C3 Molecules, Complement Pathways, Related Diseases, , ,

Complement and Cancer

In 2007, the first truly complement-targeted drug, the anti-C5 monoclonal antibody eculizumab (Eculizumab, Soliris), was approved for the treatment of PNH, and has achieved a revolutionary success, not only proving the feasibility of complement as a therapeutic target (significantly reducing the need for hemolysis and transfusion, and improving survival) but also partially alleviating the concern that long-term inhibition of complement may increase the risk of infection. It also partially alleviated concerns that long-term complement inhibition may increase the risk of infection. This has greatly encouraged both industry and academia, and combined with a deeper understanding of complement biology and advances in drug discovery and development technology, complement-targeted drug development has exploded. Based on the target of action and mechanism, existing and investigational drugs can be categorized into four main groups.

Complement Regulator Therapies

Principle: Supplements or enhances the body’s natural complement regulatory mechanisms.

Representative drugs: C1 esterase inhibitor (C1-INH)

Indications: HAE (primarily acts to inhibit the kinin-releasing enzyme system and control bradykinin production).

Emerging directions: designing regulatory proteins (e.g., soluble CR1 fragments, FH regulatory domain fusion proteins) that target the site of inflammation to achieve localized precise inhibition, preserving as much as possible the systemic anti-infective complement function.

Complement Activation Pathway Inhibitors

Principle: Block specific activation pathways at the source.

Representative drug: Humanized anti-C1s monoclonal antibody that blocks CP activation.

Indication: CAD (effective in raising hemoglobin and reducing blood transfusions).

  • Narsoplimab (OMS721): Humanized anti-MASP-2 monoclonal antibody, blocks LP activation. Status: Phase III trial (for HSCT-related TMA, etc.).
  • OMS906: Humanized anti-MASP-3 monoclonal antibody (MASP-3 activates FD, key to AP C3/C5 convertase formation). Status: Early clinical.
  • ANX005: Anti-C1q antibody fragment (targets the recognition initiation site). Direction of Inquiry: Neurodegenerative diseases (C1q is associated with microglial activation).
  • ARGX-117: Anti-C2 antibody (blocks CP activation downstream). Status: Early clinical.

Emerging Targets (oral small molecules):

  • Iptacopan (LNP023): oral factor B (FB) inhibitor. Indications explored: PNH (Phase III success, superior to anti-C5), C3 glomerulopathy, IgA nephropathy.
  • Danicopan, Vemircopan (ALXN2040, ALXN2050): Oral factor D (FD) inhibitor. Indications explored: PNH (as an add-on to anti-C5 therapy for EVH), aHUS, and other complement nephropathies. (Note: FD is the rate-limiting enzyme for AP activation, but only 1-2% activity is needed to activate FB, complete inhibition of FD is challenging).

C3 and C5 Inhibitors

Principle: Blocking C3 or C5, the core components of the complement cascade, inhibits downstream effects.

C5 inhibitors (block C5a and MAC):

  • Eculizumab (Soliris): Humanized anti-C5 monoclonal antibody (IV infusion). Indications: PNH, aHUS, anti-AChR antibody-positive gMG, NMOSD. Milestones but limitations: some patients (~30%) require transfusions due to persistent anemia in EVH; rare C5 gene polymorphisms leading to resistance; high burden of frequent IV infusions; very high cost.
  • Ravulizumab (Ultomiris): engineered upgraded version of eculizumab with significantly prolonged half-life by enhanced FcRn recovery (dosing interval extended to 8 weeks). Indications: PNH, aHUS, anti-AChR antibody-positive gMG. Efficacy non-inferior to eculizumab, cost-effectiveness may be superior.
  • Crovalimab: anti-C5 monoclonal antibody (subcutaneous, self-administered). Status: Phase III trial (PNH).
  • Avacincaptad pegol (Izervay): PEGylated aptamer that inhibits the cleavage of C5 to C5a/C5b. Indication: GA (intravitreal injection).
  • Zilucoplan: Subcutaneously injected C5 inhibitor. Indication explored: gMG (Phase III success).
  • Nomacopan: Recombinant tick-derived protein that inhibits activation of C5 by C5 convertase and also inhibits leukotriene B4 activity. Indication explored: herpetic pemphigoid.

