The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview
Abstract
:1. Introduction
2. Inhibition of Excessive Mucosal Immune Response
2.1. Budesonide
2.2. Prebiotics and Probiotics
2.3. Rifaximin
3. Inhibition of B Cell-Activating Factor (BAFF) and a Proliferation-Inducing Ligand (APRIL) Pathways
3.1. VIS649 (Sibeprenlimab)
3.2. BION-1301
3.3. Atacicept
3.4. Blisibimod
3.5. Rituximab
4. Inhibition of Complement Activation
4.1. Narsoplimab (OMS721)
4.2. Iptacopan (LNP023)
4.3. Pegcetacoplan (APL-2)
4.4. Eculizumab
4.5. Avacopan (CCX168)
4.6. Ravulizumab
4.7. Cemdisiran (ALN-CC5)
5. Inhibition of Kidney Damage and Fibrosis
5.1. Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists
5.2. Aliskiren
5.3. Sparsentan
5.4. Atrasentan
6. Other Drugs
6.1. Hydroxychloroquine (HCQ)
6.2. Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Drug | Site of Action | Clinical Research Trial/Study on Mouse Models of IgAN | Possible Outcomes | Possible Adverse Effects (AE) |
---|---|---|---|---|
Inhibition of Excessive Mucosal Immune Response | ||||
TRF Budesonide | Peyer’s patches in the distal ileum | Randomized, double-blind, placebo-controlled study Phase III clinical trial (NefIgArd) NCT03643965 Active, not recruiting | Reduction in UPCR and GFR preservation | Hypertension, peripheral oedema, muscle spasms, and acne [23] |
Prebiotics and probiotics | Inhibition of NLRP3/ASC/ Caspase 1 signaling pathway [32] | 35 patients with IgAN and C57BL/6 mice | Alleviation of gut dysbiosis and attenuation of IgAN clinicopathological manifestations | |
Rifaximin | Inhibition of microbe-induced immune response and has a direct anti-inflammatory property through binding to the pregnane X receptor (PXR) and modulating gut microbiota [37] | α1KI-CD89Tg mice | Reduction in UPCR, serum levels of hIgA1–sCD89 and mIgG–hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration | Nausea, stomach pain, dizziness, tiredness, headache, and joint pain |
Inhibition of BAFF and APRIL Pathways | ||||
VIS649 (Sibeprenlimab) | Humanized IgG2 monoclonal antibody that inhibits APRIL | Multicenter, randomized, double-blind, placebo-controlled study Phase III trial (Visionary Study) NCT05248646 [83] Recruiting | Reduction in serum APRIL, IgA, Gd-IgA1, IgG, and IgM | No serious Aes or Aes leading to study discontinuation |
BION-1301 | Novel humanized blocking antibody targeting APRIL | Part 1: randomized, placebo-controlled single ascending dose design in healthy volunteers; Part 2: randomized, placebo-controlled, multiple ascending dose design in HVs; Part 3 (MD-IgAN): open-label multiple dose design in subjects with IgAN NCT03945318 Active, not recruiting | Reduction in serum levels of APRIL, of immunoglobulins, and in proteinuria | Well-tolerated with no serious adverse events |
Atacicept | Inhibits BlyS and APRIL [50] | Phase Iib randomized, double-blind, placebo-controlled, dose-ranging study (ORIGIN 3) NCT04716231 Recruiting | Reduction in IgA, IgG, IgM, and Gd-IgA in proteinuria | Aes of special interest included cardiac failure, ischemic heart disease, cardiac arrhythmia, infections, hypersensitivity reactions, and injection-site reactions |
Blisibimod | Inhibits both soluble and membrane BAFF | Randomized, double-blind, placebo-controlled Phase 2/3 study (BRIGHT-SC) NCT02062684 Completed | Reduction in level of peripheral B cells, immunoglobulins, and UPCR | Upper respiratory tract infection, urinary tract infection, injection site erythema/reaction, and diarrhea |
Rituximab | Anti-CD20 monoclonal antibody | Multicenter, randomized, prospective, open-label trial NCT00498368 Completed | Changes in proteinuria levels | Fever; cold symptoms, such as runny nose or sore throat; flu symptoms, such as cough, tiredness, and body aches; headache; and cold sores in the mouth or throat |
Inhibition of Complement Activation | ||||
Narsoplimab (OMS721) | Anti-mannan-associated lectin-binding serine protease-2 (MASP-2) | Randomized, double-blind, placebo-controlled Phase 3 study (ARTEMIS-IGAN) NCT03608033 Recruiting | Change from baseline in UPE and proteinuria reduction, rate of change in GFR, and safety and tolerability | Headache, upper respiratory infection, and fatigue |
