Avenciguat for use in the treatment of chronic kidney disease and screening method for predicting beneficial response thereto

Abstract

This invention relates to the use of avenciguat to treat, reduce the risk of, and / or delay the progression chronic kidney disease (CKD) in CKD patients.

Description

The inventions relates to methods for using a soluble guanylate cyclase (sGC) activator to treat patients with chronic kidney disease. BACKGROUND OF THE INVENTION The prevalence of chronic kidney disease (CKD) has been increasing in recent decades. Most recent estimates indicate that approximately 840 million people globally are affected. (Jager KJ et al., A single number for advocacy and communication—worldwide more than 850 million individuals have kidney diseases. Nephrol Dial Transplant 2019; 34: 1803-5.) Reninangiotensin system (RAS) inhibition with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) has been a mainstay of evidence-based therapy to slow the progressive loss of kidney function in patients with CKD. (Chen TK et al., Chronic kidney disease diagnosis and management: a review. JAMA 2019; 322: 1294-304; Evans M et al., A narrative review of chronic kidney disease in clinical practice; current challenges and future perspectives. Adv Ther 2022; 39: 33-43; Kidney Disease: Improving Global Outcomes. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Vol 3, issue 1 (January 2013); and Garcia Sanchez JJ et al., Treatments for chronic kidney disease: a systematic literature review of randomized controlled trials. Adv Ther 2022; 39: 193-220.) Sodium glucose co-transporter 2 (SGLT2) inhibitors and the non-steroidal mineralocorticoid receptor antagonist finerenone have become part of the guideline-recommended therapy for patients with type 2 diabetes and CKD, as well as glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients who have not achieved glycemic targets despite treatment, (de Boer IH et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2022; 102: 974-89.) Despite these newer therapies reducing rates of kidney function decline and the risk of adverse clinical kidney and cardiovascular outcomes, the risk remains high, in particular for patients whose albuminuria levels remain elevated. (Mende CW. Chronic kidney disease and SGLT2 inhibitors: a review of the evolving treatment landscape. Adv Ther 2022; 39: 148-64; Zhang MZ et al., Efficacy and safety of finerenone in chronic kidney disease: a systematic review and meta-analysis of randomized clinical trials. Front Pharmacol 2022; 13: 819327; Bakris GL ct al., Effect of fincrcnonc on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383: 2219-29. Heerspink HJLet al., Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383: 1436-46; and Oshima M et al., Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a posthoc analysis from the CREDENCE trial. J Am Soc Nephrol 2020; 31: 2925-36.) Endothelial dysfunction is common in patients with CKD and has been linked to poor kidney and cardiovascular outcomes. (Theodorakopoulou MP et al., Endothelial and microvascular function in CKD: evaluation methods and associations with outcomes. Eur J Clin Invest 2021; 51: el3557; Baaten C et al., Endothelial cell dysfunction and increased cardiovascular risk in patients with chronic kidney disease. Circ Res 2023; 132: 970-92; and Krishnan SM et al., The impact of the nitric oxide (NO) / soluble guanylyl cyclase (sGC) signaling cascade on kidney health and disease: a preclinical perspective. Int J Mol Sci 2018; 19: 1712.) Soluble guanylyl cyclase (sGC) is the primary receptor for nitric oxide (NO), and a key mediator involved in the NO-cyclic guanosine monophosphate (cGMP) signaling pathway in the kidney. This pathway is impaired in patients with CKD due to insufficient NO production, increased scavenging of available NO by superoxide, and reduced responsiveness to available NO, ultimately culminating in endothelial dysfunction. (Roumeliotis S et al., Endothelial dysfunction in chronic kidney disease, from biology to clinical outcomes: a 2020 update. J Clin Med 2020; 9: 2359.) Impaired NO-sGC-cGMP signaling has been associated with increased risk of CKD progression, supporting therapeutic strategies targeting this pathway. (Stehle D et al., Novel soluble guanylyl cyclase activators increase glomerular cGMP, induce vasodilation and improve blood flow in the murine kidney. Br J Pharmacol 2022; 179: 2476-89.) Avenciguat, also known as BI 685509, is an sGC activator having the structure: Avenciguat is an NO-independent activator of sGC intended to restore endothelial function, thereby slowing the progression of kidney function loss and reducing cardiovascular disease risk in patients with CKD. (Reinhart GA et al., The novel, clinical-stage soluble guanylate cyclase activator BI 685509 protects from disease progression in models of renal injury and disease. J Pharmacol Exp Ther 2023; 384: 382-92.) A phase lb study in 74 patients with type 1 or type 2 diabetes and CKD demonstrated that avenciguat was generally well tolerated, and suggested a beneficial effect for avenciguat in lowering albuminuria. (Chemey DZI et al., Safety, tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: a randomized trial. Diabetes Obes Metab 2023; 25: 221826.) These initial data supported a larger study in a broader population to assess the effects of avenciguat on albuminuria and other kidney and haemodynamic parameters including blood pressure and estimated glomerular filtration rate (eGFR). Glomerular diseases are a subgroup of etiologies causing CKD and represent app. 15% of the overall CKD population. It can further be subdivided into mainly autoimmune, primary causes and secondary forms, where the original stimulus sits outside the kidney. The most important disease entities counting into this CKD subgroup are IgA nephropathy, focal-segmental glomerulosclerosis, minimal change disease, membranous nephropathy, lupus nephritis, post-infectious glomerulonephritis, ANCA-associated glomerulonephritis, anti-GBM glomerulonephritis, C3 / C4 glomerulopathy, immune-complex mediated glomerulonephritis, membranoproliferative glomerulonephritis, fibrillary and immunotactoid glomerulonephritis. Besides disease-specific pathophysiology, they usually share similar pathophysiological pathways such as endothelial dysfunction, inflammation and fibrosis. The kidney-related clinical presentation of the patients is variable, but usually includes impaired kidney function (i.e. reduced glomerular filtration rate) and signs / symptoms of kidney damage such as elevated levels of proteinuria, hematuria and related clinical abnormalities such as high blood pressure and peripheral edema. Prognosis of these patients is particularly poor as in general the rates of kidney function decline and subsequent risk of kidney failure is among the highest within the CKD etiologies spectrum. Current treatment options are mostly similar to the broad CKD population and include inhibition of the Renin-Angiotensin-Aldosterone-System (RAASi) and inhibition of the tubular- sodium-glucose-co-transporter-2 (SGLT2i) but are still insufficient with a remaining unmet need. Emerging treatments for some of the disease entities are in general immunosuppressive, which might be associated with severe side effects such as infections. Therefore, there is high unmet need for new therapeutics to treat patients with chronic kidney disease. BRIEF SUMMARY OF THE INVENTION In its broadest embodiment, the present invention relates methods for treating patients with chronic kidney disease, comprising administering to a patient in need thereof a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention relates to methods for treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents. In another embodiment, the invention relates to avenciguat, or a pharmaceutically acceptable salt thereof, for use in treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient, optionally in combination with one or more other therapeutic agents. In another embodiment, the CKD patient is diabetic. In another embodiment, the CKD patient in nondiabetic. In another embodiment, the CKD patient has a glomerular disease, type 1 diabetes or type 2 diabetes. In another embodiment, the CKD patient has a glomerular disease. In another embodiment, the CKD patient has a glomerular disease selected from the group consisting of IgA nephropathy, IgA vasculitis, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, lupus nephritis, minimal change disease, anti-GBM (Goodpasture’s disease), infection-related glomerulonephritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex membranoproliferative glomerulonephritis, C3 / C4 glomerulopathy, fibrillary glomerulonephritis, and immunotactoid glomerulopathy. In another embodiment, the CKD patient has a glomerular disease selected from the group consisting of IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy. In one embodiment, the patient that is at least 18 years of age. In another embodiment, the patient is at least 12 years of age. In another embodiment, the patient is at least 12 years of age but less than 18 years of age. In another embodiment, the invention relates to methods for reducing proteinuria in an adult patient with immunoglobulin A nephropathy (IgAN) I focal-segmental glomerulosclerosis / minimal-change disease (FSGS / MCD) at risk of disease progression, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents. In another embodiment, the adult patient has a urine protein-to-creatinine ratio (UPCR) >1.0 g / g. In another embodiment, the invention relates to avenciguat, or a pharmaceutically acceptable salt thereof, for reducing proteinuria in an adult patient with immunoglobulin A nephropathy (IgAN) I focal-segmental glomerulosclerosis / minimal-change disease (FSGS / MCD) at risk of disease progression, optionally in combination with one or more other therapeutic agents. In another embodiment, the adult patient has a urine protein-to-creatinine ratio (UPCR) >1.0 g / g. In another embodiment, the invention relates to methods for reducing proteinuria in an adult patient with glomerulonephritis at risk of disease progression, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents. In another embodiment, the adult patient has a urine protein-to-creatinine ratio (UPCR) >1.0 g / g. In another embodiment, the invention relates to avenciguat, or a pharmaceutically acceptable salt thereof, for use in reducing proteinuria in an adult patient with glomerulonephritis at risk of disease progression, optionally in combination with one or more other therapeutic agents. In another embodiment, the adult patient has a urine protein-to-creatinine ratio (UPCR) >1.0 g / g. In another embodiment, the invention relates to methods for reducing the loss of kidney function in an adult with glomerulonephritis who is at risk of disease progression, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents. In another embodiment, the adult patient has a urine protein-to-creatinine ratio (UPCR) >1.0 g / g. In another embodiment, the invention relates to avenciguat, or a pharmaceutically acceptable salt thereof, for reducing the loss of kidney function in an adult with glomerulonephritis who is at risk of disease progression, optionally in combination with one or more other therapeutic agents. In another embodiment, the adult patient has a urine protein-to-creatinine ratio (UPCR) >1.0 g / g. In another embodiment, the invention relates to methods for treating glomerulonephritis in adults at risk of disease progression with a urine protein-to-creatinine ratio (UPCR) >1.0 g / g, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents. In another embodiment, the invention relates to avenciguat, or a pharmaceutically acceptable salt thereof, for treating glomerulonephritis in adults at risk of disease progression with a urine protein-to-creatinine ratio (UPCR) >1.0 g / g, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents. In one embodiment, the methods or uses of the invention provide at least a 10% reduction in UPCR from baseline after 36 weeks of treatment as measured in first morning void; in another embodiment, at least a 20% reduction in UPCR from baseline after 36 weeks of treatment; in another embodiment, at least a 30% reduction in UPCR from baseline after 36 weeks of treatment. In one embodiment, the methods or uses of the invention provide a sustained decline in eGFR by >57% from baseline as measured in first morning void after 20 weeks of treatment; in another embodiment, a sustained decline in eGFR by >50% from baseline as measured in first morning void after 20 weeks of treatment; and in another embodiment, a sustained decline in eGFR by >40% from baseline as measured in first morning void after 20 weeks of treatment. In one embodiment, the methods or uses of the invention provide a sustained decline in eGFR by >57% from baseline as measured in first morning void after 36 weeks of treatment; in another embodiment, a sustained decline in eGFR by >50% from baseline as measured in first morning void after 36 weeks of treatment; and in another embodiment, a sustained decline in eGFR by >40% from baseline as measured in first morning void after 36 weeks of treatment. In another embodiment, the invention relates to the use of avenciguat, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient. In another embodiment, the invention relates to any of the embodiments above, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg. In another embodiment, the invention relates to any of the embodiments above, wherein avenciguat is administered with up-titration to the highest tolerable dose. In another embodiment, the invention relates to any of the embodiments above, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, each administered three times daily (tid). In another embodiment, the invention relates to any of the embodiments above, wherein avcnciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, each administered two times daily (bid). In another embodiment, the invention relates to any of the embodiments above, wherein avenciguat is administered to the patient tid in an amount of 3 mg, 4 mg or 5 mg. In another embodiment, the invention relates to any of the embodiments above, wherein the treatment reduces the level of albuminuria in the patient. In another embodiment, the invention relates to any of the embodiments above, wherein the method reduces the amount of albuminuria by up to 13% as compared to placebo. In another embodiment, the invention relates to any of the embodiments above, wherein the method reduces the amount of albuminuria by up to 35% as compared to placebo. In another embodiment, the invention relates to methods for lowering the albuminuria in a CKD patient, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to the embodiment immediately below, wherein the CKD patient has a glomerular disease, type 1 diabetes or type 2 diabetes. In another embodiment, the invention relates to use of avenciguat, or a pharmaceutically acceptable salt thereof, for lowering the albuminuria in a CKD patient. In another embodiment, the invention relates to the embodiment immediately below, wherein the CKD patient has a glomerular disease, type 1 diabetes or type 2 diabetes. In another embodiment, the invention relates to the four embodiments immediately above, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg; or avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, each administered three times daily (tid); or avenciguat is administered to the patient tid in an amount of 3 mg; or avenciguat is administered to the patient tid in an amount of 4 mg; or avenciguat is administered to the patient tid in an amount of 5 mg. In another embodiment, the invention relates to any of the embodiments described above, wherein avcnciguat is used in combination with, or as an add on therapy, to an additional active agent. In another embodiment, the additional active agent is selected from the group consisting of: an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB). an antihypertensive, a beta-blocker, a diabetes treatment, a statin, an antithrombotic drug, a diuretic, a mineralocorticoid receptor antagonist (MRA), a endothelin receptor antagonist (ERA), and / or an immunosuppressive. Nonlimiting examples of ACE inhibitors include captopril, lisinopril, enalapril, and ramipril. Nonlimiting examples of ARBs include losartan, valsartan, candesartan and irbesartan. Nonlimiting examples of antihypertensives include prazosin and hydralazine. Nonlimiting examples of beta blockers include atenolol, metoprolol, bisoprolol, carvedilol and propranolol. Nonlimiting examples of compounds for diabetes treatment include SGLT2 inhibitors such as empagliflozin or dapagliflozin; insulin or insulin analogs; DPP4 inhibitors such as linagliptin, sitagliptin or saxagliptin; GLP-1 receptor agonists such as liraglutide and semaglutide; and metformin. Nonlimiting examples of statins include atorvastatin, simvastatin and rosuvastatin. Nonlimiting examples of antithrombotics include warfarin; direct oral anticoagulants such as apixaban, rivaroxaban, and dabigatran; low molecular weight heparins such as cnoxaparin and dalteparin; and antiplatelet agents such as aspirin and clopidogrel. Nonlimiting example of diuretics include loop (high ceiling) diuretics such as furosemide, bumetanide, ethacrynic acid and torsemide; thiazide (low ceiling) diuretics such as hydrochlorothiazide, chlorthalidone, metolazone and betolazone; and potassium-sparing diuretics such as spironolactone, eplerenone and amiloride. Nonlimiting example of MRAs include spironolactone, eplerenone and finerenone. Nonlimiting examples of erythropoiesis-stimulating agents include epoetin alfa and darbepoetin alfa. Nonlimiting examples of immunosuppressants include prednisone, cyclophosphamide and tacrolimus. The additional active can be a RAAS inhibitor including the ARBs and ACE inhibitors mentioned