apararenone (MT-3995) / Mitsubishi Tanabe - LARVOL DELTA

Evidence for the use of a nonsteroidal mineralocorticoid receptor antagonist for the treatment of chronic kidney disease. (PubMed, Nefrologia (Engl Ed)) - "With this review we provide a global perspective on the available clinical results for these drugs to improve its evidence-based use."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Diabetic Nephropathy • Hypertension • Nephrology • Renal Disease

Insights into drug development with quantitative systems pharmacology: A prospective case study of uncovering hyperkalemia risk in diabetic nephropathy with virtual clinical trials. (PubMed, Drug Metab Pharmacokinet) - "A QSP model for generating virtual patients with diabetic nephropathy was used to quantitatively assess that the nonsteroidal MRAs, finerenone and apararenone, have a lower risk of hyperkalemia than the steroidal MRA, eplerenone. Prospective simulation studies using a QSP model are useful to prioritize pharmaceutical candidates in clinical development and validate mechanism-based pharmacological concepts related to the risk-benefit, before conducting large-scale clinical trials."

Journal • Diabetic Nephropathy • 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

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

Non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease and type 2 diabetes. (PubMed, Diabetes Obes Metab) - "Three nsMRAs (finerenone, esaxerenone and apararenone) have been evaluated but finerenone is currently the only approved nsMRA for this indication. Hyperkalaemia was the most notable treatment-related adverse event and could generally be managed through serum potassium monitoring and dose adjustments. The nsMRAs are now an important component of recommended treatment for CKD associated with T2D, providing a significant reduction in the risk of cardiorenal progression beyond what can be achieved with glucose and blood pressure control."

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

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease. (PubMed, Eur J Intern Med) - "Compared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Metabolic Disorders • Nephrology • 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

Network meta-analysis of mineralocorticoid receptor antagonists for diabetic kidney disease. (PubMed, Front Pharmacol) - "A total of 12 randomized clinical trials with 15,492 patients applying various types of MRAs covering spironolactone, eplerenone, finerenone, esaxerenone, and apararenone were included. This Bayesian network meta-analysis was the first to explore the optimal alternative among MRAs in the treatment of DKD and revealed the superiority of 20 mg of finerenone among MRAs in treating DKD. Systematic Review Registration: PROSPERO, identifier (CRD42022313826)."

Clinical • Retrospective data • Review • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Efficacy and Safety of Non-Steroidal Mineralocorticoid Receptor Antagonists in Patients With Chronic Kidney Disease and Type 2 Diabetes: A Systematic Review Incorporating an Indirect Comparisons Meta-Analysis. (PubMed, Front Pharmacol) - "Esaxerenone and apararenone may have better antihypertensive effects than finerenone. The head-to-head RCTs are still needed to compare the differences of the efficacy and safety in these non-steroidal MRAs."

Retrospective data • Review • Chronic Kidney Disease • Diabetes • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist. (PubMed, J Med Chem) - "We discovered that the novel 1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995) acted as a highly selective and potent nonsteroidal MRA. Apararenone exhibited a more potent antihypertensive and organ-protective activity than steroidal MRA eplerenone in a primary aldosteronism rat model obtained by infusing aldosterone in uninephrectomized rats."

Journal • Cardiovascular • Congestive Heart Failure • Endocrine Disorders • Heart Failure • Hypertension • 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

Nonsteroidal Mineralocorticoid Receptor Antagonism for cardiovascular and renal disorders - new perspectives for combination therapy. (PubMed, Pharmacol Res) - "Spironolactone was launched as the first antagonist of aldosterone 27 years before the MR was cloned...The second steroidal MR antagonist was eplerenone which was discovered at a time when the role of aldosterone and MR in cardiac fibrosis was rediscovered...Addition of the nonsteroidal MRA finerenone to optimal RAS blockade recently reduced CV and kidney outcomes in two large phase III trials in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We provide an outlook on further opportunities for combination therapy of nonsteroidal MRA finerenone with RAS inhibitors and sodium-glucose cotransporter-2 inhibitors (SGLT2i)."

