Treatment of diabetic nephropathy with sGC stimulators

Abstract

The present invention relates to a method of treating subjects with diabetic nephropathy by administering a fixed dosage of Compound I, a stimulator of soluble guanylate cyclase (sGC), either alone or in combination therapy. TIFF2023501344000023.tif6155

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the filing dates under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 927,454, filed October 29, 2019, and U.S. Provisional Patent Application No. 62 / 993,972, filed March 24, 2020, the entire contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE DISCLOSURE

[0002] This disclosure relates to methods of treating subjects with diabetic nephropathy (DN) by administering specific dosage regimens of stimulators of soluble guanylate cyclase (sGC), either alone or in combination therapy. [Background technology]

[0003] diabetic nephropathy

[0003] Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a common and serious microvascular complication of type 1 and type 2 diabetes mellitus, characterized by pathological urinary protein excretion (e.g., albumin excretion), glomerular lesions, hypertension, and progressive loss of renal function.

[0004] Diagnosis is based on the presence of albuminuria (urinary albumin-to-creatinine ratio [UACR] of >30 mg / g) and / or a reduced estimated glomerular filtration rate (<90 mL / min / 1.73 m 2The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline (National Kidney Foundation. KDIGO 2012 "Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease" Kidney International Supplements 2013, 3(1), pp. 1-150) provides a kidney disease classification system that risk stratifies patients based on the level of albuminuria and eGFR.

[0005]

[0005] DN is the leading cause of end-stage renal disease (ESRD, requiring renal replacement therapy in the form of dialysis or kidney transplantation) in the United States and other developed countries. DN is also a major risk factor for serious adverse cardiovascular events and the single strongest predictor of mortality in diabetic patients. An estimated 20% to 40% of patients with diabetes develop DN, with higher rates seen in middle-aged African Americans, Hispanics, and Native Americans. Along with the increasing prevalence of diabetes, the prevalence of DN is increasing in the United States and worldwide. The estimated number of people with DN in the United States increased from 3.9 million between 1988 and 1994 to 6.9 million between 2005 and 2008.

[0006]

[0006] The current standard of care for DN involves blood glucose and blood pressure (BP) control and pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) through the use of angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARB). RAAS inhibitors have been shown in clinical trials to reduce albuminuria and delay progression to ESRD and renal replacement therapy (either dialysis or kidney transplantation). However, the current standard of care does not prevent progression to ESRD, and the prevalence of DN has not declined with the increasing use of RAAS inhibitors and hypoglycemic agents. Due to the cost of treating ESRD and the strong association between DN and cardiovascular disease, the treatment burden for patients with DN is significant for both patients and the healthcare system. In recent years, promising new treatments, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, endothelin receptor antagonists (ERAs), and finerenone (a nonsteroidal anti-mineralocorticoid), have shown promising effects on renal outcomes in clinical trials, but these agents only slow disease progression, and substantial risks remain. As a result, additional treatments for DKD, especially agents with novel mechanisms of action, remain urgently needed. Summary of the Invention [Means for solving the problem]

[0007]

[0007] In a first aspect of the present invention, disclosed herein is a method for treating DN and related conditions in a human patient in need of such treatment by administering to said patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0008]

[0008] In certain embodiments, the invention disclosed herein is a method for improving albuminuria in a diabetic patient by administering to the patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0009] In certain embodiments, the invention disclosed herein provides a method for producing a 45 mL / min / 1.73 m 2 A method for improving albuminuria in a diabetic patient having an eGFR value of less than 10 mg by administering to said patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0010]

[0010] In certain embodiments, the invention disclosed herein is a method for preserving renal function in a diabetic patient by administering to the patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0011]

[0011] In certain embodiments, the invention disclosed herein is a method for delaying or preventing clinical deterioration in a patient with DN by administering to said patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0012]

[0012] In certain embodiments, the invention disclosed herein is a method for increasing survival of a patient with DN by administering to the patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0013]

