C3 Glomerulopathy: Novel Treatment Paradigms
2023; Elsevier BV; Volume: 9; Issue: 3 Linguagem: Inglês
10.1016/j.ekir.2023.12.007
ISSN2468-0249
AutoresBlanca Tarragon Estebanez, Andrew S. Bomback,
Tópico(s)Phagocytosis and Immune Regulation
ResumoC3 glomerulopathy (C3G) is diagnosed by kidney biopsy, with immunofluorescence showing isolated or dominant C3 staining, indicating hyperactivity of the alternative complement pathway as the key driver of glomerular injury. Therefore, the lesion is defined by its complement-mediated pathogenesis as much as its histological pattern. As a bevy of complement-targeting agents are moving through development and clinical trials, we review the evolution in treatment paradigms for C3G. Here we survey the limited efficacy of noncomplement targeting therapy before focusing on the work being done on targeting various components of the complement cascade in aiming to provide disease-specific therapy. C3 glomerulopathy (C3G) is diagnosed by kidney biopsy, with immunofluorescence showing isolated or dominant C3 staining, indicating hyperactivity of the alternative complement pathway as the key driver of glomerular injury. Therefore, the lesion is defined by its complement-mediated pathogenesis as much as its histological pattern. As a bevy of complement-targeting agents are moving through development and clinical trials, we review the evolution in treatment paradigms for C3G. Here we survey the limited efficacy of noncomplement targeting therapy before focusing on the work being done on targeting various components of the complement cascade in aiming to provide disease-specific therapy. C3G encompasses dense deposit disease and C3 glomerulonephritis, and is defined by its complement-mediated pathogenesis as much as its histological pattern. C3G results from a dysregulation in the alternative pathway (AP) of the complement system (Figure 1), which leads to the deposition of C3 fragments in the glomeruli, with trace or no presence of immunoglobulins.1Fakhouri F. Frémeaux-Bacchi V. Noël L.H. Cook H.T. Pickering M.C. C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499https://doi.org/10.1038/NRNEPH.2010.85Crossref PubMed Scopus (0) Google Scholar,2Pickering M.C. D'agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089https://doi.org/10.1038/ki.2013.377Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar Genetic or acquired abnormalities in 1 or more of the multiple components of the AP can lead to C3G.3Smith R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy-understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143https://doi.org/10.1038/s41581-018-0107-2Crossref PubMed Scopus (193) Google Scholar The clinical course includes proteinuria, hematuria, and progressive chronic kidney disease, with most patients reaching end-stage kidney disease within 2 decades of diagnosis.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 6Medjeral-Thomas N.R. O'Shaughnessy M.M. O'Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53https://doi.org/10.2215/CJN.04700513Crossref PubMed Scopus (172) Google Scholar Current standard-of-care for C3G includes supportive measures for patients with mild disease and immunosuppression with mycophenolate mofetil (MMF) plus glucocorticoids for those with moderate to severe disease (>0.5–1 g/d of proteinuria, declining kidney function).7Rovin B.H. Adler S.G. Barratt J. et al.KDIGO 2021 clinical practice guideline for the management of glomerular diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,8Goodship T.H.J. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551https://doi.org/10.1016/j.kint.2016.10.005Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar However, these nonspecific treatment approaches seem to have limited benefits among patients with C3G,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,6Medjeral-Thomas N.R. O'Shaughnessy M.M. O'Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53https://doi.org/10.2215/CJN.04700513Crossref PubMed Scopus (172) Google Scholar,9Caravaca-Fontán F. Díaz-Encarnación M.M. Lucientes L. et al.Mycophenolate mofetil in c3 glomerulopathy and pathogenic drivers of the disease.Clin J Am Soc Nephrol. 