KBP-5074 / Sihuan Pharmaceutical - LARVOL DELTA

Clarion-CKD: Efficacy and Safety of KBP-5074 in Uncontrolled Hypertension and Moderate or Severe CKD (clinicaltrials.gov) - P3 | N=652 | Terminated | Sponsor: KBP Biosciences | Trial completion date: Jan 2025 ➔ Jul 2024 | Active, not recruiting ➔ Terminated; Interim futility analysis showed primary endpoint not achieved

Trial completion date • Trial termination • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Renal effects and safety between Asian and non-Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists. (PubMed, J Diabetes) - "Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%."

Clinical • Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

BLOCKCKD: Phase 2b Study of KBP-5074 in Subjects With Uncontrolled Hypertension and Advanced Chronic Kidney Disease (clinicaltrials.gov) - P2 | N=162 | Completed | Sponsor: KBP Biosciences | Phase classification: P2b ➔ P2

Metastases • Phase classification • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Safety, Tolerability, and Pharmacokinetics of KBP-5074 Following Oral Administration in Chronic Kidney Disease (clinicaltrials.gov) - P1 | N=11 | Completed | Sponsor: KBP Biosciences | Phase classification: P1/2 ➔ P1

Phase classification • Chronic Kidney Disease • Nephrology • Renal Disease

Safety, Tolerability and Pharmacokinetics of KBP-5074 in Healthy Subjects and Subjects With Renal Impairment (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: KBP Biosciences | Phase classification: P1/2 ➔ P1

Phase classification • Nephrology • Renal Disease

Bioavailability of KBP-5074 Tablet vs Capsule Formulations (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: KBP Biosciences | Unknown status ➔ Completed

Trial completion

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Ocedurenone (KBP-5074) in Individuals with Moderate Hepatic Impairment. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and Cmax do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. CLINICAL TRIAL IDENTIFIER ( WWW."

Journal • PK/PD data • Cardiovascular • Chronic Kidney Disease • Hepatology • Hypertension • Nephrology • Renal Disease

Clarion-CKD: Efficacy and Safety of KBP-5074 in Uncontrolled Hypertension and Moderate or Severe CKD (clinicaltrials.gov) - P3 | N=652 | Active, not recruiting | Sponsor: KBP Biosciences | Recruiting ➔ Active, not recruiting | Trial primary completion date: Sep 2024 ➔ Jan 2024

Enrollment closed • Trial primary completion date • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Cardiovascular and Renal Benefit of Novel Non-steroidal Mineralocorticoid Antagonists in Patients with Diabetes. (PubMed, Curr Cardiol Rep) - "Non-steroidal MRAs such as esaxerenone, AZD9977, apararenone, ocedurenone (KBP-5074), and finerenone are newly approved or in clinical development for patients with cardiorenal disease including type 2 diabetes (T2D) and chronic kidney disease (CKD), hypertension -/+ CKD or heart failure. Selected candidates of this drug class reduced UACR in patients with varying degrees of CKD and T2D and have shown convincing cardiorenal protection, in particular finerenone. Furthermore, finerenone is currently tested in patients with heart failure with preserved ejection fraction."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Heart Failure • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Effect of Ocedurenone in Patients With Uncontrolled Hypertension and Stage 3b/4 Chronic Kidney Disease - Subgroup Analysis of a Phase 2b Clinical Trial (AHA 2022) - "Introduction: BLOCK-CKD is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety, efficacy, and pharmacokinetics of the nonsteroidal MRA Ocedurenone (KBP-5074) in patients with stage 3b/4 CKD and uncontrolled hypertension while taking 2 or more antihypertensive medications.Hypothesis: Although the study is not powered for subgroup analysis, it is of interest to examine the consistency of results across various subgroups. Of 162 patients randomized, 138 (85.2%) completed the study... In this Phase 2 trial, the effect of Ocedurenone on SBP reduction and serum potassium levels was consistent among clinically important subgroups. Due to the relatively small number of patients these conclusions need to be confirmed in the larger ongoing Phase 3 trial."

Clinical • P2b data • Cardiovascular • Chronic Kidney Disease • Hypertension • Metabolic Disorders • Nephrology • Renal Disease

Efficacy and Safety of Ocedurenone: Subgroup Analysis of the BLOCK-CKD Study. (PubMed, Am J Hypertens) - "Ocedurenone consistently reduced in SBP in all patient subgroups. Moreover, while small elevations in serum potassium occurred, they were not associated with Ocedurenone or study discontinuation."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Hypotension • Metabolic Disorders • Nephrology • Renal Disease

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo. (PubMed, Eur J Drug Metab Pharmacokinet) - "Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures."

Journal • PK/PD data • Preclinical • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease • ABCB1 • CYP1A2 • CYP3A4 • SLC22A1

"8/ KBP-5074 or Ocedurenone (a non-steroidal MRA) reduced SBP by an average of 10.6 mmHg with minimal hyperkalemia and dose dependent trends in albuminuria reduction (BLOCK-CKD findings) #ERA23 @PabloPergola https://t.co/WCXA6Hmocy" (@ERAkidney)

Renal Disease

Therapeutic perspective-evolving evidence of nonsteroidal mineralocorticoid receptor antagonists in diabetic kidney disease. (PubMed, Am J Physiol Endocrinol Metab) - "Finerenone, a novel and selective non-steroidal mineralocorticoid receptor antagonist (NS-MRA), was approved for treatment of patients with DKD, and is associated with lower rates of hyperkalemia. Other NS-MRAs (such as KBP-5074, BR-4628, esaxerenone, and apararenone) may also be effective drugs for treatment of DKD. This review summarizes the effects of pharmacological MR blockade on diabetes and diabetes-associated CKD, with a particular focus on the therapeutic mechanisms of NS-MRAs in preclinical studies and ongoing clinical studies. Further investigation of combined treatment with renoprotective drugs and NS-MRAs to improve treatment of DKD is needed."