[0013] In certain embodiments, the invention disclosed herein is a method for improving metabolic parameters in a patient with DN by administering to the patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0014]

[0014] In certain embodiments, the invention disclosed herein is a method for reducing the risk of cardiovascular (CV) events in a patient with DN by administering to the patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0015]

[0015] In certain embodiments, the invention disclosed herein is a method for improving metabolic outcomes in patients with DN by administering to said patients a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0016]

[0016] In certain embodiments, the invention disclosed herein is a method for lowering blood pressure in a patient with DN by administering to the patient a total oral daily dose of Compound I of 10 mg to 40 mg, either alone or in combination therapy.

[0017]

[0017] In a second aspect of the present invention, disclosed herein is the use of Compound I for the manufacture of a medicament for the treatment of DN and associated conditions in a human patient in need thereof by administering to said patient a total oral daily dose of Compound I of 10 mg to 40 mg.

[0018]

[0018] In a third aspect of the present invention, there is disclosed herein Compound I for use in treating DN and associated conditions in a human patient in need thereof, wherein a total oral daily dose of Compound I of 10 mg to 40 mg is administered to the patient.

[0019] In another aspect of the present invention, methods and uses for the treatment of DN and related conditions with Compound I in combination therapy with other therapeutic agents are disclosed herein. [Brief explanation of the drawings]

[0020] [Figure 1A]

[0020] Figures 1A and 1B are graphs showing the results of the primary efficacy outcome measure (change in UACR) in the two populations. Figure 1A shows the results for the subpopulation of patients with an eGFR of 30-45 mL / min / 1.73 m2, and Figure 1B shows the results for all patients. These figures show the cumulative % number of patients on the Y-axis and the % change in UACR from baseline at Week 12 on the X-axis for the groups receiving placebo, 20 mg of Compound I, and 40 mg of Compound I. [Figure 1B] Figures 1A and 1B are graphs showing the results of the primary efficacy outcome measure (change in UACR) in the two populations. Figure 1A shows the results for the subpopulation of patients with eGFR between 30 and 45 mL / min / 1.73 m², while Figure 1B shows the results for all patients. These figures show the cumulative % number of patients on the Y-axis and the % change in UACR from baseline at Week 12 on the X-axis for the groups receiving placebo, 20 mg of Compound I, and 40 mg of Compound I. DETAILED DESCRIPTION OF THE INVENTION

[0021] Definitions and General Terms

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0022]

[0022] As used herein, the terms "subject" and "patient" are used interchangeably. A subject or patient is a human patient or subject.

[0023] The terms "for example" and "such as" and their grammatical equivalents are understood to be followed by the phrase "including but not limited to" or "and including but not limited to," unless expressly indicated otherwise.

[0023]

[0024] As used herein, "insulin sensitivity" refers to how sensitive the body is to the action of insulin. Insulin sensitivity can be determined using the homeostatic model assessment of insulin resistance (HOMA-IR), a method that assesses beta cell function and insulin resistance from basal (fasting) glucose and insulin or C-peptide concentrations. It also evaluates the efficiency of insulin action in peripheral tissues. Normal HOMA-IR values ​​for healthy individuals range from 0.5 to 1.4. A value below 1.0 indicates that a person is insulin sensitive, which is optimal. A value above 1.9 indicates early insulin resistance. A level above 2.9 indicates increasing insulin resistance.

[0024]

[0025] As used herein, the term "therapeutically effective amount" or "pharmaceutical effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the human drug response desired by a physician or other clinician. A therapeutically or pharmaceutical effective amount of a compound is at least the minimum amount required to ameliorate, alleviate, relieve, delay, reduce, relieve or treat one or more of a disease, disorder or syndrome, or its symptoms, signs or causes. In another embodiment, it is the amount required to restore abnormal levels of a particular clinical marker of a disease, disorder or syndrome to a normal value or level. An effective amount can be administered in one or more doses throughout the day.