above; direct renin inhibitors such as aliskiren; spirolactone; and eplerenone. In another embodiment, the twice-daily dosage of avcnciguat comprises a dose up-titration from 1 mg twice per day to a maximum does of 4 mg twice per day (“dose up-titration”). In another embodiment, the dose up-titration comprises: administering avenciguat in an amount of 1 mg twice per day for at least seven days, administering avenciguat in an amount of 2 mg twice per day if the 1 mg twice per day dose is tolerated, administering avenciguat in an amount of 3 mg twice per day if the 2 mg twice per dose is tolerated, and administering avenciguat in an amount of 4 mg twice per day if the 3 mg twice per dose is tolerated. In another embodiment, the dose up-titration comprises: administering avenciguat in an amount of 1 mg twice per day for at least seven days, administering avenciguat in an amount of 2 mg twice per day for at least 14 days if the 1 mg twice per day dose is tolerated, administering avenciguat in an amount of 3 mg twice per day for at least 14 days if the 2 mg twice per day dose is tolerated, and administering avenciguat in an amount of 4 mg twice per day for at least 14 days if the 3 mg twice per day dose is tolerated In another embodiment, patients who do not tolerate an increased dose are returned to the maximum tolerated dose. In another embodiment, avenciguat is taken with food to alleviate or reduce one or more intolerabilities (adverse events). Nonlimiting examples of intolerabilities (adverse events) include very low blood pressure or signs and / or symptoms of hypotension. In one embodiment, the invention relates to a method for detecting the presence or absence of a beneficial response in an adult patient with immunoglobulin A nephropathy (IgAN) I focal-segmental glomerulosclerosis / minimal-change disease (FSGS / MCD) at risk of disease progression after administration of avenciguat, comprising: (a) obtaining a biological sample from the patient pre-treatment and post-treatment after administration of avenciguat; (b) measuring in each sample the level of one or more biomarkers, or the level of expression of one or more biomarkers in each sample pre-treatment and post-treatment; (c) comparing the pre-treatment level to post-treatment level of the biomarkers; and (d) determining the difference in levels between the pre-treatment sample and the post-treatment sample, wherein the one or more biomarkers comprise microRNAs selected from the group consisting of miR-192-5p, miR-194-5p and miR-411-5p. In another embodiment, the one or more biomarkers comprise microRNAs selected from the group consisting of miR-192-5p and miR-194-5p, wherein downregulation or upregulation posttreatment as compared to pretreatment baseline indicates beneficial response. In another embodiment, the invention relates to the embodiment immediately above wherein the biological sample is urine. In another embodiment, the invention relates to the two embodiments immediately above, wherein the levels of one or more of microRNAs miR-192-5p and miR-194-5p in urine is correlated with UACR changes. In another embodiment, the invention relates to the embodiment immediately above, wherein correlation of microRNAs and UACR is observed after administering avenciguat up to 20 weeks after the initial treatment with avenciguat. In another embodiment, the invention relates to the embodiment immediately above, wherein correlation of microRNAs and UACR is observed after administering avenciguat up to 20 weeks after the initial treatment with the maximum tolerated dose of avenciguat. In another embodiment, the invention relates to the embodiment immediately above, wherein correlation of microRNAs and UACR is observed after administering avenciguat up to 20 weeks of treatment with avenciguat administered 4 mg bid. In another embodiment, the invention relates to the four embodiments immediately above, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg; or avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, each administered three times daily (tid); or avenciguat is administered to the patient tid in an amount of 3 mg; or avenciguat is administered to the patient tid in an amount of 4 mg; or avenciguat is administered to the patient tid in an amount of 5 mg. In another embodiment, the invention relates to any of the five embodiments immediately above, further comprising continuing the administration of maintenance doses of avenciguat to the patient if the difference in levels between the pre-treatment sample and the post-treatment reflects a beneficial response in the patient. In another embodiment, the invention relates to any of the embodiments above where the avenciguat is administered to the patient as a pharmaceutical composition comprising avenciguat, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In another embodiment, the invention relates to the use of avenciguat to slow kidney function decline in adults and pediatric patients aged 12 years and older with chronic glomerulonephritis who are at risk for disease progression and weighing at least 40 kg. In another embodiment, the invention relates to the use of avenciguat to slow kidney function decline in adults and pediatric patients aged 2 years and older with chronic glomerulonephritis who are at risk for disease progression. In another embodiment, the invention relates to any of the embodiments above, wherein avenciguat is administer in the form of a free-base (that is, a non-salt form). Other embodiments of the invention are described below and in the claims. BRIEF DESCRIPTION OF THE SEVERAL VIEW OF THE DRAWINGS Figure 1 shows the subgroup analysis of change from baseline in 10-hour UACR at week 20. Data shown arc for avenciguat 3 mg versus placebo in the pooled population. BMI, body mass index. Figure 2 shows a volcano plot of treatment-mediated changes in 1,537 miRNAs in patients with glomerular diseases treated with 3 mg of avenciguat who also showed >20% reduction in UACR over 20 weeks of treatment. The data shown based on changes in miRNA from baseline (before treatment) to end of treatment. Figures 3a and 3b show the effect of tid dosing of 1 mg, 2 mg and 3 mg of avenciguat on miR-192-5p (Figure 3a) and miR-194-5p (Figure 3b) in patients with glomerular disease who also showed >20% reduction in UACR over 20 weeks of treatment. Figure 3a is a comparative analysis of hsa-miR-192-5p log2 counts per million in responders and non-responders of individual dose groups at visit 03 (baseline, V03) and end-of-treatment (EOT). Statistical significance was assessed using Wilcoxon matched pairs signed rank tests. Figure 3b is a comparative analysis of hsa-miR-194-5p log2 counts per million in responders and non responders of individual dose groups at visit 03 (baseline, V03) and end-of-treatment (EOT). Statistical significance was assessed using Wilcoxon matched pairs signed rank tests. Figure 4 shows schematic of a Phase 3 trial design according to one embodiment of the invention. DETAILED DESCRIPTION OF THE INVENTION Abbreviations: ACE Angiotensin-converting enzyme an AE Adverse event AESI Adverse event of special interest AKI Acute kidney injury ANCA Antineutrophil cytoplasmic antibody Anti-GBM disease Goodpasture’s disease ARB Angiotensin 11 receptor blocker AUC Area under the curve BID Bis in die (twice daily) BMI Body mass index cGMP Cyclic guanosine monophosphate CI Confidence interval CKD Chronic kidney disease Cmax Maximum plasma concentration COA Clinical outcome assessment DKD Diabetic kidney disease DPP-IV or DPP4 Dipeptidyl peptidase 4 eGFR Estimated glomerular filtration rate EOS End of study EOT End of treatment ERA Endothelin receptor antagonist ESKD End-stage kidney disease FMV First morning void FSGS Focal segmental glomerulosclerosis (FSGS), FUp Follow-up GD Glomerular disease GLP-1 Glucagon-like peptide 1 GN Glomerulonephritides IgAN Immunoglobulin A nephropathy IMP Investigational medicinal product IQR InterQuartile Range KDIGO Kidney disease: improving global outcomes miRNA Micro ribonucleic acid MCD Minimal change disease MMRM Mixed model with repeated MRA Mineralocorticoid receptor antagonist OATP1B1 Organic anion transporting polypeptide 1B1 NO Nitric oxide PD Pharmacodynamic PDE Phosphodiesterase PK Pharmacokinetic s PKS PK set Plc Placebo PopPK Population pharmacokinetics RAAS Renin-angiotensin-aldosterone system RAS Renin-angiotensin system REP Residual effect period RNA Ribonucleic acid SD Standard deviation sGC Soluble guanylate synthase SGLT2 Sodium glucose co-transporter 2 SGLT2i Sodium glucose co-transporter 2 inhibitor SoC Standard of care SBP Systolic blood pressure TID Ter in die (three times daily) UACR Urine albumin-to-creatinine ratio UPCR Urinary protein creatinine ratio WOCBP Woman of childbearing potential The terms “avenciguat” and “IMP” are used interchangeably herein. As used herein, the term “chronic kidney disease patient” refers to a patient having an eGFR >20 and <90 mL / min / 1 -73 m2, and urine albumin-to-creatinine ratio (UACR) >200 and <3500 mg / g. New therapies to slow the progressive loss of kidney function in patients with CKD are still needed despite recent progress. As avenciguat has a different mode of action versus current guideline-recommended medications, including SGLT2 inhibitors and finerenone and GLP-1A RAs, it could be beneficial in the treatment of CKD. Indeed, a subgroup analysis by baseline SGLT2 inhibitor use demonstrated that avenciguat reduced UACR similarly in patients using and not using SGLT2 inhibitors, supporting future clinical trials to prospectively assess potential complementary kidney protective effects of adding sGC activators to current guideline-recommended treatment. There is emerging evidence that supports a role of the NO-sGC-cGMP signalling pathway in the pathophysiology of chronic diseases including cardiovascular and kidney diseases. (See Krishnan SM et al. Int J Mol Sci 2018; 19: 1712.) Two compound classes modulating sGC in a NO-independent manner are available: sGC stimulators and sGC activators. sGC stimulators directly stimulate the native form of sGC by binding to the haem-containing moiety of the enzyme thereby sensitising sGC to low levels of NO and stabilising NO-sGC binding. (Sandner P et al., Soluble GC stimulators and activators: past, present and future. Br J Pharmacol 2021; published online Dec 01.) Conversely, sGC activators such as avenciguat bind to the unoccupied haem-binding domain of the enzyme, thereby mimicking the activation of the haem-free NO-unresponsive form of sGC or activate the haem-free (apo) NO-unresponsive form of sGC.20 In diseases associated with high oxidative stress such as CKD, sGC might be mostly prevalent in its oxidized form. Accordingly, in these diseases, patients may theoretically be more responsive to sGC activators compared with stimulators. A phase 2 study in patients with type 2 diabetes and CKD reported that the experimental sGC activator runcaciguat reduced albuminuria by -30% in both patients receiving and not receiving concomitant SGLT2 inhibitor treatment. (Gansevoort RT, The sGC activator runcaciguat is associated with a strong reduction in albuminuria and good tolerability in CKD patients with or without an SGLT2 inhibitor: results of the CONCORD study. Abstract presented at the 60th ERA Congress, June 15-18, 2023; Milan, Italy.) However, this was a small study, and larger studies are needed to confirm these initial findings with this agent. In contrast, a phase 2 study in patients with diabetic kidney disease reported that treatment with the sGC stimulator praliciguat compared to placebo resulted in a non-significant albuminuria reduction of 28%. Our study in 500 patients, including cohorts with diabetes mellitus (predominantly type 2) and without diabetes, confirms the albuminuria-lowering properties of sGC activation with avenciguat in a robust and rigorous efficacy comparison in patients with CKD with and without diabetic kidney disease. In contrast to other phase 2 studies that used UACR from an FMV urine sample to establish drug efficacy, we chose to characterise the effect of avenciguat on UACR assessed from a daytime 10-hour urine sample. (Hanrahan JP et al., Effects of the soluble guanylate cyclase stimulator praliciguat in diabetic kidney disease: a randomized placebo-controlled clinical trial. Clin J Am Soc Nephrol 2020; 16: 59-69; and Green JB et al. Design of the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using aUACR Endpoint study (CONFIDENCE). Nephrol Dial Transplant 2023; 38: 894-903.) This decision was based on the short half-life of avcnciguat and an earlier study suggesting that the albuminuria-lowering effects of avenciguat may be more pronounced when assessed during the day compared with the night. (Cherney DZI et al., Diabetes Obes Metab 2023; 25: 2218-26.) Results of the present study showed consistent effects irrespective of whether UACR was measured in 10-hour daytime urine samples or FMV samples, indicating that in steady state, the albuminuria-lowering effects of avenciguat are sustained overnight. This indicates that first morning void UACR can be used in future trials with avenciguat, reflecting the guideline recommended approach for quantification of UACR in clinical practice. Based on the robust and consistent association between early treatment effects on albuminuria and treatment effects on clinical kidney endpoints as shown in large meta-analyses, the observed reduction in albuminuria with the highest avenciguat dose has the potential to translate into long-term clinical benefit. (Coresh J et al., Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies. Lancet Diabetes Endocrinol 2019; 7: 115-27; and Heerspink HJL et al., Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol 2019; 7: 128-39.) Phase 2b Clinical Trials The results of the study described below further show that avenciguat was effective in lowering albuminuria and was well tolerated in patients with CKD. One aspect of the subject invention arose from two phase 2b, dose-finding, randomised, placebo-controlled trials to characterise the effects of avenciguat on albuminuria and its safety in patients with CKD to select the appropriate dosage for further investigation in clinical trials. The study involved two randomised, phase 2, double-blind, placebo-controlled trials of identical design. Adults with CKD (estimated glomerular filtration rate [eGFR] >20 and <90 mL / min / 1 -73 m2, urine albumin-to-creatinine ratio [UACR] >200 and <3500 mg / g) were randomised to 20 weeks of treatment with placebo or avenciguat 1, 2, or 3 mg three times daily (tid) as adjunct to angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. The primary endpoint was change from baseline in UACR in 10-hour urine at week 20. Secondary endpoints included change from baseline in UACR in first morning void (FMV) urine at week 20. Safety was monitored throughout. Pooled data analyses were prc-spccificd. A total of 500 patients (mean age 62 years [standard deviation (SD) 13]; mean eGFR 44 mL / min / 1 73 m2 [SD 18] and median 10-hour UACR 719 mg / g) were randomised and treated with placebo (n=122), or avenciguat 1 mg (n=125), 2 mg (n=126), or 3 mg (n=127) tid. All 243 patients in study one and 27 of 261 patients in study two had diabetes. Avenciguat 1, 2, and 3 mg tid reduced UACR in 10-hour and FMV urine compared with placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg tid were -15 5% (-26-4, -3 0), -13 2% (-24-6, -0 1), and -215% (-317, -9 8), respectively; corresponding changes in FMVurine were -19-4% (-30 0, -7-3), -15-5% (-26-9, -2-5), and -23 4% (-33 ■ 5, -11 8). Avenciguat was well tolerated; overall frequency of adverse events was low and similar to placebo. Applicant studied the effect of avenciguat on urinary exosomal miRNA in patients with CKD and where the underlying kidney disease is diabetic kidney disease, glomerular disease, hypertensive kidney disease, and other / unknown. (See Figure 1.) Figure 2 shows a volcano plot of treatment-mediated changes in 1,537 miRNAs in 28 patients with glomerular diseases treated with 3 mg of avenciguat tid who showed > 20% reduction in UACR over the 20-week course of treatment. As shown in Figure 2, nine miRNAs are regulated. However, only three of the regulated miRNAs correlate with UACR changes: miR-192-5p, miR-194-5p and miR-411-5p. The concentration of each miR-192-5p, miR-194-5p and miR-411-5p decreased with decreasing UACR for 3 mg tid treatment. Figures 3a and 3b show the effect of tid dosing of 1 mg (N=42), 2 mg (N=12) and 3 (N=16) mg of avenciguat on miR-192-5p (Figure 2a) and miR-194-5p (Figure 2b) in patients with glomerular disease who also showed >20% reduction in UACR over 20 weeks of treatment. The levels of miR-192-5p (Figure 2a) and miR-194-5p (Figure 2b) decreased in patients administered a 3 mg tid. However, no significant decrease in the levels of these miRNAs are observed when avenciguat is administered to these patents at a 1 mg tid or 2 mg tid dosage. The observed inhibitory effects increase with increased dosages, suggesting that an increased dosage of avenciguat, for example, greater than 6 mg daily, may provide a better treatment dosage for patients with glomerular diseases. Applicant surprisingly found that avenciguat treatment had no effect on the miR-192-5p, miR-194-5p and miR-411-5p levels of patients with diabetic kidney disease or hypertensive kidney disease who also showed >20% reduction in UACR over 20 weeks of treatment. Additionally, Applicant found that the levels of miR-192-5p, miR-194-5p and miR-411-5p are similar at staid of treatment across all the three patient groups (glomerular disease, diabetic kidney disease, and hypertensive kidney disease). Moreover, the levels of these miRNAs were similar at stall of treatment amongst all patients with glomerular disease among patients who are responders (for example, a >20% reduction in UACR over 20 weeks of treatment thought) and nonresponders. The