##common.pageHeaderLogo.altText##

Original article

Vol. 155 No. 6 (2025)

Successful targeting of the alternative complement cascade with iptacopan for the treatment of IgA nephropathy: a case report

Cite this as:
Swiss Med Wkly. 2025;155:4435
Published
30.06.2025

Summary

INTRODUCTION: Currently, approved disease-specific therapies for patients with immunoglobulin (Ig) A nephropathy in Switzerland are scarce. According to the 2024 KDIGO guidelines, current treatments focus on reducing proteinuria and nephron loss using nephroprotective regimens consisting of renin-angiotensin system blockade, the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and the dual endothelin angiotensin receptor antagonist sparsentan. Systemic glucocorticoids and a targeted-release formulation of budesonide are other therapeutic options to reduce IgA nephropathy-specific drivers of nephron loss. However, their use has been associated with adverse effects, even with targeted-release budesonide, and the benefit of these therapies remains to be weighed against the risk of treatment-emergent toxicity. This highlights the ongoing need to identify more effective and safer therapies for the treatment of IgA nephropathy. In the last few years, increasing understanding of the pathogenetic role of alternative complement pathway dysregulation in the onset and progression of IgA nephropathy has led to the development of new complement-targeting therapies. Iptacopan is an oral inhibitor of complement factor B that effectively blocks the alternative complement pathway.

CASE PRESENTATION: We report the successful treatment of a 40-year-old female patient suffering from IgA nephropathy with iptacopan. In this patient, despite maximum tolerated renin-angiotensin system blockade and fully dosed SGLT-2 inhibitor administration, we failed to achieve the desired reduction in proteinuria to <0.5 g/day. Proteinuria persisted at a level of >1 g/day despite the goal of blood pressure ≤120/70 mm Hg being achieved. Impressively, within just two months after the initiation of iptacopan, we noted a reduction in proteinuria to 0.5 g/day, and after nearly six months, we reached our goal, with proteinuria at <0.3 g/day, a value continuing to the present day. Further, the medication was well-tolerated.

CONCLUSION: To the best of our knowledge, our case report is the first in Switzerland to show that selective inhibition of the alternative complement pathway in IgA nephropathy results in significant and ongoing reduction of proteinuria after six months of therapy, supporting the innovative concept of targeting the alternative complement pathway with iptacopan to treat IgA nephropathy.

