A new alternative: inhibiting complement activation in patients with IgA nephropathy

Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN). A recent randomized controlled trial tested the efficacy and safety of iptacopan, a factor B inhibitor, in patients with IgAN. Iptacopan dose-dependently reduced proteinuria, and there was a pronounced decrease of urinary C5b-9. This offers the perspective of "personalizing" therapy, which would be a unique feature of this novel approach to IgAN. A phase III clinical trial (APPLAUSE-IgAN) is ongoing. Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN). A recent randomized controlled trial tested the efficacy and safety of iptacopan, a factor B inhibitor, in patients with IgAN. Iptacopan dose-dependently reduced proteinuria, and there was a pronounced decrease of urinary C5b-9. This offers the perspective of "personalizing" therapy, which would be a unique feature of this novel approach to IgAN. A phase III clinical trial (APPLAUSE-IgAN) is ongoing. These are exciting times for patients with IgA nephropathy (IgAN) given that more and more novel therapeutic approaches are emerging. There is widespread consensus that supportive measures should be maximized in all patients at risk for progressive loss of kidney function, but if this was not sufficient, the only other option in the past was high-dose systemic corticosteroid therapy. The efficacy of this approach has been reported variably with no benefit in a German cohort but retardation of kidney failure in a mostly Southeast Asian cohort.1Rauen T. Wied S. Fitzner C. et al.After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.Kidney Int. 2020; 98: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar,2Lv J. Wong M.G. Hladunewich M.A. et al.Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2022; 327: 1888-1898Crossref PubMed Scopus (87) Google Scholar However, consistently, high-dose corticosteroids induced a marked increase in adverse events, including infection-related mortality.1Rauen T. Wied S. Fitzner C. et al.After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.Kidney Int. 2020; 98: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar,2Lv J. Wong M.G. Hladunewich M.A. et al.Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2022; 327: 1888-1898Crossref PubMed Scopus (87) Google Scholar Thus, there was a high unmet need for safer, more specific, and effective therapies. The first approved drug for primary IgAN was Nefecon, a targeted release formulation of budesonide.3Lafayette R. Kristensen J. Stone A. et al.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; 402: 859-870Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In the phase III NefigArd trial, estimated glomerular filtration rate (eGFR) loss was retarded in the Nefecon group, and adverse events were mostly mild to moderate and in particular did not include an excess of infections or diabetes induction. At the same time, the supportive armamentarium also increased with the advent of sodium-glucose cotransporter-2 inhibitors being licensed for use in any type of chronic kidney disease and most recently the approval of sparsentan, a combined angiotensin-II receptor and endothelin A receptor blocker, for IgAN.4Nuffield Department of Population Health Renal Studies GroupSGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.Lancet. 2022; 400: 1788-1801Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar,5Travere Therapeutics. Travere Therapeutics announces confirmatory data from the phase 3 PROTECT study of FILSPARI® demonstrating long-term kidney function preservation in IgA nephropathy; narrowly missing eGFR total slope endpoint versus active control, Irbesartan.https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-confirmatory-data-phase-3-protectDate accessed: September 21, 2023Google Scholar Yet another novel approach to IgAN is based on the observations that mesangial complement C3 deposits are almost always present in biopsies of patients with IgAN. These C3 deposits are believed to result mostly from activation of the alternative and possibly lectin pathway and not from the classical pathway (Figure 1).6Duval A. Caillard S. Frémeaux-Bacchi V. The complement system in IgAN: mechanistic context for therapeutic opportunities..Nephrol Dial Transplant. 2023; 38: 2685-2693Crossref Scopus (4) Google Scholar,7Barratt J. Lafayette R. Zhang H. et al.IgA nephropathy: the lectin pathway and implications for targeted therapy.Kidney Int. 2023; 104: 254-264Abstract Full Text Full Text PDF Scopus (6) Google Scholar Iptacopan (also known as LNP023 or CCX168) is an orally available inhibitor of factor B that has been studied for its potential use in various inflammatory and autoimmune diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Inhibition of factor B prevents the activity of the alternative pathway C3 convertase, blocking the cleavage of C3, and reduces the activation and the action of the amplification loop (Figure 1). Via the later action, iptacopan also dampens the consequence of lectin and classical pathway activation. In this issue of Kidney International, Zhang et al.8Zhang H. Rizk D.V. Perkovic V. 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; 105: 189-199Abstract Full Text Full Text PDF Scopus (3) Google Scholar describe the results of a randomized controlled double-blind phase II trial of iptacopan in patients with primary IgAN and an eGFR of ≥30 ml/min per 1.73 m2. In the 3-month part 1 of the trial, patients received placebo or 10, 50, or 200 mg of iptacopan twice daily. The 6-month part 2 then followed at the same dosages but with the addition of a 100 mg twice-daily dose. Iptacopan dose-dependently led to a reduction in proteinuria (determined as a urine-protein creatinine ratio in a 24-hour collection) and at the 200 mg dose proteinuria decreased by 23% at 3 months and 40% at 6 months. In parallel, plasma levels of factor B decreased by 20% to 30%, and the Wieslab assay, which is an integrated measure of alternative complement pathway activity, confirmed the pharmacologic activity of iptacopan in the patients. More