above biomarker results show that avenciguat has antifibrotic and immunomodulatory potential, which further suggest the use of avenciguat for treating patients with glomerular kidney disease. Additionally, both miRNAs (miR-192-5p and miR-194-5p) showed enrichment in podocytes, suggesting the use of avenciguat for treating glomerulonephritis by targeting podocytes. Study design The two phase 2 studies were randomised, double-blind, placebo-controlled clinical trials. The first trial was conducted across 78 centres in 16 countries and recruited patients with diabetic kidney disease; the second involved 110 centres in 19 countries and recruited patients with a primary CKD diagnosis other than diabetic kidney disease. Participants Adults aged >18 years with chronic kidney disease characterised by eGFR >20 and <90 mL / min / 1 73 m2, and urine albumin-to-creatinine ratio (UACR) >200 and <3500 mg / g were eligible for inclusion. Patients were using a maximum tolerated dose of either an ACE inhibitor or an ARB, but not both. For study one, patients had to have type 1 or type 2 diabetes mellitus. Conversely, patients with diabetes as a primary cause of CKD were excluded from study two. In both studies, patients planning to commence chronic renal replacement therapy during the trial were excluded. Randomisation and masking Patients were randomised to avenciguat 1 mg or placebo (3:1 ratio), 2 mg or placebo (3:1), or 3 mg or placebo (3:1) three times daily (tid). The randomisation list, generated by the sponsor of both clinical trials, was created by a pseudorandom number generator, and patients were stratified according to SGLT2 inhibitor use (both trials) and, for study one, diabetes type to ensure balance between treatment groups. Investigators could deduce the dose group of each patient because of differences in appearance between the three tablet strengths, but they were unaware whether each patient was receiving avenciguat or placebo. Patients were blinded to both dose and treatment. Procedures Study treatment comprised avenciguat administered orally tid for 20 weeks at a daily dose of 3, 6, or 9 mg or matching placebo. The daily dose during weeks 1 and 2 was 3 mg in all three dose groups; this was increased to 6 mg during weeks 3 and 4 in the 6 mg and 9 mg groups, and the 9 mg dose was administered from week 5 onwards. Study treatment was administered as adjunct to ACE inhibitor or ARB treatment, with or without SGLT2 inhibitors, plus local standard of care according to applicable guidelines. For patients experiencing adverse events (AEs), downtitration to the lower daily dose (or placebo for patients receiving 1 mg tid) was permissible. The study included 4 weeks of wash-out after the 20-week treatment period to assess off-drug effects. Urine samples (for UACR assessment) and blood samples (for measurement of eGFR, safety variables, biomarkers, and phannacokinetics) were collected throughout the study, during clinic visits and while patients were at home. Patients were requested to bring remaining study medication when attending the clinic, enabling assessment of treatment compliance. Physical examinations and vital sign evaluations were performed during clinic visits, and investigators maintained detailed records of all AEs. Assessments and endpoints The primary endpoint was change from baseline in log-transformed UACR measured in 10-hour urine (sampled from a 10-hour urine collection started after first morning void [FMV] of urine) at week 20. In keeping with prior studies, UACR was measured in a 10-hour day sample to maximise detection of a treatment effect given the short half-life of avenciguat. (Chemey DZI et al., Diabetes Obes Metab 2023; 25: 2218-26.) Secondary endpoints, also assessed at week 20, were change from baseline in log-transformed UACR in FMV urine, and the proportions of patients achieving >20% decreases in UACR in 10-hour and FMV urine samples. Change from baseline in eGFR was a further endpoint. AEs were coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA) and classified as mild, moderate, or severe. AEs of special interest (AESIs) were severe orthostatic dysregulation, severe hypotension, syncope, and potential severe elevations in liver enzymes. Statistical analyses To establish the required sample size, assuming effect sizes in log UACR change from baseline to week 20 of 0, 0-10, 0 20, 0 35 (corresponding to changes of 0%, 10%, 18% and 30%, respectively) with placebo and avenciguat dosages of 1,2, and 3 mg tid, a sample size of 60 per treatment, per study, was required to reject the null hypothesis of no dose relationship with onesided alpha value of 5% and a statistical power of 88 5%. For the combined studies, assuming effect sizes in log UACR change from baseline to week 20 of 0, 0.10, 0.16, 0.22 (corresponding to changes of 0%, 10%, 15% and 20%, respectively) a sample size of 120 patients per treatment provided 83% power to detect a 20% reduction in UACR. The null hypothesis was a flat dose-response curve for change from baseline in log-transformed UACR measured in a 10-hour sample after 20 weeks of study treatment. A mixed-effect model for repeated measures (MMRM) was applied to the primary endpoint to include the fixed categorical effect of treatment at each visit, the fixed continuous effects of baseline log-transformed UACR at each visit, and the fixed effects of randomisation stratification factors. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-patient measurements. The adjusted effect of log-transformed UACR from baseline was estimated for each study group by MMRM and back transformed by the exponential function to calculate the adjusted geometric mean percentage change in UACR from baseline, enabling the benefit of avenciguat versus placebo and the dose-response relationship to be characterised. Subgroup analyses were performed for the primary endpoint, with patients stratified by the following baseline characteristics: age, gender, race, geographic region, body mass index, eGFR, systolic blood pressure, cardiovascular disease, UACR, and use of SGLT2 inhibitor. The MMRM approach was applied to the secondary endpoint change from baseline in UACR measured in FMV urine. For the analysis of secondary endpoints (a decrease of >20% in UACR measured in 10-hour urine and FMV urine), patients with missing data at week 20 were imputed as non-responders, a conservative approach to avoid overestimation. Logistic regression analysis was subsequently applied to compare the proportion of participants with a decrease of >20% in UACR between the avenciguat dose groups and placebo. Descriptive statistics were calculated for all further endpoints. Efficacy was analysed in the full analysis set (FAS: all patients with at least one baseline UACR measurement at week -2, -1, or 0 and at least one post-baseline measurement after week 6). The treated set (TS: all patients who received at least one dose of study treatment) was used for safety. The pharmacokinetics set (PKS) included all patients in the TS who provided at least one PK parameter. Results From May 2021 until March 2023, 975 patients were screened, of whom 504 were randomly allocated to avenciguat or placebo; 500 were treated. Overall, 461 (92-2%) patients completed the study and 434 (86-8%) completed treatment. The most frequent reasons for not completing the study were death (n=3 [0 6%]), loss to follow-up (n=5 [10%]), and participant decision (n=12 [2 -4%]). The most frequent reason for discontinuation of the study treatment was AEs (n=33 [6-6%]). A total of 14 (2-8%) patients discontinued treatment during the up-titration phase up to week 5. Non-compliance to study treatment—defined as (1) missing four consecutive doses or more, or (2) in the investigator’s opinion, a patient did not follow the drug administration guidance on a consistent basis—was 18 4%. Baseline characteristics were well balanced among treatment groups (Table 1). Mean (standard deviation [SD]) age was 61 7 (13-4) years, 138 (27 6%) patients were female, 284 (56 8%) were White and 264 (52.8%) had a diagnosis of diabetes. Median (interquartile range) 1 O-hour UACR was 719 mg / g (interquartile range 379, 1285) mg / g, mean (SD) cGFR was 43 6 (17-6) mL / min / 1 -73m2 and mean (SD) systolic / diastolic blood pressure was 135-1 (15-2) / 78-6 (9-2) mm Hg. At baseline, 144 (28.8%) patients were receiving treatment with SGLT2 inhibitors. Table 1: Participant demographics and disease characteristics at baseline in the pooled population, treated set. Placebo (n=122) Avenciguat 1 mg tid (n=125) Avenciguat 2 mg tid (n=126) Avenciguat 3 mg tid (n=127) All patients (N=500) Gender, female, n (%) 32 (26 2) 37 (29-6) 30 (23-8) 39 (30 7) 138 (27-6) Age, years, mean (SD) 62-4 (12-8) 59-8(14-3) 62-5 (13 6) 62-1 (12 7) 617(134) Race, n (%) American Indian or Alaska Native 6 (4 9) 4(3-2) 7(5-6) 4(3-1) 21 (4 2) Asian 30 (24-6) 41 (32-8) 36 (28-6) 28 (22 0) 135 (27-0) Black or African American 10(8-2) 9(7-2) 12 (9-5) 18 (14 2) 49 (9-8) Native Hawaiian or other Pacific Islander 1 (0 8) 1 (0 8) 0 2(1-6) 4 (0 8) White 72 (59 0) 69 (55-2) 69 (54-8) 74 (58 3) 284 (56-8) Multiple 2(1-6) 1 (0 8) 1 (0-8) 0 4 (0 8) Type 1 diabetes mellitus, n (%) 1 (0 8) 1 (0 8) 2(1-6) 2(1-6) 6(1-2) Type 2 diabetes mellitus, n (%) 61 (50 0) 65 (52-0) 68 (54-0) 64 (50 4) 258 (51 6) BMI, kg / m2, mean (SD) 29-7(5-4) 28 4 (5 71) 29-9(5-7) 30-7(6-0) 29-7(5-7) eGFR. mL / min / 1 -73 m2, mean (SD) 44-4 (17-0) 44-0(18-9) 43-5 (16 6) 42-6(18-0) 43-6(17-6) 10-hour UACR, mg / g, median (IQR) 708.5 (388.5, 1275.5) 725.7 (397.0, 1483.5) 865.0 (446.6, 1258.7) 643.0 (329.3, 1219.0) 719.0 (379.0, 1285.3) Systolic blood pressure, mm Hg, mean (SD) 1331 (16-2) 134-9 (15-2) 136 7 (15-2) 135 7(14 1) 135 1 (15 2) Diastolic blood pressure, mm Hg, mean (SD) 78 9 (9 0) 78-2(9-3) 79 0 (9 8) 78-2 (8 9) 78-6(9-2) Medications, n (%) Antihypertensive 122 (100.0) 125 (100.0) 126 (100.0) 127 (100.0) 500 (100.0) RAAS inhibitor 120 (98.4) 124 (99.2) 125 (99.2) 127 (100.0) 496 (99.2) Beta-blocker 40 (32.8) 43 (34.4) 40 (31.7) 40 (31.5) 163 (32.6) Diabetes treatment 75 (61.5) 79 (63.2) 81 (64.3) 77 (60.6) 312(62.4) SGLT2 inhibitor 33 (27.0) 38 (30.4) 35 (27.8) 38 (29.9) 144 (28.8) Insulin 33 (27.0) 34 (27.2) 37 (29.4) 34 (26.8) 138 (27.6) DPP4 21 (17.2) 14(11.2) 16(12.7) 15 (11.8) 66 (13.2) GLP1 agonists 7 (5.7) 16(12.8) 10 (7.9) 13 (10.2) 46 (9.2) Statin 77 (63.1) 80 (64.0) 82 (65.1) 80 (63.0) 319(63.8) Antithrombotic drug 47 (38.5) 44 (35.2) 50 (39.7) 54 (42.5) 195 (39.0) Diuretic 45 (36.9) 39 (31.2) 49 (38.9) 51 (40.2) 184 (36.8) Thiazide diuretic 22(18.0) 25 (20.0) 25 (19.8) 28 (22.0) 100 (20.0) Loop diuretic 23 (18.9) 15 (12.0) 21 (16.7) 22 (17.3) 81 (16.2) The baseline characteristics of patients in the diabetic kidney disease and non-diabetic kidney disease trials are shown in Tables 2 and 3, respectively. Patients in the diabetic kidney disease trial were slightly older, with a greater proportion of patients with cardiovascular co-morbidities at baseline but had similar UACR and eGFR, compared with patients in the non-diabetic kidney disease trial. Overall, within each trial, baseline characteristics were balanced among treatment groups. Table 2: Baseline characteristics in the diabetic kidney disease population. Placebo (n=60) Avenciguat 1 mg tid (n=61) Avenciguat 2 mg tid (n=61) Avenciguat 3 mg tid (n=61) All patients (N=243) Gender, female, n (%) 16(26-7) 16(26-2) 14 (23-0) 13 (213) 59 (24-3) Age, years, mean (SD) 67-6(8-7) 65-2(9-3) 64-8(11-0) 65 2 (8 8) 65-7(9-5) Race, n (%) American Indian or Alaska Native 2(3-3) 1(1-6) 3 (4 9) 3 (4-9) 9(3-7) Asian 16(26-7) 23 (37-7) 16 (26-2) 16 (26-2) 71 (29-2) Black or African American 6(10-0) 6(9-8) 11 (18 0) 10 (16 4) 33 (13 6) Native Hawaiian or other Pacific Islander 0 1(1-6) 0 0 1 (0 4) White 34 (56-7) 30(49-2) 31 (50-8) 32 (52-5) 127 (52-3) Multiple 2(3-3) 0 0 0 2(0-8) Type 1 diabetes mellitus, n (%) 1(1-7) 1(1-6) 2(3-3) 2(3-3) 6(2-5) Type 2 diabetes mellitus, n (%) 59(98-3) 60(98 4) 59 (96 7) 59 (96-7) 237 (97-5) BMI, kg / m2, mean (SD) 30-0(5-6) 30 1 (6-4) 30-5 (5-8) 318 (5 3) 30-6(5-8) Cardiovascular disease, n (%) 19 (31 7) 16(26-2) 17 (27-9) 15 (24-6) 67 (27-6) eGFR, mL / min / T73 m2, mean (SD) 47-4(17-3) 42-4(18-5) 42-9(16-2) 45-0(19-0) 44-4 (17-8) 10-hour UACR, mg / g, mean (SD) 913 1 (657-3) 1093-5 (980-3) 1090-7 (794-4) 880 8(722-4) 994-9 (799-5) Systolic blood pressure, mm Hg, mean (SD) 138 1 (16 5) 140-0(15-6) 140-6(12-9) 140 5 (12 5) 139-8 (14 4) Diastolic blood pressure, mm Hg, mean (SD) 78-4(9-5) 78-4(9-4) 77-5 (9-1) 76-8 (9 2) 77-8(9-2) Medications, n (%) Antihypertensive 60 (100-0) 61 (100-0) 61 (100-0) 61(100 0) 243 (100-0) RAAS inhibitor 60(100-0) 61 (100-0) 60 (98-4) 61 (100-0) 242 (99-6) Beta-blocker 20 (33-3) 28 (45-9) 23 (37-7) 23 (37-7) 94 (38 7) Diabetes treatment 59(98-3) 59(96-7) 58 (95 1) 61 (100-0) 237 (97-5) Insulin 31 (517) 31 (50 8) 35 (57-4) 33 (54 1) 130 (53-5) SGLT2 inhibitor 21 (35-0) 21 (34 4) 21 (34-4) 23 (37-7) 86 (35 4) DPP-4 inhibitor 19 (31 7) 13 (213) 16 (26-2) 13 (213) 61 (25 1) GLP-1 receptor agonist 7(11 7) 16(26-2) 8 (13 1) 11 (18 0) 42 (17 3) Statin 44 (73 3) 38 (62 3) 45 (73 8) 40 (65-6) 167 (68-7) Antithrombotic drug 27 (45-0) 30 (49 2) 32 (52-5) 32 (52-5) 121 (49 8) Diuretic 25 (417) 22 (36 1) 25 (410) 29 (47 5) 101 (416) Low-ceiling diuretic / thiazide 16 (26 7) 15 (24 6) 9(14 8) 18 (29-5) 58 (23-9) High-ceiling diuretic 9(15 0) 7(11-5) 14 (23-0) 11 (18 0) 41(16 9) Table 3: Baseline characteristics in the non-diabetic kidney disease population. Placebo (n=66) Avenciguat 1 mg tid (n=64) Avenciguat 2 mg tid (n=65) Avenciguat 3 mg tid (n=66) All patients (N=261) Gender, female, n (%) 17 (25 8) 21 (32-8) 16(24-6) 26 (39-4) 80 (30-7) Age, years, mean (SD) 581(14 4) 54 6 (16 3) 60 4(15 5) 59 3 (15 0) 58 1 (15 4) Race, n (%) American Indian or Alaska Native 4 (6 1) 3 (4-7) 4 (6 2) 1(1-5) 12 (4-6) Asian 15 (22-7) 18 (28 1) 20 (30-8) 12(18-2) 65 (24-9) Black or African American 5(7-6) 3(4-7) 1(1-5) 8(12 1) 17 (6 5) Native Hawaiian or other Pacific Islander 1(1-5) 0 0 2(3-0) 3(1-1) White 40 (60-6) 39 (60-9) 38 (58 5) 42 (63 -6) 159(60-9) Multiple 0 1(1-6) 1(1-5) 0 2(0-8) Diabetes mellitus, n (%) 5(7-6) 6(9 4) 10 (15 4) 6 (9 1) 27 (10 3) BMI, kg / m2, mean (SD) 29-2 (5-2) 26-8 (4 5) 29-3 (5-6) 29-7(6-4) 28 8 (5-6) Cardiovascular disease, n (%) 11 (16 7) 9 (14 1) 10 (15 4) 9(13-6) 39(14-9) eGFR, mL / min / L73 m2, mean (SD) 42-7(17-3) 45-5 (19-2) 44-0(17-0) 40 4(16 8) 43 1 (17 6) 10-hour UACR, mg / g, mean (SD) 1076-2 (1786-2) 1024-1 (920-1) 868-2 (727-7) 941 5 (1155-2) 977-6 (1213 7) Systolic blood pressure, mm Hg, mean (SD) 128 8 (14-2) 130-0 (13-2) 133 0 (16 4) 131 2 (14 0) 130 8 (14-5) Diastolic blood pressure, mm Hg, mean (SD) 79-8 (8-4) 77-9(9-2) 80-4(10-2) 79-4(8-5) 79 4 (9 1) Medications, n (%) Antihypertensive 66 (100-0) 64 (100-0) 65 (100-0) 66 (100-0) 261 (100-0) RAAS inhibitor 64 (97-0) 63 (98-4) 65 (100-0) 66 (100-0) 258 (98 -9) Beta-blocker 22 (33-3) 15 (23 4) 17(26-2) 17(25-8) 71 (27-2) Diabetes treatment SGLT2 inhibitor 16 (24 2) 17(26 6) 14 (21 5) 15 (22-7) 62 (23 8) Antithrombotic drug 21 (318) 14 (21 9) 18 (27-7) 22 (33-3) 75 (28-7) Diuretic 21 (318) 17(26 6) 24 (36 9) 22 (33-3) 84 (32-2) Low-ceiling diuretic / thiazide 7 (10 6) 10(15 6) 16 (24 6) 10(15-2) 43 (16 5) High-ceiling diuretic 14 (21 2) 8(12 5) 7 (10 8) 11 (16 7) 40 (15 3) In the placebo group, the UACR 10-hour UACR remained stable over time. At week 20, the geometric mean percentage change from baseline was 2-4% (95% confidence interval [CI] -7-2, 12-9). In the avenciguat 1 mg, 2 mg, and 3 mg tid treatment groups, the geometric mean percentage changes from baseline at week 20 were -13-5% (95% CI -21-5, -4-7), -11-2% (-19 7, -18), and —19 7% (-27 3, -113), respectively. These corresponded to placebo-corrected geometric mean changes of-15 5% (95% CI -26 4, -3 0; p=0.02), -13 2% (-24 6, -0-1; p=0.05), and -21-5% (-31-7, -9-8; p=0.001) for the 1 mg, 2 mg, and 3 mg tid avenciguat groups, respectively. The effect of avenciguat 3 mg tid on the 10-hour UACR was fully present at week 6 and this was sustained until week 20. In the individual trials studying diabetic versus non-diabetic kidney disease, consistent treatment effects were seen with avenciguat 3 mg tid compared with placebo, while avenciguat 1 mg and 2 mg tid significantly reduced 10-hour UACR in the non-diabetic kidney disease trial population only. FMV UACR changes over time were consistent with the changes observed in the 10-hour urine samples. At week 20, the placebo-corrected geometric mean changes in FMV UACR in the avenciguat 1 mg, 2 mg, and 3 mg tid groups were -19 4% (95% CI -30 0, -7-3; p=0.003), -15 5% (-26-9, -2-5; p=0.02 and -23 4% (-33 5, —118; p<0.001), respectively. After 20 weeks treatment with placebo or avenciguat 1 mg, 2 mg, or 3 mg tid, 27 (22 9%), 48 (397%), 43 (377%), and 57 (48 3%) patients, respectively, achieved a >20% reduction in 10-hour UACR. The odds ratio of achieving a >20% UACR reduction with avenciguat 1 mg, 2 mg, or 3 mg tid compared with placebo was 2 2 (95% CI 13, 3 9; p=0 006), 2 0 (1 -2, 3 6; p=0 02), and 31 (1-8, 5-5; p=<0 0001), respectively. Similar proportions of patients achieved a >20% UACR reduction based on FMV urine samples. The effect of avenciguat 3 mg tid compared with placebo in reducing 1 O-hour UACR was consistent across most prc-spccificd and post-hoc defined subgroups. Of particular’ interest, treatment effects were consistent irrespective of SGLT2 inhibitor use at baseline: in the avenciguat 3 mg tid group, placebo-corrected geometric mean change (95% CI) from baseline in UACR in 10-hour urine was -23 3% (-38 8, -3 9) in those with SGLT2 inhibitor use (n=31) and -21-4% (-34 3, -6 0) in those without (n=76). Differential treatment effects were only observed based on underlying kidney disease aetiology and the presence of cardiovascular disease at baseline. During 20 weeks’ treatment with placebo or avenciguat, mean changes from baseline in systolic and diastolic