2020; 15: 1287-1298https://doi.org/10.2215/CJN.15241219Crossref PubMed Scopus (29) Google Scholar,10Caliskan Y. Torun E.S. Tiryaki T.O. et al.Immunosuppressive treatment in C3 glomerulopathy: is it really effective?.Am J Nephrol. 2017; 46: 96-107https://doi.org/10.1159/000479012Crossref PubMed Scopus (33) Google Scholar and complement blockade is expected to be the best strategy to explore in this population. To date, no complement inhibitor is approved for C3G, although eculizumab, a terminal complement blocker, is included in some clinical guidelines as a backup agent for patients with progressive disease who fail to respond to other therapies.7Rovin B.H. Adler S.G. Barratt J. et al.KDIGO 2021 clinical practice guideline for the management of glomerular diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,8Goodship T.H.J. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551https://doi.org/10.1016/j.kint.2016.10.005Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar There are multiple reasons for the lack of an established optimal treatment for C3G. First, it is a rare entity, and often affecting pediatric population, making it difficult to carry out large randomized controlled trials; therefore, most evidence is based on retrospective analyses, case series, and observational studies. Second, the tests required to characterize genetic variants, complement functionality and complement-directed autoantibodies are costly and not generally available outside of the research setting. Lastly, comparing and interpreting these results is not straightforward because it also is a rather heterogenous disease in many aspects. In terms of disease drivers, abnormalities in complement genes are found in only 13% to 25% of patients, and the frequency of complement-targeting autoantibodies such as C3 nephritic factor (C3Nef) varies widely between populations, from 20% to 80%.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,11Iatropoulos P. Noris M. Mele C. et al.Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.Mol Immunol. 2016; 71: 131-142https://doi.org/10.1016/J.MOLIMM.2016.01.010Crossref PubMed Scopus (0) Google Scholar Clinical presentation classically includes low C3 levels; however, this is not true for about 30% to 50% of patients.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,12Iatropoulos P. Daina E. Curreri M. et al.Cluster analysis identifies distinct pathogenetic patterns in c3 glomerulopathies/immune complex-mediated membranoproliferative GN.J Am Soc Nephrol. 2018; 29: 283-294https://doi.org/10.1681/ASN.2017030258Crossref PubMed Scopus (81) Google Scholar Histopathological definition has evolved, and earlier publications included patients with a membranoproliferative glomerulonephritis (MPGN); whereas now, other patterns of injury such as mesangial or endocapillary proliferative glomerulonephritis are recognized as C3G as well. Furthermore, many of the cited publications and ongoing clinical trials combine patients with C3G and immune complex-mediated MPGN (IC-MPGN) because the distinction between the 2 is questionable.13Fakhouri F. Le Quintrec M. Frémeaux-Bacchi V. Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties.Kidney Int. 2020; 98: 1135-1148https://doi.org/10.1016/j.kint.2020.05.053Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Although the difference is based on the hypothesis that IC-MPGN results from classical complement pathway activation by deposited IC, many authors have reported a substantial involvement of the AP as seen by abnormalities in AP genes, autoantibodies, and biomarkers in serum and tissue.5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,14Noris M. Daina E. Remuzzi G. Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment.Nephrol Dial Transplant. 2023; 38: 283-290https://doi.org/10.1093/ndt/gfab281Crossref PubMed Scopus (10) Google Scholar, 15Vivarelli M. van de Kar N. Labbadia R. Diomedi-Camassei F. Thurman J.M. A clinical approach to children with C3 glomerulopathy.Pediatr Nephrol. 