Journal • Review • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Pharmacokinetics and Drug-Drug Interaction of KBP-5074 in Healthy Subjects (KIDNEY WEEK 2022) - "Conclusion A strong CYP3A inhibitor (itraconazole) had a weak effect (1.1 to 1.7 fold increase), whereas a strong CYP3A4 inducer (rifampin) had a strong effect (up to 84% decrease) on the clinical pharmacokinetics of KBP-5074. KBP-5074 was well tolerated when administered as a single 0.5-mg dose alone or in combination with itraconazole or rifampin."

Clinical • PK/PD data • Cardiovascular • Hypertension • Renal Disease

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist KBP-5074 in Individuals With Moderate Hepatic Impairment (KIDNEY WEEK 2022) - "Conclusion Small decreases of AUC and C max upon systemic exposure to KBP-5074 in subjects with moderate hepatic impairment demonstrate low hepatic extraction and is consistent with the observation that KBP-5074 is cleared predominantly in the gastrointestinal tract vs the kidney. Considering the long half-life and small decrease in AUC and C max , a dose adjustment does not appear to be warranted in patients with moderate hepatic impairment."

Clinical • PK/PD data • Gastrointestinal Disorder • Hepatology

Nonsteroidal Mineralocorticoid Receptor Blocker (KBP-5074) for Hypertension in Stage 4 CKD (KIDNEY WEEK 2022) - No abstract available

Cardiovascular • Chronic Kidney Disease • Hypertension

Novel Treatments for Resistant Hypertension in Advanced CKD (KIDNEY WEEK 2022) - "In addition, updates are given on the use of kidney denervation. Learning Objective(s) Implement the use of a novel nonsteroidal mineralocorticoid receptor blocker (KBP-5074) in patients with advanced CKD and resistant hypertension Explain the rationale for using combined endothelin A and B receptor antagonists for the treatment of resistant hypertension in patients with advanced CKD Describe the use of centrally acting aminopeptidase inhibitors for the treatment of resistant hypertension in Black patients with CKD Summarize the current state of kidney denervation therapy as a treatment modality for patients with CKD and resistant hypertension"

Cardiovascular • Chronic Kidney Disease • Hypertension

Aldosterone, Mineralocorticoid Receptor Activation, and CKD: A Review of Evolving Treatment Paradigms. (PubMed, Am J Kidney Dis) - "Multiple clinical studies have defined the efficacy of MR antagonism in attenuating progressive kidney disease, and the US Food and Drug Administration recently approved the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone for this indication...Although the FIDELIO-DKD and FIGARO-DKD clinical trials focused solely on patients with type 2 diabetes mellitus, we propose that MR activation and the resulting inflammation and fibrosis act as a substantive pathogenetic mediator not only in people with diabetic CKD but also in those with CKD without diabetes. We close by briefly discussing both recently initiated and future clinical trials that focus on extending the attributes of MR antagonism to a wider array of nondiabetic kidney disorders, such as patients with nonalbuminuric CKD."

Journal • Review • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Clarion-CKD: Efficacy and Safety of KBP-5074 in Uncontrolled Hypertension and Moderate or Severe CKD (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: KBP Biosciences | Trial completion date: Mar 2024 ➔ Jan 2025 | Trial primary completion date: Mar 2024 ➔ Sep 2024

Trial completion date • Trial primary completion date • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

A Study to Assess the Efficacy and Safety of KBP-5074, in Subjects with Uncontrolled Hypertension Who Have Moderate or Severe (Stage 3b/4) Chronic Kidney Disease Vizsgálat a KBP-5074 hatásosságának és biztonságosságának értékelésére nem kontrollálható magas vérnyomásban szenvedő betegeknél, akiknél mérs& (clinicaltrialsregister.eu) - P3 | N=600 | Ongoing | Sponsor: KBP BioSciences PTE. Ltd.

New P3 trial • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Management of hypertension in advanced kidney disease. (PubMed, Curr Opin Nephrol Hypertens) - "Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD."

Journal • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Clarion-CKD: Efficacy and Safety of KBP-5074 in Uncontrolled Hypertension and Moderate or Severe CKD (clinicaltrials.gov) - P3; N=600; Recruiting; Sponsor: KBP Biosciences; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Mineralocorticoid Receptor Antagonists-Evidence for Kidney Protection, Trials With Novel Agents. (PubMed, Adv Chronic Kidney Dis) - "The spectrum of nonsteroidal MRAs includes one agent with significant BP reduction, KBP-5074, to agents with minimal BP effects yet have demonstrated significant cardiorenal risk reduction in diabetic kidney disease, finerenone. The paper reviews the development and pharmacology of these different agents and tries to provide a perspective as to their place in the spectrum of aldosterone excess disorders."

Journal • Review • Diabetic Nephropathy • Nephrology • Renal Disease

Novel Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Disease. (PubMed, Br J Pharmacol) - "Recently, a new class of non-steroidal MRAs including esaxerenone, AZD9977, apararenone, KBP-5074, and finerenone have been developed with an improved benefit-risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non-steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice."

Journal • Review • Cardiovascular • Congestive Heart Failure • Diabetic Nephropathy • Heart Failure • Hypertension • Nephrology • Renal Disease