A new approach for glomerulonephritis: targeting the alternative complement pathway – Organised by NOVARTIS PHARMA AG

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Welcome and introduction

David Kavanagh, United Kingdom

Dysregulation of the complement alternative pathway (AP) appears to be a common pathophysiological background of several immune-mediated kidney diseases such as glomerulonephritis (GN) that are still classified based on clinical presentation, course of the disease, or biopsy appearance. Recent studies even accumulated clinical, genetic, and biochemical evidence that complement plays a significant role in the pathogenesis of IgA nephropathy (IgAN), the most common form of primary glomerulonephritis (GN). The accurate identification of the underlying pathogenic mechanisms in complement-driven renal diseases (CDRD) is the key to devise adequate therapeutic protocols and predict the response to interventions. A panel of experts summarized the role of the complement system in certain glomerulonephritis entities, presented emerging therapeutic approaches and future directions at a symposium held during the 58th ERA-EDTA Congress (only virtual).

The role of complement in glomerulonephritis

Peter Zipfel, Germany

Under physiological conditions, the complement system contributes substantially to homeostasis by coordinating the removal of apoptotic debris and infectious microbes, orchestrating immune responses, and generating and sending “danger” signals. The complement cascade has three activation routes, the classical and the lectin pathways on cell surfaces, and the alternative pathway, AP acting in the fluid phase and on surfaces. Following the three different initial triggers that activate a particular route, the common point of all three paths is the activation of the C3 component, cleaving it into a large fragment C3b, that acts as an opsonin, and a small fragment C3a that promotes inflammation. Activated C3 can triggers a second route of inflammatory via C5a and activates the lytic pathway, damaging the plasma membranes of cells and infectous microbes including bacteria. C5a, which is produced by this process, attracts macrophages and neutrophils and also activates mast cells.

When not properly controlled, the complement can take action against healthy cells, thus catalyzing a plethora of glomerular diseases. The classical/lectin pathway is associated with ANCA vasculitis, IgAN vasculitis, and antibody-mediated transplant rejection, whereas C3 glomerulopathy (C3G), hemolytic uremic syndrome (HUS), FHR1-FHR3 deficient and antibody-positive HUS, hematopoietic stem-cell associated thrombotic microangiopathy, and IgAN are predominantly related to the derangements in AP. The specific activation pathways and regulatory mechanisms of complement that are disturbed in these conditions provide the targets to act upon by therapeutic agents. The major challenge in this process is to understand complement regulation, define the roles and relationships between the many regulators, understand which inhibitor acts at which site, and how and when the absence or defect of a single regulator disturbs the cascade. This should ultimately allow designing precisely acting therapeutic agents selectively targeting particular complement activation pathways to modulate these complement-driven diseases.

Towards a targeted therapy in complement-driven renal disease: a program overview

Matthias Meier, Switzerland

The benefits of anti-complement therapy have been explored for several decades in various preclinical disease models. Despite the long history, only few anti-complement drugs have entered clinical trials until recently. Nevertheless, the growing list of renal diseases implicating complement has sparked new interest in this topic, thus triggering the development of numerous clinical anti-complement drugs for the complement-driven renal diseases (CDRD). Iptacopan (LNP023) is a first-in-class, orally-administered, potent, and highly selective factor B inhibitor that directly blocks C3 convertase thus reducing the activation of the complement AP. Multiple positive phase 2 readouts and favorable safety and tolerability profile permitted rapid transition of this agent into phase 3 trials. It is currently being evaluated for the treatment of C3 glomerulonephritis (C3GN) in the APPEAR study, IgAN in the APPLAUSE study, atypical hemolytic uremic syndrome in the APPELHUS study, as well as paroxysmal nocturnal hemoglobinuria (PNH) in the APPLY as well as APPOINT studies.

The APPEAR-C3G trial is a multicenter double-blind, parallel group study evaluating the efficacy and safety of iptacopan compared to placebo and Standard of Care (SoC) in patients with C3G in native kidneys (patients with C3G recurrence in transplanted kidney allografts were excluded). The study is expected to enroll 68 adult participants with biopsy-confirmed C3G and urine protein to creatinine ratio (UPCR) ≥1g/g. Patients will be initially randomized to receive iptacopan 200mg bid or placebo for a period of 6 months, followed by another six months of open-label treatment with iptacopan in all participants. The primary objective for double-blind treatment is to demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria, while the primary goal of the open-label treatment is to evaluate the effects of iptacopan on proteinuria at 12 months. The study is expected to initiate soon and last till August 2023.

