Sodium-glucose co-transporter-2 (SGLT2) inhibitors
SGLT2 inhibitors block the reabsorption of filtered glucose in the proximal tubules and induce glycosuria and natriuresis. They were originally developed as glucose-lowering drugs, but studies found they effectively reduce albuminuria and prevent the progression of chronic kidney disease.[75]Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020 Oct 8;383(15):1436-46.
https://www.doi.org/10.1056/NEJMoa2024816
http://www.ncbi.nlm.nih.gov/pubmed/32970396?tool=bestpractice.com
In a pre-specified sub-group analysis of 270 patients with IgAN, treatment with dapagliflozin significantly reduced albuminuria and improved the primary composite outcome (sustained decline in the estimated glomerular filtration rate ≥50%, end-stage kidney disease, or death from kidney or cardiovascular causes).[76]Wheeler DC, Toto RD, Stefánsson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021 Jul;100(1):215-24.
https://www.doi.org/10.1016/j.kint.2021.03.033
http://www.ncbi.nlm.nih.gov/pubmed/33878338?tool=bestpractice.com
Results from ongoing studies are keenly awaited.[77]US National Library of Medicine. ClinicalTrials.gov. A multicentre international randomized parallel group double-blind placebo-controlled clinical trial of EMPAgliflozin once daily to assess cardio-renal outcomes in patients with chronic kidney disease. Jan 2022 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03594110
Dapagliflozin has been approved in the US to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalisation for heart failure in adults with chronic kidney disease at risk of progression.
Enteric-coated budesonide
Given that the mucosal immune system may be an important source of poorly galactosylated IgA1 in IgAN, there is considerable interest in targeted immunosuppression using an enteric-coated formulation of budesonide that delivers budesonide to ileocecal Peyer's patches, with minimal systemic exposure or side effects. Early studies demonstrated that treatment with enteric-coated budesonide reduces proteinuria.[78]Smerud HK, Bárány P, Lindström K, et al. New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria. Nephrol Dial Transplant. 2011 Oct;26(10):3237-42.
https://academic.oup.com/ndt/article/26/10/3237/1903124
http://www.ncbi.nlm.nih.gov/pubmed/21378156?tool=bestpractice.com
[79]Selvaskandan H, Cheung CK, Muto M, et al. New strategies and perspectives on managing IgA nephropathy. Clin Exp Nephrol. 2019 May;23(5):577-88.
https://www.doi.org/10.1007/s10157-019-01700-1
http://www.ncbi.nlm.nih.gov/pubmed/30756248?tool=bestpractice.com
In a multicentre, double-blind, randomised, placebo-controlled phase 2b study of patients with IgAN, treatment with enteric-coated budesonide reduced proteinuria and stabilised the glomerular filtration rate compared with placebo.[80]Fellström BC, Barratt J, Cook H, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017 May 27;389(10084):2117-27.
http://www.ncbi.nlm.nih.gov/pubmed/28363480?tool=bestpractice.com
A phase 3 study is currently underway.
Endothelin receptor antagonists
Endothelin-1 is a potent vasoactive peptide that contributes to the progression of chronic kidney disease (CKD). Selective endothelin receptor antagonists reduce albuminuria and delay progression of CKD in patients with diabetic kidney disease. Ongoing phase 3 trials are examining sparsentan (a dual-acting endothelin receptor antagonist and angiotensin-II receptor antagonist) and atrasentan (a selective endothelin receptor antagonist) in patients with IgAN.[81]US National Library of Medicine. ClinicalTrials.gov. A randomized, multicenter, double-blind, parallel-group, active-control study of the efficacy and safety of sparsentan for the treatment of Immunoglobulin A nephropathy. June 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03762850
[82]US National Library of Medicine. ClinicalTrials.gov. A phase 3, randomized, double-blind, placebo-controlled study of atrasentan in patients with IgA nephropathy at risk of progressive loss of renal function. Oct 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04573478
Complement inhibitors
There is convincing evidence that complement activation plays a pivotal role in glomerular injury in IgAN. Several studies are underway examining novel agents that can selectively inhibit complement activation through mannose-binding lectin associated serine protease 2, C5, and factor B.[83]US National Library of Medicine. ClinicalTrials.gov. A randomized, double-blind, placebo-controlled, phase 3 study of the safety and efficacy of OMS721 in patients with Immunoglobulin A (IgA) nephropathy (ARTEMIS - IGAN). May 2019 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03608033
[84]US National Library of Medicine. ClinicalTrials.gov. A phase 2, randomized, double-blind, placebo-controlled study of cemdisiran in adult patients with IgA nephropathy. Dec 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03841448
[85]US National Library of Medicine. ClinicalTrials.gov. An open-label phase 2a clinical study to evaluate the effectiveness and safety of IONIS-FB-LRx, an antisense inhibitor of complement factor B, in adult subjects with primary IgA nephropathy. Oct 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04014335
Iptacopan, a first in class oral inhibitor of factor B, significantly reduced proteinuria in a phase 2 IgAN study, and a phase 3 trial is underway.[86]Gutiérrez E, Carvaca-Fontán F, Luzardo L, et al. A personalized update on IgA nephropathy: a new vision and new future challenges. Nephron. 2020;144(11):555-71.
https://www.doi.org/10.1159/000509997
http://www.ncbi.nlm.nih.gov/pubmed/32818944?tool=bestpractice.com
[87]US National Library of Medicine. ClinicalTrials.gov. An adaptive seamless randomized, double-blind, placebo-controlled, dose ranging study to investigate the efficacy and safety of LNP023 in primary IgA nephropathy patients. July 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03373461
[88]US National Library of Medicine. ClinicalTrials.gov. A multi-center, randomized, double-blind, placebo-controlled, parallel group, phase III study to evaluate the efficacy and safety of LNP023 in primary IgA nephropathy patients. Dec 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04578834
Selectively blocking C5a is of particular interest, as this may prevent glomerular inflammation while preserving production of C5b-9 to fight infection. In a small, open-label study, the use of avacopan (a C5a receptor antagonist) reduced proteinuria in patients with IgAN.[89]Harris CL, Pouw RB, Kavanagh D, et al. Developments in anti-complement therapy; from disease to clinical trial. Mol Immunol. 2018 Oct;102:89-119.
https://www.doi.org/10.1016/j.molimm.2018.06.008
http://www.ncbi.nlm.nih.gov/pubmed/30121124?tool=bestpractice.com
Drugs targeting BAFF and APRIL signalling to B cells
B-cell maturation and survival is dependent on the presence of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Serum BAFF and APRIL levels are elevated in patients with autoimmune disorders and correlate with autoantibody levels, and there is emerging evidence supporting a role for both BAFF and APRIL in IgAN. A number of different drugs are currently being evaluated in phase 2 clinical trials that target APRIL and/or BAFF signalling in IgAN.[90]US National Library of Medicine. ClinicalTrials.gov. A phase 1/2, multicenter trial to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BION-1301 in healthy volunteers and adults with IgA nephropathy. Dec 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03945318
[91]US National Library of Medicine. ClinicalTrials.gov. A multicenter, randomized, double-blind, placebo-controlled, multiple dose study to evaluate the efficacy and safety of VIS649 in participants with Immunoglobulin A (IgA) nephropathy. Sept 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04287985