Global Complement Inhibitors: Advancing Treatment Options For Rare Diseases

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The complement system is a key part of the innate immune system consisting of over 30 circulating and membrane-bound proteins. These proteins work together in three main pathways - the classical, lectin, and alternative pathways - that act to recognize foreign agents and destroy them. All three pathways converge at the central component C3, leading to formation of the membrane attack complex that punctures cells. Precision medicines targeting specific proteins in these pathways are advancing treatment of complement-mediated diseases.

Classical And Lectin Pathway Of Complement Inhibitor

The classical pathway Global Complement Inhibitors is activated by antibodies binding to antigens on foreign cells or viruses. The lectin pathway is activated by recognition of carbohydrate patterns on microbes. Both pathways involve initiation by C1q and proceed through C4 and C2, forming the C3 convertase C4b2a. Several drugs targeting early components are in clinical trials.

Alexion's ULTOMIRIS (ravulizumab) is a long-acting C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH) and atypical ...
... hemolytic uremic syndrome (aHUS). It prevents formation of the membrane attack complex downstream of C3 activation. In Phase 3 trials for PNH, ULTOMIRIS reduced hemolysis to a greater extent than SOLIRIS (eculizumab), an earlier-generation C5 inhibitor.

Apellis' APL-2 is a C3 inhibitor in Phase 3 trials for PNH, geographic atrophy, and IgA nephropathy. By inhibiting C3, it blocks all three complement pathways earlier in the cascade than C5 inhibitors. In Phase 2 trials, APL-2 reduced hemolysis in PNH patients similar to SOLIRIS with less frequent dosing.

Alternative Pathway Complement Inhibitor

The alternative pathway is constitutively active, constantly assessing surfaces for damage or foreignness. It is regulated by complement factor H, which helps discriminate self from non-self. Dysregulation of the alternative pathway underlies several rare diseases.

Amyndas' AMY-101 is a Factor B inhibitor in Phase 2 trials for C3 glomerulopathy, IgA nephropathy, and PNH. By inhibiting Factor B, it prevents formation of the alternative pathway C3 convertase C3bBb. Initial studies found it well tolerated with reductions in complement activation biomarkers.

Akari Therapeutics' nomacopan (AK002) is a C5 inhibitor in Phase 3 trials for hematopoietic stem cell transplant-related thrombotic microangiopathy. It has also shown potential in Phase 2 studies of bullous pemphigoid by decreasing complement-mediated inflammation. Unlike other C5 inhibitors, nomacopan does not specifically target the membrane attack complex, suggesting broader anti-inflammatory effects upstream.

Advantages Of Global Complement Inhibitors Therapies

Well-established disease mechanisms have enabled successful translation of multiple Global Complement Inhibitors programs into clinical use over the past decade. Targeting specific points in the complement cascades allows tailored suppression of disease pathways with potential for increased safety versus broad complement inhibition.Dr. David Schaffer of the University of California Berkely notes "the complement field has matured to the point of developing selective inhibitors for each pathway activation route and effector function." Companies continue advancing new drugs targeting upstream proteins like C3 and factors B and H that may offer enhanced efficacy or dosing convenience compared to existing C5 inhibitors. As understanding grows of complement's roles in additional disorders, these precision medicines hold promise to expand treatment to more rare disease patients.

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1. Source: Coherent  Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it