The APPLAUSE trial is designed as a double-blind, parallel-group study expected to enroll approximately 430 adult participants with IgAN and proteinuria ≥1g/day despite optimal stable RAS blockade. Participants will be randomly assigned in a 1:1 ratio to receive iptacopan 200mg bid or placebo. The primary objectives shall be to evaluate the effect of the study drug on UPCR at 9 months (interim analysis), and to evaluate its effect on slowing renal function decline by measuring the annualized total slope of estimated glomerular filtration rate over 24 months. The study is expected to finalize in January 2025.

C3 glomerulopathy: novel therapeutic approaches

Manuel Praga, Spain

C3 glomerulopathies (C3G) are a group of an ultra-rare kidney diseases occurring at an incidence of 1-3 cases per million only. The fundamental underlying pathogenetic mechanism of C3G is the dysregulation of the complement AP. This is generally driven by acquired factors, namely autoantibodies that target C3 or C5 convertases, which increase the half-life of these enzymes thus prolonging their activity. A less frequent cause for complement AP overactivation in C3G is genetic variation in complement-related genes.

The disease mainly affects children and younger adults, manifesting with nephrotic or nephritic syndrome, or asymptomatic urine abnormalities. The majority of C3G patients present with low serum C3 levels pointing to complement AP dysfunction. The diagnosis relies on identifying exclusive or predominant glomerular C3 deposits to confirm the two major subgroups of C3G – C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These have overlapping clinical and pathological features, with C3GN primarily manifesting with amorphous mesangial, paramesangial, subendothelial and subepithelial deposits, while DDD is distinguished by the presence of dense osmiophilic intramembranous deposits on electron microscopy. In the majority of cases, C3G follows a chronic, indolent course with a 10-year renal survival of approximately 50% only. Nevertheless, cases presenting with rapidly progressive glomerulonephritis have also been described. The major predictors of renal function loss are tubular atrophy and interstitial fibrosis, baseline eGFR, and 24-h proteinuria.

There are currently no available disease-specific treatments for C3G and the upcoming KDIGO practice guideline on glomerular diseases relies on expert opinion when proposing common supportive measures in mild cases and immunosuppression in moderate to severe disease (based on biopsy finding and proteinuria level). In the absence of monoclonal gammopathy, moderate to severe C3G should be treated initially with mycophenolates (MMF or MPS), and in nonresponsive cases with eculizumab. The superiority of corticosteroids plus MMF over other immunosuppressives or eculizumab in the treatment of C3G has been substantiated in a recent study by the Spanish Group for the Study of Glomerular Diseases GLOSEN. In this cohort, relapses occurred after treatment discontinuation in one-third of the patients who had achieved remission with corticosteroids plus MMF, and a shorter treatment length of MMF was associated with a higher risk of relapse. Different case studies reported the effectiveness of eculizumab which appears to be beneficial in crescentic rapidly progressive forms of C3G, but its effect in milder forms of the disease seems to be limited. Kidney transplantation is a suitable option in C3G, although there is a high risk of recurrence in the allograft ranging from 60 to 85%. Further studies are warranted to bridge current knowledge gaps in understanding the genotype-phenotype correlations and ultimately provide a better classification and natural clinical course of the disease allowing innovative and more targeted therapies.

IgA nephropathy: novel therapeutic approaches

Jonathan Barratt, United Kingdom

IgA nephropathy is the most common form of primary glomerulonephritis worldwide with variable geographic distribution. It appears to be more frequent in Asians than in Caucasian populations. While the disease commonly presents with an indolent course, 50% of the patients eventually develop end-stage kidney disease requiring dialysis. Even though kidney transplantation is the preferred treatment option, a large proportion of patients develop recurrent disease-causing graft loss.

Despite advances in the understanding of the pathogenesis of IgAN, little progress has been made in its treatment with no targeted therapies approved so far. The soon-to-be-published KDIGO practice guideline on glomerular diseases advocates optimized goal-directed supportive care as the foundation of disease management in the majority of IgAN cases. This approach relies on data from the STOP-IgAN trial which did not observe significant improvement in the outcomes of patients with IgAN with the addition of immunosuppressive therapy to supportive care. Nevertheless, given the risk of progression to ESRD, the 2021 KDIGO guideline suggest that high-risk patients should either be offered enrollment in clinical trials (if available) or considered for systemic corticosteroid treatment provided that the risk/benefit profile is acceptable. According to these guidelines, the key priority for future research in this field is the evaluation of therapeutic strategies that minimize or avoid systemic corticosteroid exposure. KDIGO also recommends further investigation of the value of mycophenolate mofetil and hydroxychloroquine in different racial groups with IgAN and clinical disease severity.

