Selected diseases with suspected complement involvement for which no complement therapeutics have been FDA approved
| Disease or condition | Preclinical complement involvement | Clinical complement involvement | Other treatment options |
|---|---|---|---|
| AD | Shown in multiple mouse models [132].Genome wide associations of complement proteins (clusterin, CR1) with AD [133]. Complement proteins present in plaques [134] and are upregulated in CSF [133]. | No clinical data | Lecanemab [135] aducanumab [136] |
| MS | Complement C3d fragments deposited in lesions and contribute to myelin destruction [137, 138].C3, C1q, and CR1 are associated with visual acuity loss in patients with MS [139].Reducing complement activation is protective in multiple EAE models [140]. | No clinical data | Anti-CD20 antibodies (rituximab, ocrelizumab, ofatumumab, and ublituximab) [141], IFN-1α, IFN-1β, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate [142]. |
| Select secondary TMAs | Some drug-induced TMAs are suggested to be complement related [143].In TMAs associated with autoimmune conditions (SLE, catastrophic APS, scleroderma)—complement activation is present in some patients. The CP and the AP are triggered by anti-phospholipid antibodies in vascular and obstetric APS [144]. There is strong evidence for complement activation in TMAs after organ transplant (see text). | Eculizumab showed promising data in patients with SLE/APS in the treatment of TMA and improved kidney function [145].In catastrophic APS and scleroderma, eculizumab treatment showed promising results [146, 147]. A more recent study showed the efficacy of eculizumab in patients with scleroderma renal crisis [148].Eculizumab is frequently used off label in TMA secondary to transplantation [149].Narsoplimab (OMS721) administration resulted in improvement of organ function in phase 2 trial in patients with HSCT-TMA [109]. | Multiple depending on disease, most often steroids and primary disease specific treatments. |
| NAFLD including MASH | Complement is postulated to be activated in NAFLD (C3 fragments, C4d, and MBL/C1q) [150].An increase in complement components C3, C5, CFB, and C3a was associated with an increased risk and severity of NAFLD [151]. The role of AP activation in MASH has been reported [152]. | No clinical data but complement has been proposed as a therapeutic target [150]. | NR1A2 agonist—resmetirom [153]. |
| Insulin resistance and obesity | The level of C3 is increased proportionately to the total amount of adipose tissue and blood glucose levels [154]. C3adesArg might trigger a cytokine response and induce inflammation leading to insulin resistance [155]. C5aR1 signaling in obesity has also been linked to insulin resistance in muscle cells [156].Complement activation might be occurring in T1D, and Genetic variants of C2, CFB, C4A, and C4B appear to play a role in T1D risk [157]. | No clinical data | Anti-GLP-1 antibodies are the leading drug class for the treatment of obesity and also improves blood glucose levels [158]. |
| Acute and long COVID-19 | Patients with long COVID-19 were shown to have increased MAC [159], iC3b, and Ba generation, suggesting AP activation [160].Complement system activation plays a major role in acute COVID-19 [70, 161–163]. | AMY-101 tested in patients with acute COVID-19 showed some efficacy [100].Ravulizumab and zilucoplan were also tested in patients with acute COVID-19 with limited efficacy [164].Vilobelimab showed a reduction in mortality at 28 days in patients on mechanical ventilation and has emergency authorization [90]. | Corticosteroids (particularly dexamethasone), interleukin-6 receptor antagonists (e.g., tocilizumab), and Janus kinase inhibitors (e.g., baricitinib), molnupiravir, nirmatrelvir/ritonavir, and remdesivir. |
| LN | Complement protein deficiencies can lead to SLE (C1q, C1r, C1s, C4, C2).Multiple animal models suggest that complement drives the pathogenesis of SLE [165].The LP might be activated in LN [166].C3d/creatinine levels can discriminate between active and inactive LN, while C3d alone correlates with SLE disease activity index [167]. | Iptacopan (NCT05268289)Narsoplimab (NCT02682407)Ravulizumab (NCT04564339) | Glucocorticoids, MMF, cyclophosphamide, cyclosporin A, rituximab [168], belimumab, and voclosporin [169]. |
| RA | Antibodies against citrullinated proteins activate both the CP and the AP in vitro [170, 171].Multiple animal models using knockout mice suggest a pathogenic role of complement [172–174].TT32 (CR1/CR2 fusion protein) and inhibitor of AP, CP, and LP showed efficacy in 2 animal models of arthritis reducing disease activity [175]. | Blocking C5aR1 using PMX53 did not decrease synovial inflammation and did not change biomarkers associated with clinical efficacy in patients with RA [176]. | TNF-α inhibitors, rituximab, tocilizumab, and nintedanib [177]. |
AD: Alzheimer’s disease; APS: antiphospholipid syndrome; GLP-1: glucagon-like peptide-1; LN: lupus nephritis; MASH: metabolic dysfunction-associated steatohepatitis; MMF: mycophenolate mofetil; MS: multiple sclerosis; NAFLD: non-alcoholic fatty liver disease; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; TMA: thrombotic microangiopathy; AP: alternative pathway; CFB: complement factor B; COVID-19: coronavirus disease 2019; CP: classical pathway; CR1: complement receptor 1; CR2: complement receptor 2; HSCT-TMA: hematopoietic stem cell transplantation-associated thrombotic microangiopathy; IFN-1α: interferon 1α; LP: lectin pathway; MAC: membrane attack complex; MBL: mannan-binding lectin; TNF-α: tumour necrosis alpha