Targeting APRIL in the Treatment of IgA Nephropathy

IgA nephropathy is the commonest primary glomerulonephritis worldwide. It is often diagnosed in younger adults, and the socioeconomic burden is therefore high. Recent observational data from the United Kingdom indicate that most patients (even with modest proteinuria) are at risk of kidney failure unless their annual rate of kidney function decline can be maintained at ≤1 ml/min per 1.73 m².¹

Until recently, there has been a paucity of safe and effective treatments for this condition. The therapeutic landscape is rapidly changing, in large part due to advances in our understanding of its underlying pathogenesis and the acceptance of surrogate outcomes, such as proteinuria reduction and rate of change (slope) of eGFR by regulatory authorities as the basis for accelerated approval of new therapies. This has made conducting clinical trials more feasible and has transformed drug development in IgA nephropathy. There are now two treatments that recently received conditional approval: Nefecon (Tarpeyo/Kinpeygo) and Sparsentan (Filspari). In addition, more than 20 clinical trials are under way evaluating drugs that target B cells, the complement system, the endothelin system, and other pathways. On the basis of recent trial data, sodium-glucose cotransporter-2 inhibitors are being used frequently in IgA nephropathy.

It is widely accepted that multiple hits must occur for IgA nephropathy to develop. First, there is an increase in levels of circulating IgA1 that lack galactose from its hinge region (Gd-IgA1) (hit 1). IgG and IgA autoantibodies are generated against Gd-IgA1 in susceptible individuals (hit 2), leading to the formation of circulating immune complexes (hit 3). These have a propensity to deposit in the glomerular mesangium and trigger mesangial cell activation, cytokine and extracellular matrix release, and podocyte injury (hit 4). The complement system is activated, accelerating glomerular damage, and ultimately, tubulointerstitial fibrosis and loss of kidney function ensues. Multiple lines of evidence point toward B cells derived from the mucosa-associated lymphoid tissue, especially within the gut, as being the major source of circulating Gd-IgA1 in IgA nephropathy (Figure 1).²

Figure 1.

Mucosal B-cell production of Gd-IgA1 in IgA nephropathy. IgA is mainly produced within mucosal-associated lymphoid tissue, and the gut is depicted here. Its production by mucosal B cells is driven by T-cell dependent and independent pathways. After antigen sampling by intestinal M (microfold) cells and DC, priming of naïve T cells takes place, promoting their differentiation to Tfh cells. These interact with naïve IgM-expressing and IgD-expressing B cells and promote class switch recombination preferentially to IgA-expressing cells within the mucosal environment. Dendritic cells may also produce the cytokines APRIL and BAFF that promote class switching to IgA-expressing cells in a T-cell independent manner. Overall, Gd-IgA1–producing B cells are formed that mature and traffic toward effector sites via the lymphatic system. In IgA nephropathy, there is an increase in circulating Gd-IgA1, which may be due to its overspill into the circulation from mucosal sites or its production by B cells that have mishomed to systemic sites, such as the bone marrow. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; DC, dendritic cell; Gd-IgA1, galactose deficient-IgA1; Tfh, T follicular helper.

Early studies using phenytoin to suppress total serum IgA levels did not alter the natural evolution of IgA nephropathy or IgA immune complex levels, indicating that a more specific approach is required. Targeting B-cell production of Gd-IgA1 has recently become a major area of interest. An early study demonstrated that treatment with rituximab did not reduce proteinuria or stabilize eGFR in patients with IgA nephropathy and importantly did not decrease Gd-IgA1 levels and the corresponding autoantibodies, despite depletion of peripheral B cells.³ This may be due to the inability of rituximab to deplete tissue resident B cells or CD20-negative plasma cells.

There is now significant interest in targeting the B-cell survival factors, a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF), not only in IgA nephropathy but also in other autoimmune diseases. These are related cytokines of the TNF superfamily, produced by antigen-exposed dendritic cells, myeloid cells, and mucosal epithelial cells. Both act via the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) receptors. BAFF, but not APRIL, also acts via the BAFF-receptor. Signaling via these receptors is essential for B-cell survival, maturation, and proliferation and for immunoglobulin class switching. At mucosal surfaces, APRIL via TACI promotes class switching of naïve B cells to IgA-producing B cells, where IgA plays a critical role in the host defense against pathogenic organisms and in promoting immune tolerance to host microbiota. APRIL also plays a key role in the maintenance of plasma cells, the primary source of secreted antibodies.