References

  1. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011 Feb;26(2):414–30. doi: https://doi.org/10.1093/ndt/gfq665
  2. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013 Jun;368(25):2402–14. doi: https://doi.org/10.1056/NEJMra1206793
  3. Pitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023 Jun;18(6):727–38. doi: https://doi.org/10.2215/CJN.0000000000000135
  4. Reich HN, Troyanov S, Scholey JW, Cattran DC; for the Toronto Glomerulonephritis Registry. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007 Dec;18(12):3177–83. doi: https://doi.org/10.1681/ASN.2007050526
  5. Suzuki H, Kikuchi M, Koike K, Komatsu H, Matsuzaki K, Takahashi K, et al.; Committee of Clinical Practical Guideline for IgA Nephropathy 2020. A digest from evidence-based clinical practice guideline for IgA nephropathy 2020. Clin Exp Nephrol. 2021 Dec;25(12):1269–76. doi: https://doi.org/10.1007/s10157-021-02095-8
  6. Zhang H, Barratt J. Is IgA nephropathy the same disease in different parts of the world? Semin Immunopathol. 2021 Oct;43(5):707–15. doi: https://doi.org/10.1007/s00281-021-00884-7
  7. Heerspink HJ, Radhakrishnan J, Alpers CE, Barratt J, Bieler S, Diva U, et al.; PROTECT Investigators. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023 May;401(10388):1584–94. doi: https://doi.org/10.1016/S0140-6736(23)00569-X
  8. Rovin BH, Barratt J, Heerspink HJ, Alpers CE, Bieler S, Chae DW, et al.; DUPRO steering committee and PROTECT Investigators. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet. 2023 Dec;402(10417):2077–90. doi: https://doi.org/10.1016/S0140-6736(23)02302-4
  9. Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4):753–79. doi: https://doi.org/10.1016/j.kint.2021.05.015
  10. Barratt J, Lafayette R, Kristensen J, Stone A, Cattran D, Floege J, et al.; NefIgArd Trial Investigators. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int. 2023 Feb;103(2):391–402. doi: https://doi.org/10.1016/j.kint.2022.09.017
  11. Lafayette R, Kristensen J, Stone A, Floege J, Tesař V, Trimarchi H, et al.; NefIgArd trial investigators. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet. 2023 Sep;402(10405):859–70. doi: https://doi.org/10.1016/S0140-6736(23)01554-4
  12. Cheung CK, Alexander S, Reich HN, Selvaskandan H, Zhang H, Barratt J. The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol. 2025 Jan;21(1):9–23. doi: https://doi.org/10.1038/s41581-024-00885-3
  13. Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, et al. Current Understanding of the Role of Complement in IgA Nephropathy. J Am Soc Nephrol. 2015 Jul;26(7):1503–12. doi: https://doi.org/10.1681/ASN.2014101000
  14. Rizk DV, Maillard N, Julian BA, Knoppova B, Green TJ, Novak J, et al. The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy. Front Immunol. 2019 Mar;10:504. doi: https://doi.org/10.3389/fimmu.2019.00504
  15. Kohan DE, Barratt J, Heerspink HJ, Campbell KN, Camargo M, Ogbaa I, et al. Targeting the Endothelin A Receptor in IgA Nephropathy. Kidney Int Rep. 2023 Aug;8(11):2198–210. doi: https://doi.org/10.1016/j.ekir.2023.07.023
  16. Caster DJ, Lafayette RA. The Treatment of Primary IgA Nephropathy: Change, Change, Change. Am J Kidney Dis. 2024 Feb;83(2):229–40. doi: https://doi.org/10.1053/j.ajkd.2023.08.007
  17. Schubart A, Anderson K, Mainolfi N, Sellner H, Ehara T, Adams CM, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA. 2019 Apr;116(16):7926–31. doi: https://doi.org/10.1073/pnas.1820892116
  18. Risitano AM, Röth A, Soret J, Frieri C, de Fontbrune FS, Marano L, et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021 May;8(5):e344–54. doi: https://doi.org/10.1016/S2352-3026(21)00028-4
  19. Jang JH, Wong L, Ko BS, Yoon SS, Li K, Baltcheva I, et al. Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Blood Adv. 2022 Aug;6(15):4450–60. doi: https://doi.org/10.1182/bloodadvances.2022006960
  20. Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar;390(11):994–1008. doi: https://doi.org/10.1056/NEJMoa2308695
  21. Wong E, Nester C, Cavero T, Karras A, Le Quintrec M, Lightstone L, et al. Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. Kidney Int Rep. 2023 Sep;8(12):2754–64. doi: https://doi.org/10.1016/j.ekir.2023.09.017
  22. Bomback AS, Kavanagh D, Vivarelli M, Meier M, Wang Y, Webb NJ, et al. Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial. Kidney Int Rep. 2022 Aug;7(10):2150–9. doi: https://doi.org/10.1016/j.ekir.2022.07.004