2022; 37: 521-535https://doi.org/10.1007/S00467-021-05088-7/TABLES/2Crossref PubMed Scopus (0) Google Scholar, 16Singh G. Singh S.K. Nalwa A. et al.Glomerular C4d staining does not exclude a C3 glomerulopathy.Kidney Int Rep. 2019; 4: 698-709https://doi.org/10.1016/J.EKIR.2019.02.006Abstract Full Text Full Text PDF PubMed Google Scholar Shifts from a diagnosis from IC-MPGN to C3G in repeat biopsies also support the idea that these 2 entities could be part of the same disease spectrum.15Vivarelli M. van de Kar N. Labbadia R. Diomedi-Camassei F. Thurman J.M. A clinical approach to children with C3 glomerulopathy.Pediatr Nephrol. 2022; 37: 521-535https://doi.org/10.1007/S00467-021-05088-7/TABLES/2Crossref PubMed Scopus (0) Google Scholar,17Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456https://doi.org/10.1038/ki.2013.340Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Despite these difficulties, there are multiple emerging therapies that have made their way into clinical trials for patients with C3G, all of them directed at the complement system at various levels (Table 1). In this review, we aim to present the current outlook for novel treatments of C3G.Table 1Clinical trials of complement inhibitors in C3 glomerulopathyTarget in complement cascadeMechanism of actionDrugType of inhibitorMode of administrationPharmaceutical companyClinical trial phaseIdentificationStatusPotential indication in kidney diseasesC3inhibition of the binding of C3 to C3bBb and thus of the cleavage of C3PegcetacoplanPegylated peptides.c.ApellisPhase 2 (n = 21)NCT03453619 (DISCOVERY)active, not recruitingIgAN, LN, C3G, MN, DDDPhase 2 (n = 12)NCT04572854 (NOBLE)recruitingPosttransplant recurrent C3 and IC-MPGNPhase 3 (n = 90)NCT05067127 (VALIANT)recruitingC3G, IC-MPGNPhase 3 (n = 100)NCT05809531 (VALE)not yet recruitingC3G, IC-MPGNreduction of production of C3ARO-C3RNAis.c.ArrowheadPhase 1/2a (n = 60)NCT05083364recruitingC3G, IgANFactor Binhibition of serine protease FB and thus of the cleavage of C3 and C5Iptacopan (LNP023)smallmoleculeOralNovartisPhase 2 (n = 27)NCT03832114completedC3G (native and posttransplant)Phase 2 (n = 94)NCT03955445recruitingC3GPhase 3 (n = 83)NCT04817618 (APPEAR-C3G)recruitingC3GNM8074mABi.v.NovelMedPhase 1b/2a (n = 18)NCT05647811not yet recruitingC3GFactor Dinhibition of the cleavage of FBDanicopan (ALXN2040)smallmoleculeOralAlexionPhase 2 (n = 13)NCT03369236completedC3GPhase 2 (n = 22)NCT03459443terminatedaTerminated because of inconclusive efficacy results. No safety findings were identified.C3G, IC-MPGNPhase 2a (n = 6)NCT03124368completedC3G, IC-MPGNC5inhibition of the release of C5a and C5b, and ultimately the formation of C5b9EculizumabmABi.v.AlexionPhase 1 (n = 6)NCT01221181completedC3GC5a receptorinhibition of the binding of C5a to its receptorAvacopan (CCX168)smallmoleculeOralChemoCentryxPhase 2 (n=57)NCT03301467 (ACCOLADE)completedC3GC3 convertase and C5Factor H component: inhibition of C3 convertase. C5 antibody: inhibition of release of C5a and C5bKP104Bifunctional biologici.v. and s.c.KiraPhase 2 (n = 52)NCT05517980not yet recruitingC3G, IgANMASP-2inhibition of the cleavage of C4 and C2Narsoplimab (OMS721)mABi.v. and s.c.OmerosPhase 2 (n = 54)NCT02682407completedIgAN, LN, C3G, MNC3G, C3 glomerulopathy; DDD, dense deposit disease; IC-MPGN, immune complex-mediated membranoproliferative glomerulonephritis; IgAN, IgA nephropathy; i.v., intravenous; LN, lupus nephritis; mAB, monoclonal antibody; MN, membranous nephropathy; RNAi, RNA interference; s.c., subcutaneous.a Terminated because of inconclusive efficacy results. No safety findings were identified. Open table in a new tab C3G, C3 glomerulopathy; DDD, dense deposit disease; IC-MPGN, immune complex-mediated membranoproliferative glomerulonephritis; IgAN, IgA nephropathy; i.v., intravenous; LN, lupus nephritis; mAB, monoclonal antibody; MN, membranous nephropathy; RNAi, RNA interference; s.c., subcutaneous. An increase in AP C3 convertase formation and activity is the cornerstone of C3G pathogenesis, making this axis the main target for the development of new therapies.3Smith R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy-understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143https://doi.org/10.1038/s41581-018-0107-2Crossref PubMed Scopus (193) Google Scholar Inhibition at this level can