APRIL is, therefore, a key mediator of IgA production and thereby Gd-IgA1. In observational studies, patients with IgA nephropathy had increased APRIL levels that correlated with levels of Gd-IgA1 and risk of kidney disease progression.⁴ A single-nucleotide polymorphism in the gene encoding APRIL (TNFSF13) is associated with the risk of developing IgA nephropathy.⁵ In the ddY mouse model of IgA nephropathy, use of an anti-APRIL mAb suppressed serum IgA levels; reduced circulating immune complexes; significantly lowered the spontaneous glomerular deposition of IgA, IgG, and C3; and abrogated the development of proteinuria.⁶

Sibeprenlimab (VIS649) is a humanized IgG2 mAb directed against APRIL. In nonhuman primate studies, treatment with intravenous sibeprenlimab led to a dose-dependent reduction in serum IgA of up to 70%, and a reduction in IgA⁺, IgM⁺, and IgG⁺ cells was observed in the gut-associated lymphoid tissue.⁶ In healthy volunteers, sibeprenlimab reduced serum IgA, Gd-IgA1, IgM, and to a lesser extent IgG, the latter being important given the known association of IgG hypogammaglobulinemia with risk of infection.⁷ Sibeprenlimab is now being evaluated in IgA nephropathy in a dose-finding phase 2 randomized controlled trial (enVISion; NCT04287985), which has completed enrollment and is in follow-up, and a global phase 3 randomized controlled trial (VISIONARY; NCT05248646) that is currently recruiting.

A prespecified interim analysis of 77 participants in the enVISion trial showed that treatment with sibeprenlimab resulted in a 43% mean placebo-adjusted reduction in 24-hour urine protein-creatinine ratio by 9 months, with proteinuria reduction being evident by approximately 30 days after starting treatment. Promising preliminary eGFR data were also reported.⁸ These changes corresponded with marked reductions of free APRIL and in Gd-IgA1 (by 68%), total IgA (by 63%), and to a lesser extent IgG (by 35%). A total of 155 participants have now been enrolled, and full results are expected in late 2023.

Of importance when targeting B cells and immunoglobulin production is the impact on infection risk and vaccination response. Eleven serious adverse events were reported in the interim analysis of enVISion, but none were due to infection or deemed to be related to the study drug. A substudy of enVISion showed that those treated with sibeprenlimab had preserved serological responses to coronavirus disease 2019 mRNA vaccination above the predicted protective threshold and declines in severe acute respiratory syndrome coronavirus 2 antibody titers were similar to those treated with placebo, providing reassurance in this regard.⁹ Longer-term data are required to assess the safety of targeting B cells and plasma cells by this approach and any potential impact on immunogenicity.

Other therapies targeting APRIL±BAFF in IgA nephropathy also suggest promise, including one approved in lupus nephritis. Zigakibart (BION-1301) is being studied in a single-arm phase 1/2 trial of up to 40 patients with IgA nephropathy (NCT03945318).¹⁰ Significant reductions in free APRIL, serum IgA, and Gd-IgA1 have been reported, with a mean reduction of 54% in proteinuria observed at week 24 compared with baseline, and this agent will be studied in a forthcoming phase 3 trial (BEYOND; NCT05852938). Atacicept is a fusion protein that contains the extracellular portion of TACI, hence binding and inhibiting both APRIL and BAFF. After positive findings from the dose-finding JANUS study, interim 36-week data from the phase 2 ORIGIN trial demonstrated that treatment with atacicept 150 mg resulted in substantial reductions in Gd-IgA1 levels and a mean reduction of 43% in proteinuria. The early eGFR data were also reassuring.¹¹ A phase 3 trial of atacicept in IgA nephropathy is now being planned (ORIGIN 3; NCT04716231). Other agents targeting both APRIL and BAFF include telitacicept, for which positive findings were reported from a smaller phase 2 trial in IgA nephropathy (NCT04291781), and povetacicept, which is being explored in an open-label basket trial of IgA nephropathy, membranous nephropathy, and lupus nephritis (NCT05732402).