Iptacopan (LNP023) | Inhibits factor B inhibitor of the alternative complement pathway | Randomized, double-blind, dose-ranging, parallel-group Phase 3 study (APPLAUSE-IgAN) NCT03373461 Completed | Reduction in UPCR | Headache, abdominal discomfort, blood alkaline phosphatase increase, cough, oropharyngeal pain, pyrexia, and upper respiratory infection |
Pegcetacoplan (APL-2) | Inhibits C3 protein | Phase 2 study NCT03453619 Active, not recruiting | Proteinuria reduction changes in disease-specific biomarkers (serum C3 levels, AH50 and C3a concentrations, and serum albumin levels) Stabilization or improvement in estimated GFR | No serious or severe AE were reported; stomach pain, vomiting, diarrhea, cold sores, cold symptoms, and tiredness |
Eculizumab | Inhibits C5 convertase | Case reports [61,62,63] | Temporary stabilization, but not improvement, of GFR | No AEs were described in the cited case reports |
Avacopan (CCX168) | Selective C5a receptor inhibitor | Open-label pilot study [84] | Improvement in UPCR | One serious AE of unstable angina, which was deemed to be unrelated to avacopan |
Ravulizumab | Monoclonal antibody against C5 | Phase 2, double-blind, randomized, placebo-controlled study (SANCTUARY) NCT04564339 Recruiting | Reduction in UPCR and improvement in GFR | Upper respiratory tract infection, diarrhea, nausea, vomiting, headache, high blood pressure, and fever |
Cemdisiran (ALN-CC5) | Suppresses liver production of C5 protein | Phase 2, randomized, double-blind, placebo-controlled study NCT03841448 Active, not recruiting | Reduction in UPCR | No serious or severe AEs |
Inhibition of Kidney Damage and Fibrosis | ||||
Aliskiren | Direct renin inhibitor | Randomized crossover study NCT00870493 Completed | Anti-proteinuric effect [66] | Hyperkalemia |
Sparsentan | Selective antagonist of angiotensin II receptor and endothelin A receptor | Randomized, multicenter, double-blind, parallel-group, active-controlled study (PROTECT) NCT03762850 [67] Active, not recruiting | Reduction in proteinuria | Well-tolerated with a clearly defined safety profile |
Atrasentan | Antagonist of endothelin A receptor | Phase 3, randomized, double-blind, placebo-controlled study (ALIGN) NCT04573478 Active, not recruiting Phase 2, open-label, basket study (AFFINITY) NCT04573920 Recruiting | Effect on proteinuria | Increase in weight and a reduction in hemoglobin [85] |
Other drugs | ||||
Hydroxychloroquine (HCQ) | Inhibits mucosal and intrarenal toll-like receptor signaling | Randomized, double-blind, placebo-controlled study NCT02942381 Completed | Reduction in proteinuria and GFR preservation | HCQ was well-tolerated, and no serious AEs were recorded [71] |
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) | Modulation of inflammatory and profibrotic mediators and regulation of toxic intracellular compounds (i.e., advanced glycation end products) | International, multicenter, event-driven, randomized, double-blind, parallel group, placebo-controlled study (Dapa-CKD) NCT03036150 Completed Multicenter international randomized parallel-froup double-blind placebo-controlled clinical trial (EMPA-KIDNEY) NCT03594110 Active, not recruiting | Preservation of GFR Reduction in end-stage kidney disease, in death from renal causes, in death from cardiovascular causes, or inhospitalization for heart failure | Genital infections Changes in urination, including urgent need to urinate more often, in larger amounts, or at night [79] |
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Di Leo, V.; Annese, F.; Papadia, F.; Cara, I.; Giliberti, M.; Sallustio, F.; Gesualdo, L. The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview. Future Pharmacol. 2023, 3, 517-534. https://doi.org/10.3390/futurepharmacol3020033
Di Leo V, Annese F, Papadia F, Cara I, Giliberti M, Sallustio F, Gesualdo L. The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview. Future Pharmacology. 2023; 3(2):517-534. https://doi.org/10.3390/futurepharmacol3020033
Chicago/Turabian StyleDi Leo, Vincenzo, Francesca Annese, Federica Papadia, Iris Cara, Marica Giliberti, Fabio Sallustio, and Loreto Gesualdo. 2023. "The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview" Future Pharmacology 3, no. 2: 517-534. https://doi.org/10.3390/futurepharmacol3020033
APA StyleDi Leo, V., Annese, F., Papadia, F., Cara, I., Giliberti, M., Sallustio, F., & Gesualdo, L. (2023). The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview. Future Pharmacology, 3(2), 517-534. https://doi.org/10.3390/futurepharmacol3020033