C3 inhibitor (blocks C3a, C3b, MAC and all subsequent effects):

  • Pegcetacoplan (Empaveli/Aspaveli/Syfovre): Polyethylene glycolated C3 inhibitor based on the Compstatin backbone. Indications: PNH: subcutaneous (first drug to target C3), demonstrated superiority to eculizumab (boosts hemoglobin, reduces transfusions), especially in patients with EVH despite anti-C5 therapy.GA (secondary to AMD): intravitreal (first approved GA treatment). Phase III trial showed slowed progression of GA lesions, but need to be concerned about the risk of de novo exudative AMD.PNH: subcutaneous (first drug to target C3), demonstrated superiority to eculizumab (boosts hemoglobin, reduces transfusions), especially in patients with EVH despite anti-C5 therapy.
  • AMY-101: another Compstatin-derived C3 inhibitor. Indications explored: C3 glomerulopathy, etc.

Gene therapy:

  • Cemdisiran (ARO-C3): subcutaneously administered RNAi drug that targets silencing of hepatic C3 mRNA expression. Status: In clinical development (e.g., IgA nephropathy)
  • Cendisiran: RNAi drug targeting C5. Status: In clinical development.

Complement Effector/Receptor Inhibitors

Principle: Blocking the effector molecule or its receptor produced by complement activation is more selective.

Representative drug:

  • Avacopan: oral small molecule C5aR1 antagonist. Indication: ANCA-associated vasculitis (AAV) (as an add-on to standard therapy with a significant reduction in hormone dosage). Demonstrated non-inferiority at 26 weeks and superiority at 52 weeks to hormone-reducing regimens in phase III trials.
  • Vilobelimab (Gohibic): anti-C5a monoclonal antibody. Indication: Critically ill COVID-19 hospitalized adults (based on Phase III trial showing a reduction in 28- and 60-day mortality).

Targets in development:

  • C5aR1 antagonists: ACT-1014-6470 (oral small molecule), ALS-205 (subcutaneous small molecule), Avdoralimab (anti-C5aR1 monoclonal antibody), and others are in early clinical trials.
  • C3a/C3aR1 axis: activators or inhibitors have potential therapeutic value but are relatively underdeveloped.
  • C5aR2: complex function, both a potential target and a research difficulty.
  • MAC-specific inhibitors: still in the early stages of research.

Emerging Power: Pipeline Abundance, Future Prospects

More than 40 Phase III clinical trials of complement-targeted drugs are currently underway, signaling more new drug launches and expanded indications in the coming years.

  1. Optimize existing therapies
  • Long-acting/subcutaneous/oral dosage forms: e.g., Crovalimab (subcutaneous anti-C5), Zilucoplan (subcutaneous anti-C5), oral Danicopan/Iptacopan, aimed at improving convenience, adherence, and reducing costs.
  • Biosimilars: Reduce the high cost of anti-C5 drugs.
  1. Expanding targets and pathways: e.g., Narsoplimab (anti-MASP-2), OMS906 (anti-MASP-3) against LP.
  2. Focus on common diseases and organs
  • Renal disease is the most important: a large number of phase III trials targeting C3 glomerulopathy, IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, membranous nephropathy, and acute kidney injury. Oral Iptacopan/Danicopan has great potential in this area.
  • Neurodegenerative diseases: e.g., Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), etc., targeting C1q, C5a-C5aR1 axis, etc.
  • Ophthalmology (GA and others): Avacincaptad pegol, AMY-101, etc. in ongoing development.
  • Oncology: Explore the role of complement in the tumor microenvironment and the potential for targeted therapy.
  1. Expanding patient populations: Exploring the safety and efficacy of drugs in pediatric and adolescent patients (currently most drugs, except aHUS, are only approved for use in adults).
  2. Combination therapy: Explore the use of complement inhibitors in combination with other mechanisms (e.g., immunosuppressants, anticoagulants, antifibrotic drugs, immune checkpoint inhibitors, etc.) to improve the efficacy of complex diseases.

From the epochal success of the first anti-C5 antibody, eculizumab, in PNH and aHUS, to today’s proliferation of C3 inhibitors, C5aR antagonists, oral small molecules, and inhibitors targeting different activation pathways, the therapeutic choices are becoming increasingly abundant, and the patient population is gradually expanding from rare diseases to common diseases.

With the deepening understanding of complement biology, the continuous advancement of drug discovery and development technologies, and the advancement of a huge R&D pipeline, Creative Biolabs has reason to believe that the next decade will be a critical period for complement-targeted therapies to mature and address more unmet clinical needs truly.