[0025]

[0026] The terms "administer," "administering," or "administration," with respect to a compound or pharmaceutical, refer to the introduction of a compound into the body of a patient in need of treatment. When Compound I is used in combination with one or more other therapeutic agents, "administration" and variations thereof are understood to encompass the simultaneous and / or sequential introduction of Compound I and the other therapeutic agents into a patient, respectively.

[0026]

[0027] The terms "treat," "treating," or "treatment," with respect to a disorder, disease, condition, symptom, or syndrome, refer to inhibiting or ameliorating the cause and / or consequences of the disorder, disease, condition, or syndrome (i.e., inhibiting or ameliorating a symptom, physiological, physical, psychological, emotional, or any other clinical sign, finding, or measurement, or improving a pathological assessment). As used herein, the terms "treat," "treatment," and "treating" also refer to delaying, ameliorating, or preventing the progression of a disease (i.e., the known or expected progression of a disease), the severity and / or duration, or delaying, ameliorating, or preventing the progression of one or more symptoms, clinical signs, findings, or measurements, or preventing or slowing the negative progression of a pathological assessment (i.e., "managing" without "cure" of a condition), resulting from the administration of one or more therapies.

[0027]

[0028] In some embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one physiological parameter (e.g., lowered [UARC], lowered cholesterol, lowered plasma glucose, etc.) or an improvement in at least one symptom or effect (e.g., reduced cardiovascular risk) of a DN patient.

[0028]

[0029] In other embodiments, the terms "treat," "treatment," and "treating" refer to inhibiting or slowing the progression of DN, either physically, for example, by stabilizing at least one clinically identifiable physiological parameter (e.g., [UARC]) or by stabilizing at least one measurable symptom or effect (e.g., renal function, slowing of progression to ESKD).

[0029]

[0030] As used herein, the terms "combination" (as in the phrase "combination therapy") or "co-administration" can be used interchangeably to refer to the use of more than one therapeutic modality. The use of the terms does not limit the order in which the therapeutic modalities are administered to a subject.

[0030] NO-sGC-cGMP pathway

[0031] In the body, nitric oxide (NO) is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by the sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II), found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation; and constitutive endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence has shown that reduced NO concentrations, reduced NO bioavailability, and / or reduced responsiveness to endogenously produced NO contribute to the pathogenesis of idiopathic pulmonary edema.

[0031]

[0032] sGC is the primary receptor enzyme for NO in vivo. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine 5'-triphosphate (GTP) to the second messenger cyclic guanosine 3',5'-monophosphate (cGMP). Elevated cGMP levels then regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

[0032]

[0033] Over the past decade, two classes of compounds capable of activating the sGC receptor have been identified: sGC stimulators and sGC activators. NO-independent, heme-dependent sGC stimulators have shown several important distinguishing characteristics when compared with NO-independent, heme-independent sGC activators. These include a critical dependence of their activity on the presence of the reduced prosthetic heme moiety and strong synergistic enzyme activation when combined with NO. The benzylindazole compound YC-1 was the first sGC stimulator identified. Since then, additional sGC stimulators with improved potency and specificity for sGC have been developed.

[0033]

[0034] The increase in cGMP concentration resulting from sGC stimulation leads to vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive, antiremodeling, antiapoptotic, anti-inflammatory, antifibrotic, and neuronal signaling effects in animal models. Therefore, sGC stimulators can be used to treat and / or prevent a range of diseases and disorders, including kidney disease. sGC stimulators can also be useful in preventing and / or treating diseases and disorders characterized by an undesirable decrease in NO bioavailability and / or sensitivity, such as those associated with oxidative or nitrosative stress. Compounds that stimulate sGC in an NO-independent manner offer significant advantages over alternative therapies that target abnormal NO pathways or instead benefit from upregulation of the NO pathway, such as arginine, NO donors, or PDE5 inhibitors.