blood pressure were modest and no statistically significant differences were observed between avenciguat groups versus placebo, with the exception of the change from baseline in systolic blood pressure at week 20, at which point the difference of means (95% CI) in systolic blood pressure between the placebo and avenciguat 1 mg tid group was -5 4 (95% CI -9-4, -T3). At week 20, the mean difference in systolic blood pressure between placebo and the avenciguat 2 mg and 3 mg tid dose groups were -3 0 (95% CI -74, 14) and -04 (-4 6, 3 8) mm Hg, respectively. Acute changes in systolic and diastolic blood pressure, calculated as the mean difference between the measurements prior to study drug administration to 2 hours after study drug administration, showed a reduction in the avenciguat treatment groups compared with placebo during the first 4 weeks. After 6 weeks, no differences between each avenciguat dose and placebo were observed in systolic and diastolic blood pressure changes, but acute changes in systolic blood pressure remained more pronounced for avenciguat versus placebo. An acute modest reduction in eGFR was observed in the avenciguat 2 mg and 3 mg tid treatment groups during the first 6 weeks of the treatment period: the mean differences compared with placebo in change from baseline in eGFR at week 6 were 0-2 mL / min / 1 -73m2 (95% CI -1 -4, T7), -I O mL / min / T73 m2 (-2-4, 0-5), and -10 (-2-5, 0-5) for the avenciguat 1, 2, and 3 mg doses, respectively. The nominally larger reductions in eGFR in the avenciguat 2 and 3 mg groups compared with placebo were sustained until week 20, however compared with placebo, these changes were <1.9 mL / min / 1 -73 m2 and not statistically significant. During the 4-week wash-out period after the discontinuation of placebo or avcnciguat, cGFR remained stable. The number of patients with AEs are shown in Table 4, analysed for the safety analysis set (treated set). During the 20-week treatment period, the proportion of patients who experienced any AE, or a serious AE did not differ between the avenciguat treatment groups and the placebo group. Hypotension, COVID-19, peripheral oedema, and diarrhoea were the most frequently reported AEs. Table 4. Summary of adverse events in the pooled population AEs, n (%) Placebo ( / / 5122) Avenciguat 1 mg t i d ( / / 5125) Avenciguat 2 mg tid ( / / 5126) Avenciguat 3 mg tid ( / / 5127) All Patients (A5500) Any AE 75 (62) 64 (51) 75 (60) 82 (65) 296 (59) AE leading to treatment discontinuation of study drag 4(3) 5(4) 11 (9) 11 (9) 31 (6) Any SAE 3(3) 7(6) 6(5) 6(5) 22 (4) Any AESI 1 (0.8) 1 (0.8) 4(3) 2(2) 8(2) Frequently occurring AEs " (overall incidence >5%) Gastrointestinal disorders 16 (13) 17 (14) H (9) 18 (14) 62 (12) Diarrhea 8(7) 6(5) 4(3) 7(6) 25 (5) General disorders and administrative 14 (12) 10(8) 21 (17) 23 (18) 68 (14) site conditions Peripheral edema 6(5) 2(2) 9(7) 10(8) 27 (5) Infections and infestations 24 (20) 22 (18) 25 (20) 28 (22) 99 (20) CO VID-19 7(6) 6(5) 8(6) 7(6) 28 (6) Vascular disorders 12 (10) 11(9) 17 (14) 20 (16) 60 (12) Hypertension 8(7) 5(4) 4(3) 6(5) 23 (5) Hypotension 3 (3) 7 (6) 12 (10) 10(8) 32 (6) AE, adverse event; AESI, AE of special interest; COVID-19, coronavirus disease 2019; SAE, serious AE; tid, three times daily. Hypotension occurred both in patients with and without diabetic kidney disease, and more frequently among patients receiving avenciguat compared with placebo. Few patients reduced or modified blood-pressure-lowering medication during the 20-week treatment period: 4 (3 2%), 11 (8-7%), 7 (5-5%), and 2 (1-6%), in the avenciguat 1, 2, and 3 mg tid, and placebo groups, respectively. Gastrointestinal AEs were more often reported in patients without diabetic kidney disease receiving avenciguat compared with placebo groups. This was not observed in patients with type 2 diabetes. Serum sodium, potassium, and liver function tests were not clinically significantly different among treatment groups. There was one death in the avenciguat 3 mg tid group (myocardial infarction). Blood samples of patients were obtained before initiation of treatment with avenciguat (time =0) and after 20 weeks of treatment, and the levels of nine regulated miRNAs were measured at both time points. Figure 2 shows a volcano plot of treatment-mediated changes in nine regulated miRNAs in patients with glomerular diseases treated with 3 mg of avenciguat who showed > 20% reduction in UACR over the 20-week course of treatment. As shown in Figure 2, only three of the regulated miRNAs correlated with UACR changes: miR-192-5p, miR-194-5p and miR-411-5p. In contrast, Applicant found that avenciguat had no effect on the miR-192-5p, miR-194-5p and miR-411-5p of patients with diabetic kidney disease, hypertensive kidney disease or other / unknown kidney disease. Moreover, there is no correlation of either of these miRNA’s with UACR changes in these patient populations. Further Discussion of the Results of the Phase 2b Study In this pre-specified pooled analysis of two identically designed, phase 2b, randomised clinical trials, we found that avenciguat decreased UACR in patients with CKD who were using standard-of-care treatment, including ACE inhibitors or ARBs. All tested doses of avenciguat reduced UACR compared with placebo: the highest dosage, 3 mg tid, produced the largest reduction. The effects of avenciguat 3 mg tid in reducing UACR were robust and statistically significant in the individual trials enrolling patients with or without diabetic kidney disease. In addition, the effects of 3 mg tid were largely consistent across multiple subgroups. Avcnciguat was generally well tolerated with few patients discontinuing study medication due to AEs or experiencing serious AEs. A moderate reduction in systolic and diastolic blood pressure was observed with avenciguat over the study period, which was well tolerated and infrequently led to avenciguat treatment discontinuation. The magnitude of these blood pressure effects was similar to those observed in prior studies with avenciguat and the sGC stimulator praliciguat. (Chemey DZI et al., Diabetes Obes Metab 2023; 25: 2218-26; Hanrahan JP et al,; Clin J Am Soc Nephrol 2020; 16: 59-69; and Hanrahan JP et al., An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension. Diabetologia 2020; 63: 733-43.) Acute blood pressure reductions, recorded up to 2 hours after study drug administration, were observed throughout the trial, with the most pronounced effect during the first 4 weeks of treatment, with a smaller effect thereafter. This may suggest that tolerance to the acute vasodilative effects of avenciguat develops during longer-term treatment. Previous experimental studies reported that sGC activation did not impact kidney perfusion or measures of GFR, suggesting that these therapies do not affect kidney haemodynamics and glomerular hypertension. (Chemey DZI et al., Diabetes Obes Metab 2023; 25: 2218-26.) In the present study, a modest acute reduction in eGFR was observed with the highest avenciguat dose, although differences in eGFR did not achieve statistical significance. Because eGFR changes over time were variable without a clear- consistent pattern of acute eGFR changes that are also reversible after treatment discontinuation, it is likely that avenciguat reduces albuminuria through pathways mostly unrelated to improving kidney haemodynamics. It is also unlikely that blood pressure changes contribute to the albuminuria-lowering effect because of the minimal between-group blood pressure differences and the lack of correlation between albuminuria changes and systolic blood pressure changes. Experimental studies have reported that sGC activation improves the vasoprotective properties of the endothelium along with improvements in the endothelial barrier function. (Sandner P, Follmann M, Becker-Pelster E, et al. Soluble GC stimulators and activators: past, present and future. Br J Pharmacol 2021; published online Dec 01.) Suppressing inflammation and fibrosis, as observed in experimental studies, may also contribute to the albuminuria reduction. (Reinhart GA et al., J Pharmacol Exp Ther 2023; 384: 382-92; and Kraehling JR ct al., Bcnardcau A, Schombcr T, ct al. The sGC activator runcaciguat has kidney protective effects and prevents a decline of kidney function in ZSF1 rats. Int J Mol Sci 2023; 24: 13226.) The safety and tolerability of avenciguat is reassuring, although future trials examining effects on kidney outcomes and safety over the longer term are required. The frequency of AEs leading to study drug discontinuation and the number of serious AEs was low and similar among avenciguat and placebo treatment groups. We observed a small numerical increase in the number of AEs leading to study drug discontinuation and the number of SAEs in the avenciguat group versus placebo, but was low frequencies were <10% and did not show clinically relevant differences between treatment groups. As in our previous study in patients with type 2 diabetes and CKD, hypotension was the most common drug-related AE. (Chemey DZI et al., Diabetes Obes Metab 2023; 25: 2218-26.) Further, we observed higher rates of peripheral oedema with avenciguat compared with placebo. However, both AEs appear plausible based on the vasodilator effect of avenciguat and were clinically manageable. As in the same previous study, gastrointestinal AEs occurred more frequently with avenciguat compared with placebo, although this pattern was mainly seen in patients without diabetic kidney disease and not in patients with diabetic kidney disease. While the strengths of this study include the randomised, double-blind design; rigorous methods of data collection and analysis; and low drop-out rate, there are also limitations. Firstly, the short follow-up period precluded long-term efficacy and safety assessment. Due to the short follow-up, we were also not able to assess the effects of avenciguat on eGFR change or clinical kidney endpoints. Secondly, avenciguat was administered three times daily due to its short half-life. Despite the frequent administration, treatment adherence was excellent but additional work is required to develop a more convenient, extended-release formulation or potentially a different dosing regimen. Complete blinding of dose group was not feasible due to differences in appearance between tablet strengths; however, importantly, both Investigator and patient were blinded to whether they were randomized to active drug or placebo. In addition, we estimated GFR using endogenous filtration markers, but did not measure GFR with exogenous tracers. Additional studies are required to assess GFR and renal blood flow to delineate potential haemodynamic effects of avenciguat more precisely. Finally, due to the selection of patients based on stringent inclusion and exclusion criteria, as well as other factors that influence clinical trial participation, the results can only be generalised to patients with CKD who share the characteristics of these trials. The results of the study show that at least 20 weeks of treatment with avenciguat 3 mg tid as adjunct to maximum tolerated ACE inhibitor or ARB treatment yielded a robust and statistically significant reduction in albuminuria, with an acceptable safety profile when compared with placebo. Analytical and Statistical Methods used in the Phase 2b Trials Small RNA extraction and sequencing: Urinary exosomal miRNAs were isolated using the exoRNeasy Serum / Plasma Maxi Kit (QIAGEN, Hilden, Germany). miRNA libraries were prepared using the QIAseq miRNA Library Kit (Qiagen) following the manufacturer's protocol, starting with ~ 1 ng of input RNA for each sample. Quality control and concentrations of individual libraries were assessed with Bioanalyzer 2100 Instrument and High Sensitivity DNA Kit (Agilent Technologies), small RNA sequencing was performed on the Illumina NovaSeq 6000 platform (Illumina Inc.) as 85 bp cycle single end read. Statistical analysis: Exploratory analyses of changes in miRNA expression levels over time were performed to identify differentially expressed miRNAs. This analysis was conducted using the limma package (Ritchie et al., 2015). Briefly, only miRNAs with counts per million (CPM) >= 1 in at least half the samples in at least one subgroup were included in the analysis. Data were normalized using the TMM method described by Robinson and Oshiack and voom-transformed (Robin son & Oshiack, 2010). miRNAs will be reported as differentially expressed if they fulfil the following criteria: Fold change > 1.5; P<0.01. Small RNA extraction and sequencing: Urinary exosomal miRNAs were isolated using the exoRNeasy Serum / Plasma Maxi Kit (QIAGEN, Hildcn, Germany). miRNA libraries were prepared using the QIAscq miRNA Library Kit (Qiagen) following the manufacturer’s protocol, starting with ~1 ng of input RNA for each sample. Quality control and concentrations of individual libraries were assessed with Bioanalyzer 2100 Instrument and High Sensitivity DNA Kit (Agilent Technologies), small RNA sequencing was performed on the Illumina NovaSeq 6000 platform (Illumina Inc.) as 85 bp cycle single end read. Statistical analysis: Exploratory analyses of changes in miRNA expression levels over time were performed to identify differentially expressed miRNAs. This analysis was conducted using the limma package (Ritchie et al., 2015). Briefly, only miRNAs with counts per million (CPM) >- 1 in at least half the samples in at least one subgroup were included in the analysis. Data were normalized using the TMM method described by Robinson and Oshiack and voom-transformed (Robin son & Oshiack, 2010). miRNAs will be reported as differentially expressed if they fulfil the following criteria: Fold change > 1.5; P<0.01. Differentially regulated miRNAs were investigated in a subpopulation of patients with glomerular disease who were treated with 3 mg tid avenciguat and exhibited more than 20% improvement in albuminuria (Study ID: NCT04736628). Correlation analysis was conducted to examine the relationship between miRNA expression and the UACR percentage change from baseline to EOT. Descriptive statistics were performed on candidate miRNAs across various treatment groups and disease etiologies, including diabetic kidney disease (DKD) patients (Study ID: NCT04750577). The effect of baseline albuminuria levels on changes in miRNA expression was assessed. miRNA concentrations were evaluated across different disease etiologies utilizing baseline values. Statistical analysis was performed using a Spearman’s rank correlation. In the Phase lib study described above, patients were treated with tablet (oral) formulations comprising avenciguat (or placebo). However, therapeutic pharmaceutical compositions (dosage forms) comprising avenciguat may be administered in any conventional pharmaceutical dosage form and in any conventional manner. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable to the particular dosage form selected. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdcrmally, orally, topically or by inhalation. The preferred modes of administration are oral and intravenous. The dosage forms of the invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable to the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements for the compounds of the present invention may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg / dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg / day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician. In one embodiment, patient are treated with a pharmaceutical composition comprising avenciguat. In another embodiment, patients are treated orally with a tablet comprising avenciguat. In another embodiment, the pharmaceutical composition of the invention comprises 1 mg, or 2 mg, or 3 mg of 4 mg, of 5 mg of avenciguat. Phase 3 Clinical Trial The efficacy of avenciguat may be further demonstrated in a randomised, double-blind, parallel-group, multi-centre (approximately 400 sites) Phase 3 clinical trial evaluating 4 mg avenciguat administered orally twice daily (bid) compared with placebo on top of SoC in participants with CKD due to GN at risk of progression. The selection of the 4 mg dose is based on the efficacy results from the Phase 2b trials discussed above (greater than 6 mg of daily dose) and patient adherence. Overall Trial Design The Phase 3 study involves about 1,110 participants, including approximately 30 adolescent participants aged 12 to less than 18 years at the time of consent. After the screening period, which may last up to 9 weeks, eligible participants will be randomised 1:1 to receive avenciguat or placebo as an adjunct to SoC using the big stick design. Randomisation will be stratified based on subtypes of GN (IgAN, or other GN) and baseline proteinuria (UPCR <1,500 mg / g, >1,500 mg / g). Re-screening is allowed once. The recruitment of “other GN” will be capped at 600 randomized participants. Participants should receive optimised SoC as per applicable local and global guidelines. It is expected that the most commonly used SoC includes RAASi and / or SGLT2i treatment. Participants who tolerate and are eligible as per the discretion of the investigator for treatment with an SGLT2i at screening, will be offered SGLT2i supplied or reimbursed by the sponsor (if locally approved). In case treatment with SGLT2i is initiated or the dose is adapted during screening, the screening period will be extended to ensure a steady state with regards to the effects of SGLT2i on eGFR and UPCR at the time of randomisation (defined as >4 weeks of stable dose prior to randomisation). For the participants in whom a chronic GN is suspected as per discretion of the investigator but not yet confirmed through kidney biopsy and the remaining inclusion / exclusion criteria are met, a kidney biopsy can be performed as part of screening. From the start of screening until the EoS Visit, participants’ urine samples will be collected. The primary endpoint