importantly, urinary C5b-9 levels were normalized within days at iptacopan dosages of 50 mg and higher. Adverse events for the most part were not different between the study arms, and in particular, no increase in infectious complications was noted in the iptacopan arms. Note that all patients had to be vaccinated against meningococci, pneumococci, and hemophilus influenza before randomization, and 3 patients additionally received long-term antibiotics. Taken together, the data of the above phase II trial offer an exciting perspective of a new treatment for patients with IgAN. Iptacopan can be taken orally and appears safe, based on the phase II data in IgAN but also data in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, as long as patients are adequately vaccinated before initiation of the drug. The proteinuria reduction observed over 3 and 6 months compares well with that seen in other trials in IgAN2Lv J. Wong M.G. Hladunewich M.A. et al.Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2022; 327: 1888-1898Crossref PubMed Scopus (87) Google Scholar,3Lafayette R. Kristensen J. Stone A. et al.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; 402: 859-870Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,5Travere Therapeutics. Travere Therapeutics announces confirmatory data from the phase 3 PROTECT study of FILSPARI® demonstrating long-term kidney function preservation in IgA nephropathy; narrowly missing eGFR total slope endpoint versus active control, Irbesartan.https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-confirmatory-data-phase-3-protectDate accessed: September 21, 2023Google Scholar and is a predictor of long-term eGFR benefit to be tested in the ongoing phase III APPLAUSE-IgAN (Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients) trial (NCT04578834). A unique feature of the phase II study is that the activity of and biological response to iptacopan could be monitored via biomarkers in blood but in particular via C5b-9 in the urine. Importantly, the pronounced more than 15-fold drop of urinary C5b-9 levels within days of starting iptacopan finally resolves the concern that urinary C5b-9 largely reflects proteinuria and thus spillage from blood. Rather, the iptacopan data suggest that urine C5b-9 mostly originates from intrarenal C5b-9 generation. This raises the hope that the activity of IgAN can be assessed noninvasively via urinary C5b-9 excretion. As is standard in clinical trials in IgAN nowadays, all patients in the phase II iptacopan trial required a 3-month run-in period, where renin-angiotensin system (RAS) blockers were uptitrated. At randomization, 49% of the patients were indeed on the maximally allowed dosage and 75% had received at least 50% of the maximum dose. However, a 6-month run-in period might have led to higher proteinuria reductions,9Bagchi S. Mani K. Swamy A. et al.Supportive management of IgA nephropathy with renin-angiotensin blockade, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) study.Kidney Int Rep. 2021; 6: 1661-1668Abstract Full Text Full Text PDF Scopus (12) Google Scholar and, more importantly, a systematic uptitration of RAS blockers, as in the phase III PROTECT trial with irbesartan, might have led to more patients receiving maximally allowed RAS-blocker dosages (note that >90% of the patients with IgAN assigned to the irbesartan arm of PROTECT reached the maximally allowed dose of 300 mg/d).5Travere Therapeutics. Travere Therapeutics announces confirmatory data from the phase 3 PROTECT study of FILSPARI® demonstrating long-term kidney function preservation in IgA nephropathy; narrowly missing eGFR total slope endpoint versus active control, Irbesartan.https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-confirmatory-data-phase-3-protectDate accessed: September 21, 2023Google Scholar Given the small group sizes in the iptacopan phase II study (only 10 patients in the placebo group provided data at 6 months), eGFR data are difficult to interpret. But it is notable that the placebo group lost over 3 ml/min of eGFR during 6 months compared with approximately less than 2 ml/min per 6 months in the irbesartan arm of PROTECT (A Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy). More reliable data will obviously be generated in the ongoing APPLAUSE-IgAN trial. More long-term data on the course of eGFR during iptacopan therapy are also eagerly awaited because iptacopan may not only reduce inflammatory glomerular damage but, based on preclinical data, could also reduce the progression of kidney tubulointerstitial damage and fibrosis.7Barratt J. Lafayette R. Zhang H. et al.IgA nephropathy: the lectin pathway and implications for targeted therapy.Kidney Int. 2023; 104: 254-264Abstract Full Text Full Text PDF Scopus (6) Google Scholar The latter effect of iptacopan would be unlikely to be detectable via eGFR data after 6 months but might affect eGFR levels after 2 years or longer as in the APPLAUSE-IgAN trial. Given the rapidly evolving field of IgAN therapy, it is important that the phase III APPLAUSE-IgAN study contain a subgroup of patients who receive both iptacopan and a sodium-glucose cotransporter-2 inhibitor, which is now a widely accepted standard of care on top of RAS blockade in patients with IgAN. In summary, the authors and sponsor are to be congratulated for performing phase II trial, which may ultimately result in the approval of yet another approach to progressive IgAN. The key challenge of the future will then be to design optimal (personalized) combinations of therapies to ideally induce full remission of IgAN. At least in the case of iptacopan, there is hope that these decisions can be based on urinary C5b-9 levels. JF has received consultancy and speaker honoraria from AstraZeneca, Boehringer, Calliditas, Chinnok, CSL Vifor, Novartis, Omeros, Stadapharm, and Travere. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathyKidney InternationalVol. 105Issue 1PreviewTargeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m2 and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Full-Text PDF Open Access