of care for all PNH patients requiring treatment.
Expanding Indications For Global Complement Inhibitors
Given the success of eculizumab in PNH, researchers have explored the use of Global Complement Inhibitors for other complement-mediated disorders. In 2017, the FDA approved eculizumab for atypical hemolytic uremic syndrome (aHUS), another rare disorder caused by dysregulated alternative pathway activation leading to thrombotic microangiopathy. Eculizumab was shown to improve kidney function and prevent harmful sequelae like end-stage kidney disease in aHUS patients. More recently, other inhibitors have gained approval - ravulizumab for PNH and ALXN1210 (ravulizumab-cwvz) for generalized myasthenia gravis, highlighting the growing interest in targeting the complement system for different rare diseases.
Novel Global Complement Inhibitors
While eculizumab has changed the landscape for treating certain complement-mediated disorders, it does have limitations like the need for intravenous infusions and monitoring of meningococcal infection risk. Therefore, pharmaceutical companies are developing second-generation oral Global Complement Inhibitors with improved pharmacokinetics and efficacy profiles. Some examples are:
- Sakigake (avanfilcon A) - A topically administered eye drop targeted against C5 for geographic atrophy wet AMD.
- ALN-CC5 - Small interfering RNA drug targeting C5 for complement-mediated diseases in development for PNH and aHUS.
- LNP023 - Peptide inhibitor of C3 for PNH, aHUS, cold agglutinin disease in Phase 2 trials.
- BCX9930 - Oral Factor D inhibitor for complement-mediated diseases in Phase 1 trials. Could provide alternative pathway inhibition.
Growing Acceptance Of Complement Targeting
With the clinical success of eculizumab and other approved drugs, complement has gained considerable recognition as a therapeutic target. Awareness about rare complement-mediated disorders is also rising within the medical community. Regulatory agencies are more receptive to approving Global Complement Inhibitors based on well-designed clinical trials involving relatively small patient populations. The recognition of complement's role in many disease areas beyond hematology, like nephrology, neurology and ophthalmology indicates a much wider scope for drug development. Substantial investment is ongoing to develop novel oral and tissue-targeted Global Complement Inhibitors that offer improved dosing convenience over monoclonal antibodies. Complement-targeted therapies have truly revolutionized the treatment of previously fatal rare diseases and this area of drug development continues to expand rapidly.
Get more insights on this topic: https://www.newsanalyticspro.com/breaking-down-the-complement-inhibitors-how-inhibitors-are-revolutionizing-treatment/
Author Bio
Vaagisha brings over three years of expertise as a content editor in the 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: https://www.linkedin.com/in/vaagisha-singh-8080b91)
*Note:
1. Source: Coherent Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it