TABLE 1.
Diseases associated with activation of the alternative pathway (AP) and therapeutic approaches using small‐molecule inhibitors
| Disease | Rationale for involvement of the alternative pathway | Low‐molecular weight antagonists in Phase 2/3 trials |
|---|---|---|
| ||
| Paroxysmal nocturnal hemoglobinuria (PNH) |
Genetic: Mutations in the X‐linked phosphatidylinositol glycan class A (PIG‐A) gene on some hematopoietic stem cell clones reduces membrane expression the C3bBb regulator CD55 and the C9 regulator CD59 135 Functional: Erythrocytes from conditional PIG‐A−/− mice show sensitivity to complement attack, 136 , 137 PNH patient erythrocytes are susceptible to complement lysis 138 Pharmacological: Clinical efficacy of eculizumab 139 and ravulizumab 140 in PNH |
Danicopan Vemircopan BCX9930 Iptacopan |
| Atypical hemolytic uremic syndrome (aHUS) |
Genetic: Surface dysregulation of the AP by diverse genetic or acquired mechanisms in 26–62% or patients 12 Functional: Mice with hyperfunctional C3 or aHUS‐related factor H mutation show aHUS‐like disease 141 , 142 Pharmacological: Clinical efficacy of eculizumab 143 and ravulizumab 144 |
Iptacopan |
| Age‐related macular degeneration (AMD) and secondary geographic atrophy (GA) |
Genetic: Polymorphisms in factor H (e.g., Y402H), C3 or FB/C2 145 Functional: Cfh−/− mice show disturbed retinal morphology and blood supply, 146 , 147 Pharmacological: Systemic eculizumab did not show clinical benefit in AMD patients 148 |
Danicopan Iptacopan |
|
C3 glomerulopathy (C3G) |
Genetic: Mutations in factor H (similar to aHUS 149 ) or factor H related proteins 150 ; or autoantibodies against factor H, or C3 stabilizing antibodies (nephritic factors, C3nef) 151 Clinical: Glomerular C3 staining and glomerular/sub‐endothelial electron‐dense deposits. Low plasma C3 levels common Functional: Cfh−/− mice 116 and humanized C3 mice lacking C3 regulation by (murine factors 152 ) show C3G‐like disease Pharmacological: Case report for efficacy of eculizumab in C3G 153 , 154 |
Danicopan BCX9930 Iptacopan |
| ||
| IgA nephropathy |
Pathophysiology: Immune complexes of galactose‐deficient (Gd‐)IgA1 and autoantibodies in urine 155 or blood. 156 Deficiency in FHR1 and FHR3 protects 157 , 158 Clinical: Mesangial IgA/C3 deposits 159 ; mesangial C3 deposition, 160 MBL deposition 30 or rare C1q deposition 161 correlates with severity; IgA can activate alternative 27 or lectin 30 pathway Functional: C5a−/− or C3a−/− are protected in a mouse model of IgAN 162 Pharmacological: Case report for partial efficacy of eculizumab 163 |
Vemircopan BCX9930 Iptacopan |
| Lupus nephritis |
Pathophysiology: Multifactorial. Genetic variants of factor H are associated with lupus 164 Clinical: C3 deposition in the kidney without C1q/C4 deposits had worse outcomes in patients, 165 serum factor H levels correlate negatively with disease score/SLEDAI 166 Functional: Factor B‐or Factor D‐deficient MRL/lpr mice are protected, 117 , 120 factor H‐deficient MRL/lpr mice show faster disease progression 167 Antisense oligonucleotides targeting FB improve lupus nephritis in MRL/lpr and NZB/W mice 168 Pharmacological: Case report for efficacy of eculizumab 169 |
Vemircopan Iptacopan |
| Cold agglutinin disease (CAD) |
Pathophysiology: Clonal proliferative disorder of B cells producing cold agglutinin (erythrocyte anti‐I antigen IgM). No known genetic link. Clinical: Monospecific direct antiglobulin test detects C3d on surface of erythrocytes. 170 Alternative pathway as amplification loop. Pharmacological: Clinical efficacy of sutimlimab (anti‐C1s, 171 ) modest efficacy of eculizumab 172 |
Iptacopan |
| (Primary) immune Thrombocytopenia/ (Idiopathic) immune thromboctopenic purpura (ITP) |
Pathophysiology: Autoantibodies against platelet surface glycoproteins. No known genetic link. Clinical: Patients with ITP activate the classical complement pathway (CP) and/or fix complement on platelet surfaces. 173 , 174 Alternative pathway as amplification loop. Pharmacological: Clinical efficacy of sutimlimab (anti‐C1s 175 ) |
Iptacopan |
| Idiopathic/primary membranous nephropathy (iMN) |
Pathophysiology: Associated with anti‐phospholipase A2 receptor antibodies, which bind to the corresponding antigens on podocytes to form immune complexes. Not a genetic disease. Functional: Cfb−/− mice are protected from proteinuria induced by α3NC1 immunization, 176 LNP023 protects in rat passive Heymann nephritis 9 |
BCX9930 Iptacopan |