for interim analysis (relative change in UPCR) will be assessed from FMV urine samples collected from baseline until Week 36 in participants with IgAN. The primary endpoint for the final analyses (total eGFR slope) will be calculated from the safety laboratory samples. Following randomisation, participants will begin taking the trial medication at a dose of 1.0 mg bid avenciguat or matching placebo. If tolerated, the dose will be up-titrated every two weeks in 1.0 mg increments to a maximum dose of 4.0 mg (2x2.0 mg) bid avenciguat or matching placebo. Every effort should be made to up-titratc the dose to the 4.0 mg (2x2.0 mg) bid, if tolerated. The goal is for patients to be treated with 4.0 mg (2x2.0 mg) bid avenciguat or matching placebo for the duration of the study. However, if the dose is not tolerated, dose reduction can be considered at the investigators’ discretion. After approximately 300 randomised participants with IgAN have completed 36 weeks of treatment, an interim analysis will be performed. Recruitment will continue whilst the analysis takes place. The aim of the interim analysis is to establish efficacy. Participants will remain on treatment until the last randomised participant still on treatment reaches 104 weeks of treatment, with planned visits every 8 to 12 weeks after the end of the titration period. Once the last randomised participant still on treatment reaches 104 weeks of treatment, EoT Visits will be triggered for all remaining participants. Upon completion of the EoT Visit, all participants will enter a 4-week follow-up period. The participant’s involvement in the trial will be complete when they have performed the last planned visit (i.e. EoS / FU Visit). During the entire follow-up period the participants will not be treated with trial medication but should, if possible, continue with any background treatment as used during the treatment period of the trial. Additional urine and blood samples will be collected at the EoS Visit. If participants discontinue trial medication prematurely in the trial, they will return to the site for an Early Discontinuation (ED) Visit and will be asked to continue the trial visits as planned until end of study. If a participant is not willing to stay in the trial, a FU Visit should be scheduled 28 days after the last trial medication administration. All efforts should be made to follow-up on all trial participants until trial end. If a trial par ticipant is not willing to return to the predefined trial visits, several options can be offered to the participant. Participants will be asked for a remote visit (if allowed per local regulations) or a phone call after the last participant on treatment reaches 104 weeks of treatment will be performed to document the occurrence of outcome events, vital status, and adverse events (AEs) - this will be considered the EoS visit for the respective participant. The start of the trial is defined as the date when the first participant in the whole trial signs informed consent. The end of the trial is defined as the date of the last visit of the last participant in the whole trial (“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last participant in the whole trial is administered the last dose of trial medication (as scheduled per clinical trial protocol [CTP] or prematurely). Individual investigators will be notified of suspected unexpected serious adverse reaction (SUSARs) occurring with the trial medication until 30 days after LPLT at their site. The final database lock will occur after the last participant has completed their final visit. A schematic of the trial design is provided in Figure 4. Participants selected for this trial have a risk for further progression into ESKD, a severe outcome. A data monitoring committee (DMC), independent from the sponsor, will therefore be established to review unblinded safety data at intervals to identify any potential risks and / or the need for implementation of further safety measures. The tasks and responsibilities of the DMC members, including specific considerations for the paediatric study part, will be detailed in the DMC charter. All proposed primary and secondary endpoints are laboratory based and / or objectively assessable (such as receipt or a kidney transplant), no endpoint adjudication is planned; therefore, there will be no adjudication committee. Selection of Endpoints for Interim and End of Treatment Analysis A prespecified interim analysis will be performed once approximately 300 participants with IgAN have completed Week 36 Visit, evaluating the first primary endpoint of this study (relative change in UPCR assessed in FMV urine from baseline to Week 36) for efficacy. The quantitative relationship between changes in UPCR and in eGFR is to date only established in IgAN, justifying the focus of the interim analysis on this trial subpopulation [R24 3827], For other GN subtypes, a surrogate endpoint of absolute change in eGFR from baseline to Week 104has been proven to be associated with improved renal outcomes (see below). UPCR has been used as surrogate endpoint in pivotal trials for medicinal products that received conditional approval in the EU for the treatment of patients with primary IgAN based on this endpoint (Filspari [sparsentan], Tarpeyo / Kinpeygo [budesonide] and Fabhalta [iptacopan]). In addition, the FDA has listed UPCR as a reasonably likely surrogate endpoint to support conditional approval in the disease or patient population of “primary glomerular diseases associated with significant proteinuria”, including IgAN (Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure | FDA ). The use of UPCR as a surrogate endpoint is supported by scientific evidence demonstrating the strong prognostic value of change of UACR / UPCR with long-term clinical kidney outcomes in both clinical trials as well as observational databases. Heerspink HJL et al., “Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials,” Lancet Diabetes Endocrinol 2019. doi: 10.1016 / S2213 8587(18)30314-0; and Coresh J, Heerspink HJ et al., “Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies,” Lancet Diabetes Endocrinol 2019;7(2): 115 127. A meta-analysis using patient-level data from 28 observational databases demonstrated that a 30% reduction in UACR and UPCR over a follow-up period of 1, 2 or 3 years was associated with a significant reduction in the risk for ESKD |R22 1391]. A trend towards even more pronounced risk reduction was seen in patients with higher baseline proteinuria levels, i.e. a patient population proposed for this Phase 3 clinical trial. More importantly, the individual patient-level metadata from 12 randomised trials of IgAN patients with UPCR measurements at baseline, after 6 months and 12 months evaluated the association of change in UPCR with eGFR change over time. In all analysed trials, treatment effects on UPCR reliably predicted treatment effects on the total eGFR slope. These data further support using UPCR as a surrogate endpoint for studies in patients with at risk of CKD disease progression and particularly in IgAN patients. Last, a meta-analysis using patient-level data from 41 clinical trials including various interventions (RAASi, SGLT2i and immunosuppressive treatments) was performed [P19 00650]. Similarly to the analysis mentioned above, the aim was to evaluate the correlation of short-term changes in UACR (i.e. treatment period of 6 and 12 months) with longterm clinical outcomes. The authors demonstrated that a 30% reduction in UACR was associated with a statistically significant risk reduction for the clinical composite studied, i.e. treated ESKD, eGFR <15 mL / min / 1.73 m2 or doubling of serum creatinine from baseline. The association strengthened when the analysis was limited to patients with higher baseline UACR levels (i.e. >30 mg / g) or to patients with glomerular diseases. This analysis provides evidence that a change in albuminuria can serve as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria. Applicant acknowledges that the latter mcta-analysis only evaluated UACR but not UPCR. However, a current National Kidney Foundation-led initiative currently compares the predictive and prognostic performance of UACR vs. UPCR in different clinical trials and observational databases. Interim analysis results were presented at a recent meeting held in Amsterdam, the Netherlands. These analyses consistently showed a similar performance of both UACR and UPCR ratios regarding their association with kidney-related clinical outcomes. Overall, these data further support using UPCR as a surrogate endpoint for studies in patients at high risk of CKD disease progression and particularly in GN patients. Inker LA et al., “Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis,” Am J Kidney Dis. 2021 Sep;78(3):340 349; and Heerspink HJLet al., “Change in albuminuria as a surrogate endpoint for progression of kidney disease: a metaanalysis of treatment effects in randomised clinical trials,” Lancet Diabetes Endocrinol 2019. doi: 10.1016 / S2213 8587(18)30314-0. The UPCR as the primary endpoint at Week 36 will be assessed from FMV urine samples. Despite 24 hour urine being the gold standard for UPCR assessments in clinical trials because it is proposed to account for biomarker urinary excretion variability throughout the day, it is more cumbersome for patients and prone to collection errors. Therefore, the FMV urine in a clinical setting is often preferred for its convenience and ease of collection. Also, scientific evidence supports similar performance of 24 h urine vs. FMV urine with regards to its predictive capabilities. Several studies compared the prognostic values of the two sampling methods and concluded that FMV urine sample represents a reliable alternative for UPCR assessment. In a cohort of CKD patients, UPCR from FMV and 24 hour urine samples were similarly predictive of the hard clinical endpoints including composite outcome of death, ESKD or >30% decline in eGFR. Yang F et al., “An equation to estimate 24 hour total urine protein excretion rate in patients who underwent urine protein testing,” BMC Nephrol. 2022 Jan 29;23(1):49. Other studies demonstrated that spot samples were equal or even superior to 24 hour samples in predicting clinical outcomes, in patients with IgAN and diabetic nephropathy. Zhao YF et al., “Measures of Urinary Protein and Albumin in the Prediction of Progression of IgA Nephropathy. Clin J Am Soc Nephrol. 2016 Jun 6;ll(6):947-955; and Lambers Heerspink HJ et al., “Comparison of different measures of urinary protein excretion for prediction of renal events,” J Am Soc Nephrol. 2010 Aug;21 (8): 1355-60. Thus, we propose UPCR assessment from FMV urine as a balance of convenience, efficiency, and reliable predictive value for clinical events. In addition, it is proposed to assess the primary endpoint of change in UPCR through a Mixed model for repeated measures (MMRM) using values from multiple FMV urine samples over time. This approach aims to minimize the bias on the actual treatment effect that could be caused by natural UPCR variability. The bias would be more pronounced with fewer samples, as would be the case if 24 hour urine is collected (i.e. at randomisation and Week 36 visit). Having multiple 24 hour urine samples for MMRM would be less patient centric and overwhelmingly burdensome for patients, therefore FMV urine analysis is proposed. At scheduled timepoints, two consecutive FMV urine samples will be taken and the UPCR measurement will be averaged to reduce variability and improve reliability. In addition to UPCR change, exploratory analyses of eGFR slope data at Week 56 will also be evaluated at the interim analysis in participants who have completed this follow-up visit, and a positive trend, if demonstrated, will support the benefit of avenciguat treatment on kidney function to support a conditional marketing authorisation. Access to comparative interim results will be limited to individuals who will be involved in the preparation work of the submission. Logistical aspects related to preserving the blind will be described in the Logistics and Access Plan. The primary endpoint for the final analyses is absolute change in eGFR from baseline to Week 104. Change in eGFR from baseline as a surrogate endpoint for kidney disease progression is proposed instead of a classic clinical composite endpoint, as such an endpoint is not deemed feasible due to the rarity of the disease and therefore limited trial feasibility. The trial is powered to demonstrate statistically significant superiority of avenciguat vs. placebo on change in eGFR from baseline to Week 104 at a power of 90%, which has been demonstrated to have high prognostic value for clinical endpoints such as kidney failure. In line with the guidance (CHMP Case No.: EMA / SA / 00000104642) advocating for clinical endpoints to corroborate eGFR-based endpoints, Applicant will use a hierarchical clinical composite endpoint as a key secondary endpoint. This endpoint encompasses all-cause mortality, onset of ESKD (defined by the onset of chronic kidney replacement therapy, receipt of kidney transplant or death from kidney failure), sustained eGFR decline to <10 mL / min / 1.73 m2, sustained >57%, >50% and >40% eGFR decline, and total eGFR slope [R24 2832]. This hierarchical clinical composite endpoint has advantages over a classical time-of-event composite endpoint (e.g. sustained eGFR decline, sustained eGFR decline to <10 mL / min / 1.73 m2, kidney failure, death from kidney failure) for demonstrating kidney protective effects in this trial. This is due to the relatively small sample size and limited follow-up time, resulting in a limited number of events. As the trial cannot be powered for a classical clinical composite endpoint and per EMA guidance, classical endpoints should only contribute to the risk-benefit assessment. Hence, a hierarchical clinical composite endpoint is the most suitable choice to demonstrate consistency of treatment effects across different clinical endpoints vs. eGFR slope. Hierarchical composite endpoints also better recognize the clinical importance of different clinical endpoints compared with classical time-to-first-event composite endpoints, while being more sensitive to detect treatment effects. Last, a hierarchical composite endpoint including eGFR slope implies that every participant will contribute to the endpoint, while in classic time-to-event endpoints the majority of participants only contributed time. However, a classical clinical time-to-first event composite clinical endpoint for kidney disease progression will also be analysed as a secondary endpoint. Details around the statistical analysis approach, including the alpha spent at these analyses and the alpha remaining for the primary endpoint of the final analysis and the key secondary endpoints are described below. Placebo will be used as a control group on top of the SoC. This design helps to isolate the effect of avenciguat by comparing it to the placebo and ensures that any observed differences in outcomes can be attributed to avenciguat rather than variations in the SoC treatment or natural biomarker variability. A placebo arm can also be considered ethically justified as participants will otherwise receive optimised SoC. Therefore, treatment of avenciguat on top of the SoC will give insights in additional benefits beyond the current best treatment practices. To date, there are no treatments targeting a pathophysiology that would be universally applicable for the broad GN patient population at high risk of progression available, and the current treatment options to slow down kidney function decline in GN patients, similar to broad CKD, include RAASi and SGLT2i (“KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease”). GN affects both adults and adolescents similarly in terms of pathophysiology, symptoms, and disease progression. Gipson DS, et al., “Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis,” JAMA Netw Open. 2022 Aug l;5(8):e2228701; Requiao-Moura LR et al., “Should adolescents with glomerulopathies be treated as children or adults? Nephron Clin Pract. 