also have a downstream effect and may help regulate an overactivation of the terminal pathway. Different findings can point us to an altered function at the level of C3. C3NeFs, any autoantibody capable of stabilizing alternative C3 convertase activity, can be found in a large percentage of patients with C3G, especially among patients with dense deposit disease.5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,18Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274https://doi.org/10.2215/CJN.07900811Crossref PubMed Scopus (161) Google Scholar,19Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473https://doi.org/10.1038/ki.2012.212Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Pathogenic variants in complement genes have been identified in up to 20% to 25% of cases, although more modern analyses using stricter standards for pathogenicity have yielded far lower percentages of case (closer to 10%–15%). These variants mostly affect the activity of C3/C3 convertase axis, such as variants in the genes encoding for C3, C3 gene; factor B, CFB gene; factor H (FH), CFH gene; factor I, CFI gene; or rearrangements, duplications, and deletions in FH-related proteins, CFHR gene.20Caravaca-Fontán F. Lucientes L. Cavero T. Praga M. Update on C3 glomerulopathy: a complement-mediated disease.Nephron. 2020; 144: 272-280https://doi.org/10.1159/000507254Crossref PubMed Scopus (29) Google Scholar,21Heiderscheit A.K. Hauer J.J. Smith R.J.H. C3 glomerulopathy: understanding an ultra-rare complement-mediated renal disease.Am J Med Genet C Semin Med Genet. 2022; 190: 344-357https://doi.org/10.1002/ajmg.c.31986Crossref PubMed Scopus (10) Google Scholar C3 serum levels, a biomarker of C3 convertase activation in the fluid phase, are low in 50% to 70% of patients with C3G.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,22Ravindran A. Fervenza F.C. Richard S.J.H. De Vriese A.S. Sethi S. C3 glomerulopathy: ten years' experience at Mayo Clinic.Mayo Clin Proc. 2018; 93: 991-1008https://doi.org/10.1016/j.mayocp.2018.05.019Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Patients with normal serum C3 levels, in which convertase overactivation can occur in the tissue, may still benefit from C3 inhibition. Other biomarkers such as breakdown products of factor B and C3 could be of interest to better assess AP C3 convertase activation. An upstream inhibition of the AP should allow the integrity of the classical and lectin pathways, which would potentially reduce the risk of infection by encapsulated bacteria that has been described with direct C5 inhibition.23McNamara L.A. Topaz N. Wang X. Hariri S. Fox L. MacNeil J.R. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine.MMWR Morb Mortal Wkly Rep. 2017; 66: 734-737https://doi.org/10.15585/MMWR.MM6627E1Crossref PubMed Google Scholar C3 convertase inhibition could reduce the formation of opsonins (C3b, iC3b, and C3d), leading to a potential reduction in immune complex and pathogen removal, whereas a more AP-selective inhibition targeting factor B or factor D should not affect opsonization and terminal complement activity via the classical and lectin pathways.24Mannes M. Dopler A. Zolk O. et al.Complement inhibition at the level of C3 or C5: mechanistic reasons for ongoing terminal pathway activity.Blood. 2021; 137: 443-455https://doi.org/10.1182/BLOOD.2020005959Crossref PubMed Scopus (0) Google Scholar However, complete genetic deficiency of factor B25Slade C. Bosco J. Unglik G. Bleasel K. Nagel M. Winship I. Deficiency in complement factor B.N Engl J Med. 2013; 369: 1667-1669https://doi.org/10.1056/NEJMC1306326Crossref PubMed Scopus (0) Google Scholar and factor D26Biesma D.H. Hannema A.J. van Velzen-Blad H. et al.A family with complement factor D deficiency.J Clin Invest. 2001; 108: 233-240https://doi.org/10.1172/JCI12023Crossref PubMed Scopus (0) Google Scholar have been associated with infections by encapsulated bacteria. Prophylactic measures such as vaccination against Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae; and antibiotic use should be applied to patients receiving C3/AP inhibition. Given the critical role of this proximal portion of the AP in the disease, many new drugs targeting the numerous components are being investigated (Figure 1, Table 1). Pegcetacoplan is a subcutaneous, second-generation compstatin derivative. Compstatins comprise a family of peptides that selectively bind to C3, inhibiting access to C3 convertases, thereby blocking C3 cleavage from all 3 pathways.27Sahu A. Kay B.K. Lambris J.D. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library.J Immunol. 1996; 157: 884-891https://doi.org/10.4049/JIMMUNOL.157.2.884Crossref PubMed Google Scholar,28Sahu A. Morikis D. Lambris J.D. Compstatin, a peptide inhibitor of complement, exhibits species-specific binding to complement component C3.Mol Immunol. 2003; 39: 557-566https://doi.org/10.1016/S0161-5890(02)00212-2Crossref PubMed Scopus (75) Google Scholar A phase 2 clinical trial including patients with C3G, the DISCOVERY (NCT03453619), enrolled 21 participants with IgA nephropathy (IgAN), lupus nephritis, membranous nephropathy, and C3G. Results of the 8 patients in the C3G cohort were recently published.29Dixon B.P. Greenbaum L.A. Huang L. et al.Clinical safety and efficacy of pegcetacoplan in a Phase 2 study of patients with C3 glomerulopathy and other complement-mediated glomerular diseases.Kidney Int Rep. 2023; 8: 2284-2293https://doi.org/10.1016/j.ekir.2023.08.033Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar All patients received pegcetacoplan for 48 weeks, with the option to continue treatment in an extension phase. During the treatment period, all 8 participants were concomitantly on renin-angiotensin-aldosterone system inhibition, 5 were also receiving MMF, and 3 were receiving corticosteroids. Proteinuria reduction, the primary end point, was 50.9%, from a mean 24h urine protein-to-creatinine ratio (UPCR) of 3.3 mg/mg at baseline to 1.2 mg/mg at week 48 in the intention-to-treat group (n = 7). Serum albumin levels normalized; and kidney function, starting at a mean estimated glomerular filtration rate (eGFR) of 102.4 ml/min per 1.73 m2 at baseline, was stable throughout the study. Complement serum mean levels improved from baseline to week 48, with a 6-fold increase in C3 (from 44 to 243.1 mg/dl) and a 57.3% decrease of sC5b-9 (although it remained above normal range). No severe treatment-related adverse events or serious adverse events occurred. Posttransplant recurrent C3G, which is expected in nearly all patients with C3G who undergo kidney transplant, will be represented in the NOBLE study (NCT04572854), a phase 2 trial designed to evaluate the safety and efficacy of pegcetacoplan in 12 patients with posttransplant C3G or IC-MPGN. The first portion of the study is a 12-week randomized controlled period with one arm receiving pegcetacoplan 1080 mg twice weekly and the other arm receiving no intervention. The primary outcome is the proportion of subjects with reduction in C3c staining on renal biopsy at the 12-week time point, after which all patients will be given pegcetacoplan until week 52. The VAILANT trial (NCT05067127), a phase 3 study, is aiming to recruit 90 participants with native or recurrent C3G or IC-MPGN. Participants will be given pegcetacoplan (1080 mg for adults and adolescents ≥50 kg, dose reductions for adolescents <50 kg) twice weekly or a matched placebo for 6 months, followed by an open-label assignment of active therapy for all participants for another 6 months. Outcomes include proteinuria, renal function, and repeat biopsy findings at week 26, including changes in the activity score of the C3G histologic index score4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar as well as C3c staining. The VALIANT trial will have an extension study, the VALE study (NCT05809531), to evaluate the agent's long-term safety and efficacy in this population. Iptacopan (LNP023) is a first-in-class, oral small molecule that inhibits the enzymatic activity of factor B. Factor B is a key node in the AP: its breakdown product, Bb, is the component with proteolytical activity of the AP C3 convertase (C3bBb) and AP C5 convertase (C3bBb3b). Iptacopan is expected to have a suppressive effect on both convertases, resulting in an upstream and downstream regulation of the AP.30Schubart A. Anderson K. Mainolfi N. et al.Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.Proc Natl Acad Sci U S A. 2019; 116: 7926-7931https://doi.org/10.1073/PNAS.1820892116Crossref PubMed Scopus (0) Google Scholar The results of a phase 2, open-label study using iptacopan in 27 patients with native (n = 16) or posttransplant C3G (n = 11), were recently published (NCT03832114).31Wong E. Nester C. Cavero T. et al.Efficacy and safety of iptacopan in patients with C3 glomerulopathy.Kidney Int Rep. 2023; 8: 2754-2764https://doi.org/10.1016/j.ekir.2023.09.017Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar All patients received an 84-day (12-week) course of iptacopan, at a dose of 10 to 100 mg twice a day on days 1 to 21, and 200 mg twice a day on days 22 to 84. All patients in the native cohort were on maximally tolerated renin-angiotensin-aldosterone system inhibition, 5 were on concomitant treatment with MMF, and 3 were receiving glucocorticoids up to 7.5 mg/day of prednisolone. Proteinuria, the primary end point in this cohort, decreased from a mean 24h-UPCR of 401.9 g/mol to 220.1 g/mol at week 12 (45% reduction). The posttransplant cohort included patients at ≥90 days posttransplant, with a stable immunosuppression regimen (calcineurin inhibitors, n = 11; MMF n = 9; glucocorticoids, n = 9; azathioprine, n = 2; cyclophosphamide, n = 1) and no evidence of rejection. The primary end point for the posttransplant cohort was C3 deposit score (proteinuria was predominantly normal at baseline), which decreased significantly from baseline to day 84 by 2.5 (scale: 0–12). Kidney function remained stable throughout the study in both cohorts. Iptacopan treatment reduced sC5b-9 levels in plasma (from a mean of 1306 ng/ml to 398.8 ng/ml on day 84) and urine in the native cohort. In the posttransplant cohort, levels were comparable to healthy subjects at baseline, and remained stable. Both cohorts showed reductions in plasma Bb levels. All patients were vaccinated against N meningitidis, S pneumoniae and H influenzae prior to iptacopan treatment, and no infection by encapsulated bacteria were recorded. Twenty-six of the 27 participants of this trial (16 with native C3G and 10 with posttransplant C3G) joined the extension study (NCT03955445) for long-term efficacy, safety, and tolerability of iptacopan. An interim analysis was performed after 12 months of treatment with iptacopan and presented in abstract form.32American Society of Nephrology12M interim analysis of an open-label, non-randomized extension of a Phase 2 study to evaluate the long-term efficacy, safety, and tolerability of iptacopan in subjects with C3G. American Society of Nephrology kidney week 2022.https://www.asn-online.org/education/kidneyweek/2022/program-abstract.aspx?controlId=3764344Date accessed: October 1, 2023Google Scholar Patients with native C3G showed a proteinuria reduction of 57%, an increase in eGFR by 6.83 ml/min per 1.73 m2, and an increase in serum C3 by 253%. In patients with C3G in the allograft, eGFR was stable and serum C3 levels increased by 96%; proteinuria reduction was not assessed as median baseline proteinuria was already normal. These preliminary results supported the rationale for a phase 3 study, the Alternative Complement Pathway Inhibition with Iptacopan for the Treatment of C3G trial (NCT04817618).33Bomback A.S. Kavanagh D. Vivarelli M. 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; 7: 2150-2159https://doi.org/10.1016/j.ekir.2022.07.004Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar This randomized and placebo-controlled study, with an estimated enrollment of 83 adults and adolescents with native C3G,33Bomback A.S. Kavanagh D. Vivarelli M. 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; 7: 2150-2159https://doi.org/10.1016/j.ekir.2022.07.004Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar will look at outcomes, including changes in UPCR, eGFR, activity score on renal biopsy and Functional Assessment of Chronic Illness Therapy-Fatigue score, as well as safety measurements, at 6 months and at 12 months, after an open-label 6-month phase of iptacopa
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