Combination therapy • Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study. (PubMed, Hepatol Res) - "In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers and was safe and well tolerated. Pathological findings showed anti-inflammatory and antifibrotic effects of apararenone."

Clinical • Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease. (PubMed, Pharmaceuticals (Basel)) - "Non-steroidal MRA still block the damaging effects of mineralocorticoid receptor overactivation (extracellular fluid volume expansion, inflammation, fibrosis), but with fewer side effects (hormonal, hyperkalemia) than steroidal MRA. This review article summarizes the current knowledge and newer research conducted on MRA in DKD."

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

Role of mineralocorticoid receptor antagonists in kidney diseases. (PubMed, Drug Dev Res) - "Mineralocorticoid receptor (MR) antagonists, for example, spironolactone and eplerenone, are in clinical use to treat hypertension...Other nonsteroidal MRA such as apararenone, finerenone, AZD9977, and LY2623091 are in different clinical trials in patients with hypertension suffering from renal or hepatic fibrotic diseases...The new generation nonsteroidal MRAs like esaxerenone are less likely to cause hyperkalemia at therapeutic doses. It appears that the nonsteroidal MRAs can provide optimum therapeutic benefit for patients suffering from kidney diseases."

Journal • Review • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Hypertension • Immunology • Inflammation • Nephrology • Renal Disease

Drug-Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone with Midazolam, Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers. (PubMed, Clin Ther) - P1 | "The findings from this analysis of data from healthy volunteers suggest minimal risk for potential drug-drug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568."

Clinical • Journal • P1 data

[VIRTUAL] MT-3995, A NOVEL NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST, HAS BENEFICIAL EFFECTS ON THE PROGRESSION OF NON-ALCOHOLIC STEATOHEPATITIS IN CHOLINE-DEFICIENT L-AMINO ACID-DEFINED DIET-FED F344 RATS AND TRANS-FAT DIET-FED OB/OB MICE. (AASLD 2020) - "As a reference substance, eplerenone (100 mg/kg/day) and obeticholic acid (10 mg/kg/day) were used in the CDAA study and trans-fat study, respectively. We showed, for the first time, that MT-3995, a non-steroidal MR antagonist, has the beneficial effect on the development of steatohepatitis and hepatic fibrosis in rodent NASH models. MT-3995 could be a novel therapeutic approach for the treatment of NASH."

Late-breaking abstract • Addiction (Opioid and Alcohol) • Cardiovascular • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • COL1A1 • TGFB1 • TNFA

Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study. (PubMed, Clin Exp Nephrol) - P2 | "The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable."

Clinical • Journal • P2 data • Diabetic Nephropathy • Fibrosis • Immunology • Nephrology • Renal Disease

Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers. (PubMed, Clin Pharmacol Drug Dev) - "Study 3 assessed the PK, PD, and safety/tolerability of single-dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted."

Clinical • Journal • P1 data • PK/PD data

Safety, Tolerability and Pharmacokinetic Study of MT-3995 at a Low Dose in Subjects With Diabetic Nephropathy (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: Mitsubishi Tanabe Pharma Corporation

New P2 trial • Biosimilar • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Renal Disease

Safety, tolerability and pharmacokinetic study of MT-3995 in subjects with diabetic nephropathy (clinicaltrials.gov) - P1/2, N=30; Sponsor: Mitsubishi Tanabe; Not yet recruiting; New P1/2 trial.

New P1/2 trial • Renal Disease

Efficacy and Safety of MT-3995 in Patients With Non-Alcoholic Steatohepatitis(NASH) (clinicaltrials.gov) - P2; N=48; Completed; Sponsor: Mitsubishi Tanabe Pharma Corporation; Active, not recruiting ➔ Completed

Clinical • Trial completion

New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure. (PubMed, J Nephrol) - "This review summarizes the results of published preclinical and clinical studies on the nonsteroidal MRA, apararenone esaxerenone and finerenone. For this reason, nonsteroidal MRA represent an interesting new therapeutic approach for the prevention of CHF and CKD progression. Some basic research findings also yielded interesting results in acute clinical settings such as myocardial infarction and acute kidney injury."

Journal • Review