  23. Kavanagh D, Greenbaum LA, Bagga A, Karki RG, Chen CW, Vasudevan S, et al. Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome. Kidney Int Rep. 2023 Apr;8(7):1332–41. doi: https://doi.org/10.1016/j.ekir.2023.04.029
  24. Zhang H, Rizk DV, Perkovic V, Maes B, Kashihara N, Rovin B, et al. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Kidney Int. 2024 Jan;105(1):189–99. doi: https://doi.org/10.1016/j.kint.2023.09.027
  25. Perkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, et al.; APPLAUSE-IgAN Investigators. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. N Engl J Med. 2025 Feb;392(6):531–43. doi: https://doi.org/10.1056/NEJMoa2410316
  26. Berger J, Hinglais N. [Intercapillary deposits of IgA-IgG]. J Urol Nephrol (Paris). 1968 Sep;74(9):694–5.
  27. Duval A, Caillard S, Frémeaux-Bacchi V. The complement system in IgAN: mechanistic context for therapeutic opportunities. Nephrol Dial Transplant. 2023 Nov;38(12):2685–93. doi: https://doi.org/10.1093/ndt/gfad140
  28. Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestecky J, et al. The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy. Front Immunol. 2016 Apr;7:117. doi: https://doi.org/10.3389/fimmu.2016.00117
  29. Gesualdo L, Di Leo V, Coppo R. The mucosal immune system and IgA nephropathy. Semin Immunopathol. 2021 Oct;43(5):657–68. doi: https://doi.org/10.1007/s00281-021-00871-y
  30. Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int. 2012 May;81(9):833–43. doi: https://doi.org/10.1038/ki.2011.501
  31. Matsumoto Y, Aryal RP, Heimburg-Molinaro J, Park SS, Wever WJ, Lehoux S, et al. Identification and characterization of circulating immune complexes in IgA nephropathy. Sci Adv. 2022 Oct;8(43):eabm8783. doi: https://doi.org/10.1126/sciadv.abm8783
  32. Evans DJ, Williams DG, Peters DK, Sissons JG, Boulton-Jones JM, Ogg CS, et al. Glomerular deposition of properdin in Henoch-Schönlein syndrome and idiopathic focal nephritis. BMJ. 1973 Aug;3(5875):326–8. doi: https://doi.org/10.1136/bmj.3.5875.326
  33. Poppelaars F, Faria B, Schwaeble W, Daha MR. The Contribution of Complement to the Pathogenesis of IgA Nephropathy: Are Complement-Targeted Therapies Moving from Rare Disorders to More Common Diseases? J Clin Med. 2021 Oct;10(20):4715. doi: https://doi.org/10.3390/jcm10204715
  34. Caravaca-Fontán F, Gutiérrez E, Sevillano AM, Praga M. Targeting complement in IgA nephropathy. Clin Kidney J. 2023 Dec;16 Suppl 2:ii28–39. doi: https://doi.org/10.1093/ckj/sfad198
  35. Schmitt R, Ståhl AL, Olin AI, Kristoffersson AC, Rebetz J, Novak J, et al. The combined role of galactose-deficient IgA1 and streptococcal IgA-binding M Protein in inducing IL-6 and C3 secretion from human mesangial cells: implications for IgA nephropathy. J Immunol. 2014 Jul;193(1):317–26. doi: https://doi.org/10.4049/jimmunol.1302249
  36. Chiu YL, Lin WC, Shu KH, Fang YW, Chang FC, Chou YH, et al. Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients. Front Immunol. 2021 Jun;12:638309. doi: https://doi.org/10.3389/fimmu.2021.638309
  37. Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006 Jun;17(6):1724–34. doi: https://doi.org/10.1681/ASN.2005090923
  38. Barratt J, Lafayette RA, Zhang H, Tesar V, Rovin BH, Tumlin JA, et al. IgA nephropathy: the lectin pathway and implications for targeted therapy. Kidney Int. 2023 Aug;104(2):254–64. doi: https://doi.org/10.1016/j.kint.2023.04.029
  39. Suzuki K, Honda K, Tanabe K, Toma H, Nihei H, Yamaguchi Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003 Jun;63(6):2286–94. doi: https://doi.org/10.1046/j.1523-1755.63.6s.2.x
  40. Zwirner J, Burg M, Schulze M, Brunkhorst R, Götze O, Koch KM, et al. Activated complement C3: a potentially novel predictor of progressive IgA nephropathy. Kidney Int. 1997 Apr;51(4):1257–64. doi: https://doi.org/10.1038/ki.1997.171
  41. Janssen U, Bahlmann F, Köhl J, Zwirner J, Haubitz M, Floege J. Activation of the acute phase response and complement C3 in patients with IgA nephropathy. Am J Kidney Dis. 2000 Jan;35(1):21–8. doi: https://doi.org/10.1016/S0272-6386(00)70296-4
  42. Mizerska-Wasiak M, Małdyk J, Rybi-Szumińska A, Wasilewska A, Miklaszewska M, Pietrzyk J, et al. Relationship between serum IgA/C3 ratio and severity of histological lesions using the Oxford classification in children with IgA nephropathy. Pediatr Nephrol. 2015 Jul;30(7):1113–20. doi: https://doi.org/10.1007/s00467-014-3024-z