Several new therapeutic approaches for IgAN are currently being evaluated in ongoing clinical trials with results expected in the coming years. Endothelin receptor antagonists sparsentan and atrasentan are being assessed in the PROTECT and ALIGN studies respectively, while the DAPA-CKD trial recently demonstrated that inhibition of sodium-glucose transporter-2 with dapagliflozin attenuates the risk of progression of chronic kidney disease in patients with IgAN. Other drugs currently being evaluated include a targeted-release corticosteroid formulation of budesonide (TRF-budesonide) and complement inhibitors. The topline results from the NeflgArd study demonstrated significant proteinuria reduction after 9 months of treatment with TRF-budesonide compared to placebo. Complement inhibitors under investigation are directed at the lectin or alternative pathway, which are predominantly involved in the pathogenesis of IgAN. Recently published results of a phase 2 study suggests that narsoplimab, a human monoclonal antibody against mannan-associated lectin-binding serine protease-2 (MASP-2), is safe, well-tolerated, and results in a clinically meaningful reduction in proteinuria and stability of eGFR in high-risk patients with advanced IgAN. Finally, a phase 2, proof of concept dose-ranging study evaluating iptacopan in IgAN has recently completed showing a significant dose-dependent reduction in proteinuria and a trend to eGFR stabilization compared to placebo at 12 weeks. Results from this study provided the foundation for the initiation of the currently recruiting APPLAUSE-IgAN trial. The future will hopefully deliver a number of novel therapeutics that may make it possible to stop the use of systemic corticosteroids. and thereby avoid the associated side effects, in IgAN and other complement-associated renal diseases.

Further reading

Zipfel PF, Wiech T, Rudnick R, Afonso S, Person F, Skerka C. Complement Inhibitors in Clinical Trials for Glomerular Diseases. Front Immunol. 2019;10:2166. doi: 10.3389/fimmu.2019.02166.

Hou J, Markowitz GS, Bomback AS, et al. Toward a working definition of C3 glomerulopathy by immunofluorescence. Kidney Int. 2014;85(2):450-6. doi: 10.1038/ki.2013.340.

Sethi S, Fervenza FC, Zhang Y, et al. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int. 2012 Aug;82(4):465-73. doi: 10.1038/ki.2012.212

Fakhouri F, Le Quintrec M, Frémeaux-Bacchi V. Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties. Kidney Int. 2020;98(5):1135-1148. doi: 10.1016/j.kint.2020.05.053.

Caravaca-Fontán F, Díaz-Encarnación MM, Lucientes L; Spanish Group for the Study of Glomerular Diseases GLOSEN. Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease. Clin J Am Soc Nephrol. 2020;15(9):1287-1298. doi: 10.2215/CJN.15241219.

Caravaca-Fontán F, Trujillo H, Alonso M; C3G Study Group of the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Validation of a Histologic Scoring Index for C3 Glomerulopathy. Am J Kidney Dis. 2021;77(5):684-695.e1. doi: 10.1053/j.ajkd.2020.11.011.

Ruggenenti P, Daina E, Gennarini A; EAGLE Study Group. C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial. Am J Kidney Dis. 2019;74(2):224-238. doi: 10.1053/j.ajkd.2018.12.046.

Caravaca-Fontán F, Lucientes L, Cavero T, Praga M. Update on C3 Glomerulopathy: A Complement-Mediated Disease. Nephron. 2020;144(6):272-280. doi: 10.1159/000507254.

Rauen T, Eitner F, Fitzner C; STOP-IgAN Investigators. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015;373(23):2225-36. doi: 10.1056/NEJMoa1415463. PMID: 26630142.

Anders HJ, Peired AJ, Romagnani P. SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions. Nephrol Dial Transplant. 2020:gfaa329. doi: 10.1093/ndt/gfaa329.

Barratt J, Rovin B, Diva U; PROTECT Study Design Group. Implementing the Kidney Health Initiative Surrogate Efficacy Endpoint in Patients With IgA Nephropathy (the PROTECT Trial). Kidney Int Rep. 2019;4(11):1633-1637. doi: 10.1016/j.ekir.2019.08.007.

Lafayette RA, Rovin BH, Reich HN, Tumlin JA, Floege J, Barratt J. Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP-2 Inhibitor for the Treatment of IgA Nephropathy. Kidney Int Rep. 2020;5(11):2032-2041. doi: 10.1016/j.ekir.2020.08.003.