[0034] Praliciguat (IW-1973)

[0035] Compound I (praliciguat, prl, IW-1973, IWP-121) is a novel sGC stimulator characterized by multidimensional pharmacology and broad distribution across multiple tissue layers in animal models, including the renal medulla and cortex (Tobin JV et al. (2018), "Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-inflammatory, and Antifibrotic Effects in Preclinical Models of Disease," 365, pp. 664-675; Buys ES et al. (2018), "Discovery and development of next-generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential," Nitric Oxide, 78, pp. 72-81).

[0035] [ka]

[0036]

[0036] The present invention is based on the surprising finding that the sGC stimulator Compound I, administered in a specific dosing regimen to a population of DN patients, exhibits the ability to positively influence relevant clinical markers associated with DN.

[0037] The present invention is also based on the surprising finding that the sGC stimulator Compound I, administered in a particular dosing regimen to a population of DN patients, improves albuminuria in said patients when compared to placebo. In certain embodiments, patients have an albuminuria of 30-45 mL / min / 1.73 m 2 In certain embodiments, the patient has an eGFR of 45-60 mL / min / 1.73 m 2 have an eGFR value of

[0038]

[0038] The present invention also provides a specific dosing regimen of 30 to 45 mL / min / 1.73 m 2 This is based on the surprising finding that the sGC stimulator Compound I administered to a subpopulation of DN patients with eGFR values ​​of 0.05 or greater has a superior effect on reducing albuminuria in said patients when compared to placebo.

[0039]

[0039] The present invention is also based on the surprising finding that the sGC stimulator Compound I, administered in a specific dosing regimen to a population of DN patients, improves metabolic parameters in said patients when compared to placebo.

[0040] The present invention is also based on the surprising finding that the sGC stimulator Compound I, administered in a specific dosing regimen to a population of DN patients, reduces blood pressure in said patients when compared to placebo. While a reduction in blood pressure in diabetic patients has previously been observed by the present inventors in human patients, DN patients are known to often be resistant to treatment with other blood pressure medications (Rossignol P et al., "The double challenge of resistant hypertension and chronic kidney disease." Lancet. 2015 Oct. 17;386(10003):1588-98).

[0041] treatment The diagnosis of DN or DKD is based on the presence of albuminuria (urinary albumin-to-creatinine ratio [UACR] of >30 mg / g) and / or a reduced estimated glomerular filtration rate (<90 mL / min / 1.73 m 2Based on eGFR. Recent studies and meta-analyses have supported the relationship between reduced urinary albumin loss (measured by UACR assessment) and delayed renal function decline for intervention in chronic kidney disease, including DKD (Cherney DZI et al., "Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomized, placebo-controlled trial," Lancet Diabetes Endocrinol., 5(8), 610-621, 2017; 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., 7(2), 115-127, 2019; Heerspink HJL et al., "Change in albuminuria as a surrogate endpoint for progression of "Kidney disease: a meta-analysis of treatment effects in randomized clinical trials," Lancet Diabetes Endocrinol., 7(2), 128-139, 2019. Therefore, attenuation of albuminuria in early-phase clinical trials may be a predictor of long-term renal benefit in diabetic patients, including preservation of renal function and delay or prevention of progression to ESKD or renal replacement therapy (in the form of dialysis or transplantation) and death.

[0042] The goal of the study described in the experimental section was to evaluate the tolerability and safety of praliciguat in patients with type 2 diabetes mellitus (T2D) and moderate to severe albuminuria who were receiving a stable dose of a RAAS inhibitor, and to determine whether albuminuria decreased after 12 weeks of treatment. In some embodiments of the methods and uses of the present invention, the patients had a UACR value greater than 200 mg / g and less than 5000 mg / g at the start of treatment. In other embodiments of the methods and uses of the present invention, the patients had a UACR value greater than 200 mg / g at the start of treatment. In some embodiments of the methods and uses of the present invention, the patients had a UACR value less than 5000 mg / g at the start of treatment. In some embodiments of the methods and uses of the present invention, the patients had a UACR value between 30 mg / g and 300 mg / g or between 30 mg / g and 200 mg / g. In some embodiments of the methods and uses of the present invention, the patients were receiving a stable regimen of an ACEi or ARB at the start of treatment.