2008;109(3):cl61-7; and Windpessl M et al.,“Glomerular diseases across lifespan: key differences in diagnostic and therapeutic approaches, “Semin Nephrol 2023;434:151435. Therefore, therapeutic response is expected to be comparable across these age groups. Including adolescents in the adult Phase 3 trial is ethically justified, as it ensures adolescents are not excluded from potential therapeutic benefits and enables collection of safety and efficacy data in adolescent patients to support timely access to efficacious treatment in the future. Based on the Phase 2 results, avenciguat is safe and well tolerated in patients with CKD with a wide range in bodyweight (~40 kg to 158 kg). By adolescence, ADME processes are fully mature and, thus, comparable drug exposure would be expected between adults and adolescents. Therefore, adolescents and adults with a body weight of >40 kg will be included in the Phase 3 trial, and adult doses are expected to be safe and tolerable for this age group. This trial will include an option for adult participants to complete questionnaires to provide feedback on their clinical trial experience. Providing this feedback is not required for trial participation, and information collected from these questionnaires will not be analysed as part of the clinical data for the trial. To decrease the burden for participants, trial medication may be shipped to and from a participant’s home (if allowed per local law and regulations). In addition, biological samples may be taken at a participant’s home and shipped to the central laboratory. The follow-up visit might be conducted remotely (if allowed per local regulations) in case the participant is not able to attend the visit at the clinical trial site. Selection of Trial Population It is expected that approximately 1,100 participants including adult and approximately 30 adolescent participants will be randomised from approximately 400 sites. Main diagnosis for trial entry The trial will be performed in participants with GN diagnosis at increased risk for disease progression as defined by baseline eGFR and UPCR levels (eGFR >20 mL / min / 1.73 m2 and UPCR >750 mg / g for the participants that are receiving stable SoC treatment). For participants that will initiate SGLT2i during screening, separate criteria apply (see inclusion criterion 6). Kidney biopsy is considered the gold standard for diagnosis of glomerular diseases. However, there are clinical conditions where a diagnosis can be confirmed based on serologic testing and the clinical presentation alone e.g. systemic vasculitis - ANCA positive or systemic lupus erythematosus (KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases). In addition, participants should have a chronic disease state (as per KDIGO criteria, for more than 3 months prior to Visit la) and be on stable background medication. Inclusion criteria 1. Signed and dated written informed consent or written informed consent provided by the patient’s parent or legal representative and assent provided by the patient (if applicable) at the time of informed consent signature in accordance with ICH-GCP and local legislation prior to admission to the trial 2. Male or female patients >12 years of age at the time of consent (for China, Hong Kong and Japan: Male or female patients >18 year’s (or who are of legal age in countries where that is greater than 18 years) of age at time of consent) 3. Body weight >40 kg at randomisation 4. Diagnosis of GN confirmed by kidney biopsy or, in case of specific GN disease entities, serologic testing and the clinical presentation. See Appendix 9.1. for a listing of allowed GN entities and associated diagnosis requirements. 5.     Chronic CKD (as per KDIGO criteria [P24 01939]) for at least 3 months prior to Visit la 6.    Patients on stable SoC: eGFR >20 mL / min / 1.73 m2 and UPCR >750 mg / g in FMV urine taken at Visit la. In case of a planned initiation of SGLT2i during screening: eGFR >20 mL / min / 1.73 m2 and UPCR >900 mg / g in FMV urine taken at Visit la. 7. Any patient on RAASi and / or SGLT2i must be on a stable optimised / maximally tolerated dose for >4 weeks prior to Visit 2 (randomisation), with no planned change of the therapy during the trial. 8. Any patient treated with Mineralocorticoid receptor antagonists (MRA) and / or Endothelin receptor antagonists (ERA) must be on stable dose for >4 weeks prior to Visit la, with no planned change of the therapy during the trial. 9. Any patient on oral immunosuppressives (e.g. calcineurin inhibitors, antimetabolites) must be on a stable dose for >3 months prior to Visit la. Further, oral corticosteroids are only allowed at <10 mg / day prednisolone or equivalent. 10. Male or female participants. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Exclusion criteria 1. Patients with rapid progressive kidney disease as measured by eGFR loss >50% over a period of 3 months prior to Visit la 2. Patients with secondary GN due to infection or malignancy 3.     Any cholestatic condition or alkaline phosphatase >4x upper limit of normal (ULN) 4.     AKI, according to the Kidney Disease: Improving Global Outcomes (KDIGO) definition in the 30 days prior to Visit la until the start of trial medication treatment 5. Patients with a history of kidney transplant, kidney transplant planned during the study period, or ongoing or planned dialysis. 6. Patients with a systolic blood pressure (SBP) < 100 mmHg - at Visit la OR any clinically significant symptoms of hypotension at any time from Visit la until stall of treatment. 7. QTcF-interval >450 ms in men or >470 ms in women at any time from Visit la until start of treatment 8. A family history of long QT syndrome 9. Concomitant use of therapies with a known risk of Torsade de Pointes within 1 week (or 5 half-lives if longer) prior to randomisation (Visit 2) or planned initiation of such therapies during the trial 10. Treatment with phosphodiesterase (PDE) inhibitors, nitrates, NO-donors, sGC-stimulators / activators or any other restricted medication (including organic anion transporting polypeptide 1B1 and 1B3 [OATP1B1 / 3] inhibitors e.g. cyclosporine), within 1 week (or 5 halflives if longer) prior to randomisation Visit (Visit 2) or planned initiation of such therapies during the trial. 11. Administration of intravenous immunosuppressives within 6 months prior to Visit la (e.g. Rituximab, Eculizumab, Cyclophosphamide) 12. Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial 13. Confirmed diagnosis of malignancy within 5 year’s prior to Visit la, except for basal- or squamous-cell carcinoma of the skin that has been treated successfully. Trial participants with a history of other malignancies that have been treated with curative intent and who have no demonstrable disease recurrence within 5 year’s may also be eligible if approved following discussion with the sponsor. Trial participants under evaluation for malignant disease currently are not eligible for trial participation. 14. Major surgery (major according to the investigator’s assessment) planned during the trial 15. History of clinically relevant allergy / hypersensitivity that would interfere with trial participation including allergy to IMP / placebo or its excipients (see Investigator’s brochure, [c02778238]) 16. Participants not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the participant an unreliable trial participant) 17. Previous randomisation in this trial 18. Currently enrolled in another investigational device or drug trial, or at Visit la less than 30 days or 5 half-lives (whichever is longer) since ending another investigational device or drug trial(s) or receiving other investigational treatment(s) 19. Women who are pregnant, nursing or planning to become pregnant while in the trial 20. Any condition not covered by any of the other exclusion criteria that, in the investigator’s opinion, might jeopardise the participant’s safety or compliance with the protocol Treatments The trial medications will include avenciguat and matching placebo. The characteristic avenciguat and the comparator (placebo) are described in Table 5 and Table 6. Table 5. Avenciguat (BI 685509) Substance: Avenciguat (BI 685509) Pharmaceutical formulation: Film-coated tablets Unit strength: 1.0 mg, 2.0 mg, 3.0 mg Posology: 1.0 mg bid, 2.0 mg bid, 3.0 mg bid, 4.0 mg (2x2.0 mg) bid Mode of administration: Oral Table 6. Comparator product (Placebo) Substance: Placebo Pharmaceutical formulation: Film-coated tablets, matched in size and weight to the IMP Unit strength: Not applicable Posology: Identical to corresponding active ingredient Mode of administration: Oral The residual effect period (REP) of avenciguat is 3 days. As described above for the Phase 2b trials, the 3.0 mg tid regimen after titration period demonstrated the highest treatment effect based on UACR reduction in the overall population. In the GN subgroup treated with 3.0 mg tid avenciguat, placebo-corrected UACR reduction was 34%, which represents 1.6-fold higher reduction compared with the overall trial population and other CKD entities included in those trials. The maximum tested dose 3.0 mg tid was found to be generally safe and well tolerated after up-titration every two weeks, including in patients with GN in the 1366-0022 trial. The results of the Phase 2b trials suggest that an increased dosage of avcnciguat, for example, greater than 6 mg daily, may provide a better treatment dosage for patients with glomerular diseases. A 4.0 mg (2x2.0 mg) bid dosage is proposed for Phase 3. In order to evaluate the impact of change in dosage on the efficacy and safety in the proposed Phase 3 study, a population PK / PD (PopPK / PD) model was developed to assess 4.0 mg bid vs. 3.0 mg tid on UACR and blood pressure. In addition, 3.0 mg bid was also assessed in case participants did not tolerate the higher dose of 4.0 mg bid and remain on the 3.0 mg bid regimen. Assuming area under the curve (AUC) is the driver of efficacy, PopPK / PD results suggested minimal differences in total exposure and UACR reductions between the two dosing regimens (4.0 mg bid vs. 3.0 mg tid). In addition, the predicted Cmax is slightly higher for 4.0 mg bid vs. 3.0 mg tid, thus, even if AUC is not the driver for efficacy, the 4.0 mg bid dosage is still not expected to compromise overall efficacy compared with 3.0 mg tid. Results also suggested that participants who do not tolerate the highest recommended dosage (i.e. 4.0 mg bid) may still benefit from the lower dose of 3.0 mg bid. As Cmax is assumed to be the driver of safety / tolerability, PopPK / PD results suggested a concentration dependent effect on the blood pressure. However, the effect on blood pressure for the proposed 4.0 mg bid dosage is expected to be generally tolerated and is expected to improve over time with dose titration. Based on Phase 2 data, acute drops in blood pressure after dosing tend to attenuate over time, indicating that participants will adjust to stable doses of avenciguat over time. Hence, a flexible initial dose titration scheme based on tolerability will be applied. Further, participants will be advised to take avenciguat with food to improve tolerability. This recommendation is based on results from the food effect studies that showed -40% lower Cmax when avenciguat is administered with food without any effect on AUC. In cases where nontolerance is due to an external reason (e.g. hypotension due to hot weather), the investigator may down titrate the dose or temporarily discontinue avenciguat and restart / up-titrate once external factor is resolved, and the participant’s condition is stabilised. In summary, the PopPK / PD predictions suggest no substantial differences in exposure, efficacy and safety / tolerability between 4.0 mg bid vs. 3.0 mg tid, and the Phase 3 trial includes strategics to manage any potential intolerance associated with the hemodynamic effects of the trial medication. Based on these considerations, it is proposed that the 4.0 mg (2x2.0 mg) bid will overall provide a favourable balance between benefit and risk and should be further evaluated in this Phase 3 trial. Administration of doses for each trial participant Trial medication will be dispensed at the investigational sites. At dispensing visits participants will be given the appropriate number of medication kits depending on the interval between the visits. The last dose of trial medication will be administered in the evening of the day before the EoT Visit. All trial medication assignments, including dose up-titration, reduction and provision of replacement kits, will be managed through the interactive response technology (IRT) system. From the stall of the randomised treatment period (i.e. from Visit 2), and until reaching the EoT Visit, participants will be instructed to take the trial medication orally twice a day (bid). Each dose will consist of one (1.0, 2.0, and 3.0 mg dose or matching placebo) or two (2.0 mg dose or matching placebo) film-coated tablets, hence 2 or 4 tablets will be taken per day. It is recommended that the first daily dose is taken in the morning, and the second dose in the evening. Ideally there should be at least 10 h in between the intake of each dose. Doses of the trial medication should be taken at approximately the same time every day. Trial medication can be taken with or without food, but it is recommended that the trial medication should be administered with or immediately following meals, as this may improve tolerability. If a dose is missed, this must not be rectified by taking two doses (i.e. double doses) at the next time point; if a dose is missed by more than 6 h, that dose should be skipped altogether and the next dose taken as scheduled. On the morning of a visit, the trial medication will be administered as part of the visit. Therefore, on these days, participants should be instructed not to take their morning dose in advance of the visits. This is of particular importance for visits when PK sampling is planned. Participants who fail to follow these instructions should have the visit re-scheduled as soon as possible, ideally on the following day. On days with no scheduled visit, the participants will sclf-administcr their medication at home. Participants should be instructed to bring all unused trial medication and empty wallets I packaging with them when they return for clinic visits to the investigational site. From the date of first dosing until 14 days after Visit 5 (Week 8) participants are requested to record morning blood pressure daily. In addition, the participants should also record the time of dosing with trial medication and fasting status on the 3 days that precede visits with PK sampling. A blood pressure monitoring device, IMP administration diary / reminder card will be provided for this purpose. In the event of force majeure or other disrupting circumstances (e.g. pandemic, war), participant’s physical visits to sites may not be feasible or may need to be restricted to ensure participant’s safety. Based on a thorough assessment of the benefits and risks, the investigator may still decide to continue trial medication, and, if acceptable according to local law and regulations, trial medication may be shipped from the site to the participant’s home. Initial up-titration period All participants will begin treatment with the trial medication at Visit 2 with a dose of 1.0 mg avcnciguat bid or matching placebo. At Visits 3, 4 and 5, each of which should be 14 days after the preceding visit, the dose will be up-titrated to 2.0 mg, 3.0 mg and 4.0 mg (2x2.0 mg) avenciguat bid or matching placebo, respectively. Every effort should be made to up-titrate the dose to the 4.0 mg (2x2.0 mg) bid or to the maximum tolerated dose. Before any up-titration, participant must have taken the preceding dose for at least 7 consecutive days. In addition, the investigator should up-titrate the dose when SBP is >95 mmHg and there are no signs or symptoms of hypotension. Following the initial administration of each new titration dose, sites should call participants within 1 - 2 working days. The call aims to assess the participant’s tolerance of the new dose and review the recommendation of taking the IMP with food in case of intolerance. If participant reports any relevant AE, an additional unscheduled visit to adjust the dose level should be considered. Dose modifications All dose modifications of trial medication will require a site visit, whether it is a scheduled or unscheduled, for the dispensation of new IMP kits. Dose modifications will be done in 1.0 mg increments. If a dose is not tolerated (i.e. any AE, based on investigator’s judgement, related to trial medication or external factors), the investigator should consider any of the following actions: • Check whether the participant has been taking the trial medication in the fasted state. If so, recommend administering the IMP with or immediately following meals to improve tolerance. • Delay the next dose up-titration • Reduce IMP dose • Temporarily discontinue IMP • Permanently discontinue IMP For further guidance on dose modification based on SBP assessment, refer to Table 7 below. Table 7. Guidance on study treatment dose modification based on SBP assessments Blood Pressure Assessment (pre dose measurement) Dose modification SBP >95 mmHg and without signs or symptoms of hypotension Up-titrate the dose or remain at 4.0 mg (2x2.0 mg) bid SBP >90 and <94 mmHg and without signs or symptoms of hypotension Maintain dose and reassess at the next visit SBP <90 mmHg OR signs or symptoms of hypotension Reduce the dose Dose reductions must not be performed by taking less than the two daily doses or by splitting tablets so that a whole tablet is not taken. If a participant is not able to tolerate the lowest dose in this trial (1.0 mg bid), IMP needs to be discontinued. Dose up-titration after initial titration If during the initial up-titration the maximum dose of 4.0 mg (2x2.0 mg) bid was not achieved, further dose up-titration to 4.0 mg (2x2.0 mg) bid is permitted at any time during the study if the investigator deems it safe and beneficial for a participant to receive a higher dose, considering that all participants should be treated with the maximally tolerated dose. If the dose of IMP was reduced or interrupted due to an AE with contributing external factors (e.g., hypotension due to reduced fluids intake), the drug can be restarted or up-titrated once the AE has resolved and the external factors have been corrected, based on investigator’s judgement. If there was no interruption of IMP, the dose can be up-titrated to the next dose level. Before any dose up-titration occurs, the participant must have taken the preceding dose for at least 7 consecutive days, have SBP >95 mmHg and no signs or symptoms of hypotension (Table 7). Interruption of trial medication An interruption of trial medication may have an influence on the tolerability. For this reason, depending on the length of the interruption, it might be required to re-start titration again (Table 8). Table 8. Guidance on the restart of trial medication after interruption Length of interruption Restart dose < 3 days / 6 doses If there is no ongoing AE, administer the next dose of trial medication as scheduled and continue dosing as planned > 3 days / 6 doses Restart the trial medication at 1.0 mg bid, and up-titrate the dose Other Treatments, Emergency Procedures, and Restrictions Prior and concomitant therapies Participants should keep their existing therapies as stable as possible, from at least 4 weeks prior to randomisation (Visit 2) until the end of follow-up at EoS Visit. New therapies should only be initiated if necessary for medical reasons. Participants should receive optimised SoC as per appropriate local or global