Targeting APRIL alone or in combination with BAFF holds great potential for the treatment of IgA nephropathy, and we have now observed that lowering production of Gd-IgA1 may result in rapid clinical improvements for proteinuria reduction, indicating a renoprotective effect. Successful recruitment into ongoing phase 3 trials, and strategies to guarantee representation of patients of different ethnicities in those studies, will ensure our ability to deliver promising therapies to all patients with IgA nephropathy in the foreseeable future.

Disclosures

J. Barratt reports receiving consulting and speaker fees from Alnyam, Argenx, Astellas, BioCryst, Calliditas, Chinook, Dimerix, Galapagos, Novartis, Omeros, Otsuka, Travere Therapeutics, Vera Therapeutics, and Visterra; grant support from Argenx, Calliditas, Chinook, Galapagos, GSK, Novartis, Omeros, Travere Therapeutics, and Visterra; consultancy for Alebund, Alnylam, Alpine, Argenx, Astellas, BioCryst, Calliditas, Chinook, Dimerix, HiBio, Kira, Novartis, Omeros, Otsuka, Q32 Bio, Roche, Sanofi, Takeda, Travere Therapeutics, Vera Therapeutics, Vifor, and Visterra; research funding from Argenx, Calliditas, Chinook, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, and Visterra; reports serving as scientific/medical advisor to Alnylam, Astellas, Calliditas, Chinook, Galapagos, GlaxoSmithKline, Novartis, Omeros, Roche, Travere Therapeutics, UCB, and Visterra, Inc.; is a member of the Editorial Boards of CJASN, Clinical Science, Glomerular Diseases, and Kidney International is a member of Kidney Health Initiative; is Treasurer of International IgA Nephropathy Network; and has lectured, chaired, or participated in symposia/panel discussions for Calliditas, Omeros, and Travere Therapeutics. K. Carroll reports employment with KJC Statistics Limited; consultancy fees from Cerium Pharmaceuticals Inc., Chinook Therapeutics Inc., Dimerix, GSK, Omeros Corp, Reata Pharmaceuticals, Sanifit Therapeutics, and Travere Therapeutics Inc., as a part of KJC Statistics Limited with ownership interests; ownership interest in KJC Statistics Limited; and advisory or leadership roles for Omeros Academic Advisory Board and GSK Steering Committee. C.K. Cheung reports receiving consulting and speaker fees from Alpine Immune Sciences, Calliditas, Chinook, CSL Vifor, George Clinical, Novartis, Otsuka, Roche, Stada, Travere Therapeutics, Vera Therapeutics; receiving grant support from GlaxoSmithKline and Travere Therapeutics; being on a data monitoring committee for Roche; and being on the speakers bureau for Stada Pharma. R.A. Lafayette reports receiving personal fees and grants from Alexion, Aurinia, Calliditas, GlaxoSmithKline, HI-Bio, Novartis, Omeros, Otsuka, Pfizer, Roche, Travere Therapeutics, and Vera Therapeutics; consultancy for Alexion, Inc., Aurinia, Calliditas, Inc., Chinook, Inc., Novartis, Omeros, Inc., Otsuka, Inc., Travere, Inc., Vera, Inc., and Visterra, Inc.; research funding from Apellis, Calliditas, Chemocentryx, Chinook, NIH, Omeros, Otsuka, Pfizer, Roche, Travere, and Vera; and being on a data monitoring committee for Alkahest and Equillium. A. Liew reports employment with The Kidney & Transplant Practice Pte Ltd; consultancy for DaVita Inc; Alnylam Pharmaceuticals, Baxter Healthcare, Bayer, Boehringer-Ingelheim, Chinook Therapeutics, Eledon Pharmaceuticals, George Clinical, Kira Pharmaceuticals, Otsuka Pharmaceuticals, and ProKidney; honoraria from Alnylam Pharmaceuticals, AstraZeneca, Baxter Healthcare, Bayer, Boehringer-Ingelheim, Chinook Therapeutics, and Otsuka Pharmaceuticals; advisory or leadership