  43. Kawasaki Y, Maeda R, Ohara S, Suyama K, Hosoya M. Serum IgA/C3 and glomerular C3 staining predict severity of IgA nephropathy. Pediatr Int. 2018 Feb;60(2):162–7. doi: https://doi.org/10.1111/ped.13461
  44. Ispasanie E, Muri L, Schubart A, Thorburn C, Zamurovic N, Holbro T, et al. Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals. Front Immunol. 2021 Oct;12:747594. doi: https://doi.org/10.3389/fimmu.2021.747594
  45. Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, et al. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar;384(11):1028–37. doi: https://doi.org/10.1056/NEJMoa2029073
  46. Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol. 2009 Feb;20(2):289–98. doi: https://doi.org/10.1681/ASN.2008050497
  47. Jayne DR, Merkel PA, Bekker P. Avacopan for the Treatment of ANCA-Associated Vasculitis. Reply [Reply]. N Engl J Med. 2021 May;384(21):e81.
  48. Liu L, Zhang Y, Duan X, Peng Q, Liu Q, Zhou Y, et al. C3a, C5a renal expression and their receptors are correlated to severity of IgA nephropathy. J Clin Immunol. 2014 Feb;34(2):224–32. doi: https://doi.org/10.1007/s10875-013-9970-6
  49. Zhang Y, Yan X, Zhao T, Xu Q, Peng Q, Hu R, et al. Targeting C3a/C5a receptors inhibits human mesangial cell proliferation and alleviates immunoglobulin A nephropathy in mice. Clin Exp Immunol. 2017 Jul;189(1):60–70. doi: https://doi.org/10.1111/cei.12961
  50. Bruchfeld A, Magin H, Nachman P, Parikh S, Lafayette R, Potarca A, et al. C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study. Clin Kidney J. 2022 Jan;15(5):922–8. doi: https://doi.org/10.1093/ckj/sfab294
  51. Kohan DE, Barton M. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. 2014 Nov;86(5):896–904. doi: https://doi.org/10.1038/ki.2014.143
  52. Smeijer JD, Kohan DE, Webb DJ, Dhaun N, Heerspink HJ. Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease. Curr Opin Nephrol Hypertens. 2021 Jul;30(4):456–65. doi: https://doi.org/10.1097/MNH.0000000000000716
  53. Heerspink HJ, Kohan DE, de Zeeuw D. New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction. Kidney Int. 2021 Feb;99(2):346–9. doi: https://doi.org/10.1016/j.kint.2020.09.026
  54. Kowala MC, Murugesan N, Tellew J, Carlson K, Monshizadegan H, Ryan C, et al. Novel dual action AT1 and ETA receptor antagonists reduce blood pressure in experimental hypertension. J Pharmacol Exp Ther. 2004 Apr;309(1):275–84. doi: https://doi.org/10.1124/jpet.103.055855
  55. Heerspink HJ, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, et al.; ALIGN Study Investigators. Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025 Feb;392(6):544–54. doi: https://doi.org/10.1056/NEJMoa2409415
  56. Gutiérrez E, Carvaca-Fontán F, Luzardo L, Morales E, Alonso M, Praga M. A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges. Nephron J. 2020;144(11):555–71. doi: https://doi.org/10.1159/000509997
  57. Knoppova B, Reily C, King RG, Julian BA, Novak J, Green TJ. Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment. J Clin Med. 2021 Sep;10(19):4501. doi: https://doi.org/10.3390/jcm10194501
  58. Fenoglio R, Sciascia S, Naretto C, De Simone E, Del Vecchio G, Ferro M, et al. Rituximab in severe immunoglobulin-A vasculitis (Henoch-Schonlein) with aggressive nephritis. Clin Exp Rheumatol. 2020;38 Suppl 124(2):195-200.
  59. Lafayette RA, Canetta PA, Rovin BH, Appel GB, Novak J, Nath KA, et al. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction. J Am Soc Nephrol. 2017 Apr;28(4):1306–13. doi: https://doi.org/10.1681/ASN.2016060640
  60. Barratt J, Tumlin J, Suzuki Y, Kao A, Aydemir A, Pudota K, et al.; JANUS study investigators. Randomized Phase II JANUS Study of Atacicept in Patients With IgA Nephropathy and Persistent Proteinuria. Kidney Int Rep. 2022 May;7(8):1831–41. doi: https://doi.org/10.1016/j.ekir.2022.05.017
  61. Lafayette R, Barbour S, Israni R, Wei X, Eren N, Floege J, et al. A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy. Kidney Int. 2024 Jun;105(6):1306–15. doi: https://doi.org/10.1016/j.kint.2024.03.012
  62. Barratt J, Barbour SJ, Brenner RM, Cooper K, Wei X, Eren N, et al.; ORIGIN Phase 2b Investigators. Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy. J Am Soc Nephrol. 2025 Apr;36(4):679–87. doi: https://doi.org/10.1681/ASN.0000000541