guidelines. This might include the maximally tolerated dose of RAASi, with or without SGLT2i treatment. Participants must be on a stable RAASi and / or SGLT2i dose for >4 weeks prior to Visit 2, with no planned change of the therapy during the trial. In case the SGLT2i is initiated, or the dose is adapted during screening, the dose has to be stable for >4 weeks prior to randomisation (Visit 2). In this case the screening period will be extended to ensure a steady state with regards to the effects of SGLT2i on eGFR and UPCR at the time of randomisation. Participants who do not tolerate newly induced SGLT2i can still be randomised once eGFR and UPCR have reached a steady state again. Participants treated with MRA, or ERA must be on a stable dose for >4 weeks prior to Visit la, with no planned change of the therapy during the trial. Participants on oral immunosuppressives (e.g. calcineurin inhibitors, antimetabolites) must be on a stable dose for >3 months prior to Visit la. The administration of intravenous immunosuppressives (e.g. Rituximab, Eculizumab, Cyclophosphamide) is not allowed within 6 months prior to Visit la. Restricted medications and therapies The concomitant therapies mentioned below must not be co-administered with avenciguat. These restrictions apply from within 4 weeks (or 5 half-lives if longer) prior to randomisation (Visit 2), until the EoT Visit plus 3 days. • NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl trinitrate, isosorbide di- or mono-nitrate, molsidomine), PDE-5 inhibitors (e.g. sildenafil, tadalafil, and vardenafil), non-specific PDE inhibitors (dipyridamole and theophylline) or sGC-stimulators / activators (e.g. riociguat, vericiguat) • Clinically relevant OATP1B1 / 3 inhibitors (e.g. cyclosporine) In addition, concomitant therapies with a known risk of Torsade de Pointes must not be coadministered with avcnciguat. These restrictions apply from 1 week (or 5 half-lives if longer) prior to randomisation (Visit 2) until the EoT Visit plus 3 days. In the event of temporary concomitant use of such a therapy, trial medication must be temporarily stopped and can then be re-stalled after a period of at least 5 half-lives after the concomitant therapy with the known risk of Torsade de Pointes has been stopped, as long as the interruption rules are followed.. Oral corticosteroids are only allowed at <10 mg / day for prednisolone and equivalent doses for other steroid compounds. Efficacy assessments Urinary protein creatinine ratio (UPCR): Urinary protein and creatinine measurements are the basis for the calculation of UPCR. FMV and 24-hour urine samples will be collected by the participant at home. Urinary protein and creatinine will be analysed at a central laboratory using routine validated methods. First Morning Void (FMV): The FMV urine is the first urination after the participant wakes up at their usual time to start their day. Thus, if the participant goes back to sleep after urinating early in the morning this void does not need to be collected or documented. This applies also to any urinations earlier during the night in participants who have nocturia. There may be cases when a participant might go back to bed after their usual rising time. In those cases, the void at their usual rising time constitutes the FMV urine. Intake of trial medication in the morning should always occur after the FMV has been collected. Containers for collection of urine will be provided by the same central lab that will perform specimen management. For the selected visits, FMV urine samples should be collected on two consecutive mornings prior to the visit to average biological variability of the baseline sample. The mean of the two UPCR measurements per visit will be considered for analysis. For eligibility assessment during screening, the FMV urine samples should be collected after SoC treatment has been stabilised for at least 4 weeks and no more than 2 weeks prior to randomisation visit. The collection of FMV urine samples from the home of the participant is possible, if allowed by local regulations. In case UPCR at screening is 600-749 mg / g for participants on stable treatment and 750-899 mg / g for patients with a planned initiation of SGLT2i during screening, a re-test can be done once (again consisting of 2 samples collected at consecutive days). If the participant cannot meet eligibility criterion at the re-test, the participant should be screen failed. 24-hour urine collection should be started by collecting a FMV urine in the provided container. The FMV urine sample collection starts the clock for the 24-hour collection. During this period all following urine voids should be collected in the provided container. An aliquot of this sample will be used as the 24-hour urine sample. Urinary albumin creatinine ratio (UACR): Urinary albumin and creatinine measurements are the basis for the calculation of UACR. FMV urine and 24-hour urine samples will be collected by the participant at home. Urinary albumin and creatinine will be analysed at a central laboratory using routine validated methods. Estimated glomerular filtration rate (eGFR): Samples for eGFR calculation will be collected and assessed using Creatinine, enzymatic assays (CREE) according to standard procedures. For participants >18 years of age at the time of consent the CKD-EPI 2021 equation is used for reporting eGFRcr (eGFR based on serum creatinine) and eGFRcr-cys. For eGFRcys, the CKD-EPI 2012 equation will be used. For participants <18 years of age at the time of consent CKiD U25 equations will be used. Clinical outcome assessments Clinical outcome assessments (COAs) must be used in the IRB / EC-approved version and format provided by the sponsor (or vendor, if applicable). COAs must not be modified, except as indicated for the administration of the assessments, as per trial instructions. COAs will be selfadministered by the participants in paper format and transcribed by site staff into the eCRF. Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) is a 13-item measure that assesses self-reported fatigue and its impact upon daily activities and function. The response scale is a 5 point Likert-type scale. The higher the score, the better the quality of life and the less fatigue. Participants under the age of 18 years at the time of Visit 2 should not complete the FACIT-Fatigue questionnaire throughout the trial. Kidney disease quality of life (KDQoL)-36 The KDQOL-36, is a 36-item health-related quality of life survey with five subscales: • The SF-12 measure of physical (physical component summary [PCS]) and mental (mental component summary [MCS]) functioning (questions 1-12) • Burden of kidney disease subscale (questions 13-16) • Symptoms and problems subscale (questions 17-28) • Effects of kidney disease on daily life subscale (questions 29-36) The objective of the KDQoL is to assess quality-of-life concerns of individuals with kidney disease. Participants under the age of 18 years at the time of Visit 2 should not complete the KDQoL-36 questionnaire throughout the trial. ANALYSIS Interim analysis primary endpoint - UPCR: The primary endpoint UPCR will be assessed and compared between avenciguat and placebo at Week 36 with IgAN participants. The two-sided null hypothesis of the primary endpoint UPCR is: ^OJJPCR- ^UPCR;Avenciguat = ^UPCR,Placebo vs. the alternative hypothesis: Ha_UPCR-^UPCR;Avenciguat ^UPCR;Placebo ^upcr is percent change from baseline to Week 36 in log transformed UPCR. The further subscripts represent the two arms, i.e. Avenciguat denotes the treatment arm and Placebo denotes the placebo arm. Final analysis primary endpoint - change from baseline of eGFR to Week 104: The primary endpoint eGFR will be assessed and compared between avenciguat and placebo at Week 104 Visit with all GN participants. The two-sided null hypothesis of the primary endpoint eGFR is: Ho_eGFR- ^eGFR,Avenciguat   ^eGFR,Placebo vs. the alternative hypothesis: ^A_eGFR- ^eGFR,Avenciguat   ^eGFR,Placebo ^eGFR is the change from baseline of eGFR to Week 104 Visit. The further subscripts represent the two arms, i.e. Avenciguat denotes the treatment arm and Placebo denotes the placebo arm. Confirmatory analysis & Japan analysis - change from baseline of eGFR to Week 104: The primary endpoint eGFR will be assessed and compared between avenciguat and placebo at Week 104 Visit with IgAN participants. The two-sided null hypothesis of the primary endpoint eGFR is same as the final analysis primary endpoint. The alpha level described in this TDO is by default two-sided. Alpha splitting between those two endpoints is needed to control the overall trial level Type I error at alpha = 0.05. An alpha = 0.01 will be allocated to the UPCR primary analysis of IgAN participants at interim and an alpha = 0.04 will be allocated to the eGFR primary analysis of all GN participants at final. If the UPCR primary endpoint is statistically significant, the alpha =0.01 will be transferred to the eGFR primary analysis of IgAN participants at final. If this analysis is statistically significant, the alpha=0.01 will be preserved so that the eGFR primary analysis of all GN participants at final may be tested at alpha=0.05. If either of the first two tests are not statistically significant, the eGFR primary analysis of all GN participants at final will only be tested at alpha=0.04. If the test of the eGFR primary analysis of all GN participants at final is significant, the alpha will be preserved to test the key secondary endpoints as follows. Chronic eGFR slope will be tested first. If statistically significant, the last three key secondary endpoints will be tested as a family using the Hochberg procedure. Key secondary analyses - chronic eGFR slope: Chronic eGFR slope will be assessed and compared between avenciguat and placebo from Week 10 until the EoT Visit. The two-sided null hypothesis of the chronic eGFR slope is: Ho_eGFRcs- ^eGFRcs-Avenciguat — ^eGFRcs-.Placebo vs. the alternative hypothesis: ^A_eGFRcs ■ ^eGFRcs;Avenciguat ^eGFRcs;Placebo ^eGFRcs is ^e annual decline in chronic eGFR slope from Week 10 to EoT Visit. The further subscripts represent the two arms, i.e. Avenciguat denotes the treatment aim and Placebo denotes the placebo arm. Key secondary analyses - Hierarchical clinical composite endpoint, time to sustained full or partial remission of proteinuria, and time to occurrence of CKD progression: The key secondary endpoints(hierarchical clinical composite endpoint and time to sustained full or partial remission of proteinuria up to Week 104) and the secondary endpoint time to occurrence of CKD progression will be assessed and compared between avenciguat and placebo as a family using the Benjamini-Hochberg procedure. For simplicity, notation 0= I. 2, 3 will be used to denote the key secondary endpoints, respectively. The two-sided null hypothesis of the hierarchical clinical composite endpoint, time to sustained full or partial remission of proteinuria endpoint, and time to occurrence of CKD progression is: ^OKS' ^KS;Avenciguat ^KS;Placebo vs. the alternative hypothesis: ^A KS ■ ^KS; Avenciguat   ^KS;Placebo The Benjamini-Hochberg procedure will be used to control the false discovery rate (FDR) at a level. Ho 1? Ho 2, and Ho 3 null hypotheses will be tested and let P1? P2, and P3 denote their corresponding p-values. The three p-values from the statistical tests will be ranked in ascending order and denoted by P^y, P^2y and P^y The smallest p-value P^ has a rank of i = 1, then next smallest value has i = 2, etc. Each individual p-value will be compared to its Benjamini-Hochberg critical value, (i / m~)Q, where i is the rank, m is the total number of tests, and Q is the false discovery rate (e.g. 5%). For this case m=3 and Q= a remaining after the tests of both primary endpoints and the first key secondary endpoint. The largest p-value where Py < (i / m)Q will determine that Pay and all of the p-values smaller to be statistically significant, even the p-values that are not less than their Benjamini-Hochberg critical value. Further embodiments of the Invention: Embodiment 1. A method for treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof. Embodiment 2.      The method of embodiment 1, wherein the CKD patient is diabetic. Embodiment 3.      The method of embodiment 1, wherein the CKD patient is nondiabetic. Embodiment 4.      The method of embodiment 1, wherein the CKD patient has a glomerular disease, type 1 diabetes or type 2 diabetes. Embodiment 5.      The method of embodiment 4, wherein the CKD patient has a glomerular disease selected from the group consisting of IgA nephropathy, IgA vasculitis, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, lupus nephritis, minimal change disease, anti-GBM (Goodpasture’s disease), infection-related glomerulonephritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex membranoproliferative glomerulonephritis, C3 / C4 glomerulopathy, fibrillary glomerulonephritis, and immunotactoid glomerulopathy. Embodiment 6. The method of embodiment 4, wherein the glomerular disease is selected from the group consisting of IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy. Embodiment 7.      The method of any of embodiments 1 to 6, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg. Embodiment 8. The method of any one of embodiments 1 to 7, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, each administered three times daily (tid). Embodiment 9. The method of any one of embodiments 1 to 8, wherein avenciguat is administered to the patient tid in an amount of 3 mg, 4 mg or 5 mg. Embodiment 10. The method of any one of embodiments 1 to 9, wherein the treatment reduces the level of albuminuria in the patient. Embodiment 11. The method of any one of embodiments 1 to 10, wherein the method reduces the amount of albuminuria by up to 13% as compared placebo. Embodiment 12. The method of any one of embodiments 1 to 11, wherein the method reduces the amount of albuminuria by up to 35% as compared to placebo. Embodiment 13. A method for reducing the amount of albuminuria in a chronic kidney disease (CKD) patient, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof. Embodiment 14. The method of embodiment 13, wherein the CKD patient has a glomerular disease, type 1 diabetes or type 2 diabetes. Embodiment 15. The method of embodiment 13 or 14, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg. Embodiment 16. The method of any one of embodiments 13 to 15, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg each administered three times daily (tid) Embodiment 17. The method of any one of embodiments 13 to 16, wherein avenciguat is administered to the patient tid in an amount of 3 mg, 4 mg or 5 mg. Embodiment 18. The method of any of embodiments 13 to 17, wherein the CKD patient is diabetic. Embodiment 19. The method of embodiments 13 to 17, wherein the CKD patient is nondiabetic. Embodiment 20. The method of embodiment 14, wherein the CKD patient has a glomerular disease selected from the group consisting of IgA nephropathy, IgA vasculitis, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, lupus nephritis, minimal change disease, anti-GBM (Goodpasture’s disease), infection-related glomerulonephritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex membranoproliferative glomerulonephritis, C3 / C4 glomerulopathy, fibrillary glomerulonephritis, and immunotactoid glomerulopathy. Embodiment 21. The method of embodiment 20, wherein the glomerular disease is selected from the group consisting of IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy. Embodiment 22. The method of any one of embodiments 13 to 21, wherein the method reduces the amount of albuminuria by up to 13% as compared placebo. Embodiment 23. The method of any one of embodiments 13 to 23, wherein the method reduces the amount of albuminuria by up to 35% as compared to placebo. Embodiment 24. The method of any one of embodiments 13 to 23, the method further comprising administering to the patient an additional active agent. Embodiment 25. The method of embodiment 24, wherein the additional active agent is selected from the group consisting of: an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB). an antihypertensive, a RAAS inhibitor, a beta-blocker, a diabetes treatment (for example, a SGLT2 inhibitor, insulin or insulin analog, a DPP4 inhibitor, or a GLP1 agonists), a statin, an antithrombotic drug, and a diuretic (for example, a thiazide diuretic or a loop diuretic). Embodiment 26. Use of avenciguat, or a pharmaceutically acceptable salt thereof, for treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient. Embodiment 27. Use of avenciguat, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient Embodiment 28. The use according to embodiment 26 or 27, wherein the CKD patient is diabetic. Embodiment 29. The use according to embodiment 26 or 27, wherein the CKD patient is nondiabetic. Embodiment 30. The use according to embodiment 26 or 27, wherein the CKD patient has a glomerular disease, type 1 diabetes or type 2 diabetes. Embodiment 31. The use according to embodiment 30, wherein the CKD patient has a glomerular disease selected from the group consisting of IgA nephropathy, IgA vasculitis, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, lupus nephritis, minimal change disease, anti-GBM (Goodpasture’s disease), infection-related glomerulonephritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex mcmbranoprolifcrativc glomerulonephritis, C3 / C4 glomerulopathy, fibrillary glomerulonephritis, and immunotactoid glomerulopathy. Embodiment 32. The use according to any of embodiments 26 to 31, wherein the treatment reduces the level of albuminuria in the patient. Embodiment 33. The use according to embodiment 32, wherein the method reduces the amount of albuminuria by up to 13% as compared placebo. Embodiment 34. The use according to embodiment 32, wherein the method reduces the amount of albuminuria by up to 35% as compared to placebo.