[0043]

[0043] Estimated glomerular filtration rate (eGFR) is a measure of the level of renal function. As used herein, eGFR is measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI et al. (2009) "A new equation to estimate glomerular filtration rate," Annals of Internal Medicine 150(9):604-12).

[0044] In some embodiments of the methods and uses of the present invention, the patient has a blood flow rate of 30-45 mL / min / 1.73 m at the start of treatment. 2 In other embodiments, patients have an eGFR of greater than 45 to 60 mL / min / 1.73 m at the start of treatment. 2 In yet other embodiments, patients have an eGFR of greater than 60 and up to 75 mL / min / 1.73 m at the start of treatment. 2In certain embodiments, patients have an eGFR of 75-90 mL / min / 1.73 m at the start of treatment. 2 have an eGFR of

[0045] In certain embodiments of the methods and uses of the present invention, the patient has a HOMA-IR level of 2.9 or greater, indicating significant insulin resistance.

[0046] In some embodiments of the above methods and uses, the sGC stimulating agent is administered before symptoms of a disease, disorder, or condition are fully developed in the patient. In other embodiments of the above methods and uses, the sGC stimulating agent is administered after one or more symptoms of a disease, disorder, or condition are developed in the patient.

[0046]

[0047] One skilled in the art can determine improvement in any measurable clinical or pathological parameter or assessment using routine means (e.g., including, but not limited to, clinical tests, physical tests, cognitive tests, imaging tools, etc.).

[0047]

[0048] In some embodiments of the methods and uses of the present invention, the patient has a history of hypertension. In some of these embodiments, the patient is receiving at least one antihypertensive drug. In other embodiments, the patient has a sitting blood pressure [BP] of >140 / 90 mmHg before treatment begins. In other embodiments, the patient has a sitting blood pressure [BP] of >130 / 85 mmHg before treatment begins. In other embodiments, the patient is receiving a stable regimen of one or more antihypertensive drugs.

[0048]

[0049] In certain embodiments of the methods and uses of the present invention, the patient has a systolic blood pressure of ≧140 mmHg and / or a diastolic blood pressure of ≧90 mmHg before initiating treatment. In certain embodiments of the methods and uses of the present invention, the patient has a systolic blood pressure of ≧130 mmHg and / or a diastolic blood pressure of ≧85 mmHg before initiating treatment.

[0049]

[0050] In certain embodiments of the methods and uses of the present invention, the patient has a fasting blood glucose level of 150 mg / dL or greater. In certain embodiments of the methods and uses of the present invention, the patient has a fasting blood glucose level of 140 mg / dL or greater. In certain embodiments of the methods and uses of the present invention, the patient has a fasting blood glucose level of 130 mg / dL or greater. In certain embodiments of the methods and uses of the present invention, the patient has a fasting blood glucose level of 120 mg / dL or greater. In other embodiments, the patient has a fasting blood glucose level of 110 mg / dL or greater. In other embodiments, the patient has a fasting blood glucose level of 100 mg / dL or greater. In other embodiments, the patient has a fasting blood glucose level of 95 mg / dL or greater. In still other embodiments, the patient has been diagnosed with type 2 diabetes mellitus. In other embodiments, the patient has been diagnosed with prediabetes. In some of these embodiments, the patient is being treated for diabetes or prediabetes. In still other embodiments, the patient has a hemoglobin A1c value of ≧5.6%. In still other embodiments, the patient has a hemoglobin Alc value of ≧6.5%. In still other embodiments, the patient has a hemoglobin Alc value of ≧7.0%. In still other embodiments, the patient has a hemoglobin Alc value of ≦12%. In still other embodiments, the patient has a hemoglobin Alc value of 7.0-8.5%. In still other embodiments, the patient has a hemoglobin Alc value of 7.5-8.5%. In some embodiments, the patient is receiving a stable regimen of one or more antihyperglycemic agents.