roles for Kidney and Blood Pressure Research (Editorial Board), Kidney International (Editorial Board), Kidney Research and Clinical Practice (Editorial Board), Nephrology (Associate Editor), and Peritoneal Dialysis International (Editorial Board); other interests or relationships as Secretary and Executive of ISPD, Chair of ISN Renal Disaster Preparedness Working Group, Working Group Member of KDIGO Guideline on Diabetes Management in CKD, Working Group Member of KDIGO Guideline Update on Glomerular Diseases, and Chair of Asian-Pacific Society of Nephrology Guideline on Diabetic Kidney Disease; has served as a consultant and member of advisory boards for Alnylam Pharmaceuticals, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer-Ingelheim, Chinook Therapeutics, Dimerix Limited, Eledon Pharmaceuticals, George Clinical, GlaxoSmithKline, Kira Pharmaceuticals, Otsuka Pharmaceuticals, Prokidney, Visterra Inc., and Zai Lab Co. Ltd; has received speaker's honorarium from AstraZeneca, Baxter Healthcare, Boehringer-Ingelheim, Chinook Therapeutics, and Otsuka Pharmaceuticals; and has served as a member of Data Safety and Monitoring Committee for Dimerix Limited and Zai Lab Co. Ltd. V. Perkovic is employed by UNSW Sydney and the Royal North Shore Hospital and serves as a Board Director for St. Vincents Health Australia, George Clinical, and several Medical Research Institutes. V. Perkovic has led or served on the Steering Committees of trials funded by AbbVie, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, Janssen, Novartis, Novo Nordisk, Otsuka, Pfizer, Travere Therapeutics, and Tricida. V. Perkovic also reports having received honoraria for scientific presentations and/or advisory board attendance from AbbVie, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Reata, Relypsa, Roche, Sanofi, and Servier; consultancy for AbbVie, Astellas, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chinoo, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, PharmaLink, Relypsa, Retrophin, Roche, Sanofi, Servier, Travere, Tricida, UpToDate, and Vitae; ownership interest in George Clinical; research support from the Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant); honoraria from AbbVie, Astellas, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Retrophin, Roche, Sanofi, Servier, Travere, Tricida, UpToDate, and Vitae; advisory or leadership roles for Steering committees for AbbVie, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novartis, Pfizer, Travere; and role on Board Director for St. Vincents Health Australia, George Clinical. D.V. Rizk reports research funding from Calliditas Therapeutics (Pharmalinks), Chinook Pharmaceuticals, Otsuka Pharmaceuticals (Visterra), Pfizer Pharmaceuticals, Reata Pharmaceuticals, Travere Therapeutics, Vera Therapeutics, and Vertex Pharmaceuticals; consulting fees from Calliditas Therapeutics (Pharmalinks), Chinook Pharmaceuticals, Eledon Pharmaceuticals, George Clinical, GSK, Novartis, Otsuka Pharmaceuticals (Visterra), and Roche-Group; ownership in Reliant Glycosciences LLC; and advisory or leadership roles for Visterra Inc. Scientific Advisory Board, Calliditas advisory board, Eledon Pharmaceuticals Steering Committee, George Clinical National Leader, Novartis pharmaceuticals Steering Committee, Otsuka Steering Committee, and Vera Therapeutics Executive Advisory Committee. Y. Suzuki reports research funding from Argenx, Astellas Pharma Inc., AstraZeneca, Aurinia Pharmaceuticals, Baxter Limited, Bayer, Boeringer, Chinook, Chugai, Daiichi Sankyo Company, Limited, Eisai, Kissei, Kyowa Kirin, Mochida, Moderna, Ono