Claims

1. A method for treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents.

2. Avenciguat, or a pharmaceutically acceptable salt thereof, for use in treating, reducing the risk of, and / or delaying the progression of chronic kidney (CKD) disease in a CKD patient, optionally in combination with one or more other therapeutic agents.

3. The method of claim 1 or use according to claim 2, wherein the CKD patient has a glomerular disease.

4. The method or use according to claim 3, wherein the glomerular disease selected from the group consisting of IgA nephropathy, IgA vasculitis, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, lupus nephritis, minimal change disease, anti-GBM (Goodpasture’s disease), infection-related glomerulonephritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex membranoproliferative glomerulonephritis, C3 / C4 glomerulopathy, fibrillary glomerulonephritis, and immunotactoid glomerulopathy.

5. The method or use according to claim 4, wherein the glomerular disease is selected from the group consisting of IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy.

6. A method for reducing proteinuria in an adult patient with glomerulonephritis at risk of disease progression, the method comprising administering to the patient a pharmaceutically effective amount of avenciguat, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other therapeutic agents.

7. Avenciguat, or a pharmaceutically acceptable salt thereof, for reducing proteinuria in anadult patient with glomerulonephritis at risk of disease progression, optionally in combination with one or more other therapeutic agents.

8. The method of claim 6 or use of claim 7, wherein the adult patient has a glomerular disease selected from the group consisting of IgA nephropathy, IgA vasculitis, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, lupus nephritis, minimal change disease, anti-GBM (Goodpasture’s disease), infection-related glomerulonephritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex membranoproliferative glomerulonephritis, C3 / C4 glomerulopathy, fibrillary glomerulonephritis, and immunotactoid glomerulopathy9. The method or use according to claim 8, wherein the glomerular disease is selected from the group consisting of IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy.

10. The method of claim 6 or use of claim 7, wherein the adult patient has immunoglobulin A nephropathy (IgAN) / focal-segmental glomerulosclerosis / minimal-change disease (FSGS / MCD) and is at risk of disease progression, optionally in combination with one or more other therapeutic agents.

11. The method or use according to any of the preceding claims, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg.

12. The method or use according to any of the preceding claims, wherein avenciguat is administered to the patient in an amount of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, each administered two times daily (bid).

13. The method or use according to claim 12, comprising:administering avenciguat as a stalling dose in an amount of 1 mg twice per day for at least seven days,administering avenciguat in an amount of 2 mg twice per day if the 1 mg twice per day dose is tolerated,administering avenciguat in an amount of 3 mg twice per day if the 2 mg twice per dose is tolerated, andadministering avenciguat in an amount of 4 mg twice per day if the 3 mg twice per dose is tolerated.

14. A method for detecting the presence or absence of a beneficial response in an adult patient with immunoglobulin A nephropathy (IgAN) I focal-segmental glomerulosclerosis / minimal-change disease (FSGS / MCD) at risk of disease progression after administration of avenciguat, or a pharmaceutically acceptable salt thereof, comprising:obtaining a biological sample from the patient pre-treatment and post-treatment after administration of avenciguat;measuring in each sample the level of one or more biomarkers, or the level of expression of one or more biomarkers in each sample pre-treatment and post-treatment;comparing the pre-treatment level to post-treatment level of the biomarkers; and determining the difference in levels between the pre-treatment sample and the posttreatment sample,wherein the one or more biomarkers comprising microRNAs is selected from the group consisting of miR-192-5p, miR-194-5p and miR-411-5p.

15. The method of claim 14, wherein the microRNA is selected from the group consisting of miR-192-5p and miR-194-5p, wherein downregulation or upregulation post-treatment as compared to pretreatment baseline indicates beneficial response.

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