[0050]

[0051] In certain embodiments of the methods and uses of the present invention, the patient is a male with a waist circumference of 102 cm (40 inches) or greater and a female with a waist circumference of 88 cm (35 inches) or greater.

[0052] In some embodiments of the methods and uses of the present invention, the patient has a weight of >25 kg / m 2 In other embodiments, the patient has a body mass index (BMI) of 30 kg / m 2In yet another embodiment, the BMI is 40 kg / m 2 Higher.

[0051]

[0053] In some embodiments of the methods and uses of the present invention, the patient has fatty liver disease. In some embodiments, the patient has non-alcoholic fatty liver disease (NAFLD). In other embodiments, the patient has NASH.

[0052]

[0054] In certain embodiments of the methods and uses of the invention described herein, the human patient has DN. In some embodiments, the human patient is an adult. In other embodiments, the human patient is 50-75 years old. In other embodiments, the patient is 55-70 years old.

[0053]

[0055] In some embodiments of the methods and uses of the present invention, the patient is African American, Native American, or Asian American. In some embodiments, the patient is African American. In other embodiments, the patient is Native American. In still other embodiments, the patient is Asian American. In still further embodiments, the patient is Asian. In still other embodiments, the patient is African. In still other embodiments, the patient is Black. In still other embodiments, the patient is Caucasian. In still other embodiments, the patient is Latino. In still other embodiments, the patient is non-Latino.

[0054]

[0056] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of 10 mg to 40 mg, 10 mg to 20 mg, 20 mg to 40 mg, 20 mg to 30 mg, or 30 mg to 40 mg of Compound I.

[0055]

[0057] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of Compound I of 10 mg.

[0058] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of 15 mg of Compound I.

[0056]

[0059] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of 20 mg of Compound I.

[0060] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of 25 mg of Compound I.

[0057]

[0061] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of 30 mg of Compound I.

[0062] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a single oral daily dose of 40 mg of Compound I.

[0058]

[0063] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a 5 mg oral dose of Compound I twice daily. In one embodiment, the methods and uses comprise administering to a patient a first oral dose of 5 mg and a second oral dose of 5 mg, wherein the first and second doses are 5 to 15 hours, 8 to 15 hours, or 10 to 15 hours apart. In another embodiment, the first and second doses are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours apart.

[0059]

[0064] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a 7.5 mg oral dose of Compound I twice daily. In one embodiment, the methods and uses comprise administering to a patient a first oral dose of 7.5 mg and a second oral dose of 7.5 mg, wherein the first and second doses are 5 to 15 hours, 8 to 15 hours, or 10 to 15 hours apart. In another embodiment, the first and second doses are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours apart.

[0060]

[0065] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a 10 mg oral dose of Compound I twice daily. In one embodiment, the methods and uses comprise administering to a patient a first oral dose of 10 mg and a second oral dose of 10 mg, wherein the first and second doses are 5 to 15 hours, 8 to 15 hours, or 10 to 15 hours apart. In another embodiment, the first and second doses are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours apart.

[0061]

[0066] In certain embodiments, the methods and uses described herein comprise administering to a patient a 12.5 mg oral dose of Compound I twice daily. In one embodiment, the methods and uses comprise administering to a patient a first oral dose of 12.5 mg and a second oral dose of 12.5 mg, wherein the first and second doses are 5 to 15 hours, 8 to 15 hours, or 10 to 15 hours apart. In another embodiment, the first and second doses are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours apart.

[0062]

[0067] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a 20 mg oral dose of Compound I twice daily. In one embodiment, the methods and uses comprise administering to a patient a first oral dose of 20 mg and a second oral dose of 20 mg, wherein the first and second doses are 5 to 15 hours, 8 to 15 hours, or 10 to 15 hours apart. In another embodiment, the first and second doses are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours apart.