Pharmaceutical Co., Ltd., Otsuka US, Pfizer, Retrophin, Sanwa Kagaku Kenkyusho Co., Ltd., Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical, Tanabe Mitsubishi, Teijin Pharma, Torii Pharmaceutical Co., Ltd, Travere Therapeutics, and Visterra; consulting fees from Argenx, Chinook, Novartis, Otsuka, Takeda, Travere Therapeutics, and Visterra; speaker fees from Astellas, AstraZeneca, Bayer Yakuhin, Daiichi Sankyo Co., Kissei Pharmaceutical Co., Kowa Company, Kyowa Kirin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Novartis, and Otsuka; honoraria from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Kyowa Kirin, Novartis, Sumitomo Dainippon, Takeda, and Tanabe Mitsubishi Pharmaceutical company; and advisory or leadership roles for ARGENX Inc., Chinook Therapeutics, Kyowa Kirin Co., Ltd, Morphosys Inc., Novartis Pharma Co. Ltd, Travere/Retrophin Inc., and Visterra/Otsuka Inc. V. Tesař reports consultancy fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Calliditas, Eli Lilly, Fresenius Medical Care, GSK, Novartis, Omeros, Otsuka, Swixx BioPharma, and Travere; advisory or leadership role as a member of the scientific advisory board of B.Braun and Fresenius Medical Care; and member of the steering committee of clinical trials sponsored by Calliditas, Novartis, Omeros, Otsuka, and Travere. H. Trimarchi is a consultant in nephrology to George Clinical and is on the Advisory Board and is a Steering Committee member of glomerular disease trials funded by Calliditas, Chinook, Dimerix, Novartis, Omeros, Otsuka, Travere Therapeutics, Vera Therapeutics, and Visterra; reports receiving honoraria from AstraZeneca, Genzyme-Sanofi, and GlaxoSmithKline; consultancy for Alexion, AstraZeneca, Bayer, Biocryst, Calliditas, Chinook, Dimerix, Gador, George Clinical, GlaxoSmithKline, Novartis, Raffo, Roche, Sanofi-Genzyme, Travere, Vera, and Visterra-Otsuka; honoraria from AstraZeneca, Bayer, Biocryst, Calliditas, Chinook, Dimerix, Gador, George Clinical, GlaxoSmithKline, Novartis, Raffo, Roche, Sanofi-Genzyme, Travere, Vera, and Visterra-Otsuka; and advisory or leadership roles for AstraZeneca, Bayer, Biocryst, Calliditas, Chinook, Dimerix, Gador, George Clinical, GlaxoSmithKline, Novartis, Raffo, Roche, Sanofi-Genzyme, Travere, Vera, and Visterra-Otsuka. M.G. Wong reports consultancy for Chinook, Eledon, CSL Behring, Dimerix Ltd, George Clinical, Otuska, and Travere Therapeutic; honoraria from Alpine, Amgen, AstraZeneca, Baxter, Borringher, Chinook, CSL Behring, Dimerix, Eledon, George Clinical, Horizon, Otsuka, and Travere Therapeutics for scientific presentation; and advisory or leadership roles for Chinook, CSL Behring, Dimerix Ltd, Eledon, Horizon, Otuska, and Travere Therapeutic. H. Zhang is employed by Peking University First Hospital and reports receiving consultancy fees for being a Steering Committee member from Calliditas, Chinook, Novartis, Omeros, and Otsuka. H. Zhang also reports having participated in symposia or panel discussions and received honoraria for scientific presentations from Novartis and Omeros.

Funding

None.

Author Contributions

Conceptualization: Jonathan Barratt, Kevin Carroll, Chee Kay Cheung, Richard A. Lafayette, Adrian Liew, Vlado Perkovic, Dana V. Rizk, Yusuke Suzuki, Vladimír Tesař, Hernán Trimarchi, Muh Geot Wong, Hong Zhang.

Writing – original draft: Chee Kay Cheung, Dana V. Rizk.

Writing – review & editing: Jonathan Barratt, Kevin Carroll, Chee Kay Cheung, Richard A. Lafayette, Adrian Liew, Vlado Perkovic, Dana V. Rizk, Yusuke Suzuki, Vladimír Tesař, Hernán Trimarchi, Muh Geot Wong, Hong Zhang.