[0063]

[0068] In certain embodiments, the methods and uses of the invention described herein comprise administering to a patient a 15 mg oral dose of Compound I twice daily. In one embodiment, the methods and uses comprise administering to a patient a first oral dose of 15 mg and a second oral dose of 15 mg, wherein the first and second doses are 5 to 15 hours, 8 to 15 hours, or 10 to 15 hours apart. In another embodiment, the first and second doses are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours apart.

[0064]

[0069] In some embodiments, the methods and uses of the invention described herein comprise administering to a patient an initial dose of 10 mg to 20 mg once daily for 7 to 14 days, followed by an increasing maintenance dose of 20 mg to 40 mg once daily.

[0065]

[0070] In some embodiments, the maintenance dose continues indefinitely, so long as the patient continues to experience clinical benefit. Thus, in some embodiments, the methods and uses of the invention described herein comprise administering to the patient an initial oral dose of 10 mg to 20 mg once daily for 7 to 14 days, followed by administering to the patient a maintenance dose of 20 mg to 40 mg once daily. In some embodiments, the administration of the maintenance dose continues indefinitely, so long as the patient continues to experience clinical benefit with minimal undesirable side effects.

[0066]

[0071] In some embodiments, the methods and uses described herein comprise administering to a patient an initial dose of 5 mg to 20 mg twice daily for 7 to 14 days, followed by a maintenance dose of 10 mg to 40 mg once daily. In some embodiments, the methods and uses described herein comprise administering to a patient an initial dose of 5 mg twice daily for 7 to 14 days, followed by a maintenance dose of 10 mg once daily. In some embodiments, the methods and uses described herein comprise administering to a patient an initial dose of 7.5 mg twice daily for 7 to 14 days, followed by a maintenance dose of 15 mg once daily. In some embodiments, the methods and uses described herein comprise administering to a patient an initial dose of 10 mg twice daily for 7 to 14 days, followed by a maintenance dose of 20 mg once daily. In some embodiments, the methods and uses of the invention described herein comprise administering to a patient an initial dose of 15 mg twice daily for 7-14 days, followed by a maintenance dose of 30 mg once daily. In some embodiments, the methods and uses of the invention described herein comprise administering to a patient an initial dose of 20 mg twice daily for 7-14 days, followed by a maintenance dose of 40 mg once daily. In some embodiments, administration of the maintenance dose continues indefinitely, as long as the patient continues to experience clinical benefit with minimal undesirable side effects.

[0067]

[0072] In some embodiments, the methods and uses of the invention described herein comprise administering an initial total oral daily dose of 10 mg for 3-14 days, followed by a total oral daily dose of 20 mg for 3-14 days, and then increasing to a maintenance dose of 40 mg. In some embodiments, titration to 15 mg or 25 mg for 3-14 days each may be added. In some embodiments, the methods and uses of the invention described herein comprise administering an initial total oral daily dose of 10 mg for 3-14 days, followed by a total oral daily dose of 15 mg for 3-14 days, followed by a total oral daily dose of 20 mg for 3-14 days, and then increasing to a maintenance dose of 40 mg. In some embodiments, the methods and uses of the invention described herein comprise administering an initial total oral daily dose of 10 mg for 3-14 days, followed by a total oral daily dose of 15 mg for 3-14 days, followed by a total oral daily dose of 20 mg for 3-14 days, followed by a total oral daily dose of 25 mg for 3-14 days, and then increasing to a maintenance dose of 40 mg. In some embodiments, administration of the maintenance dose continues indefinitely, so long as the patient continues to experience clinical benefit with minimal undesirable side effects. In some embodiments, the methods and uses of the invention described herein comprise administering an initial total oral daily dose of 10 mg for 3-14 days, followed by a total oral daily dose of 15 mg for 3-14 days, followed by a maintenance total oral daily dose of 20 mg. In some embodiments, the methods and uses of the invention described herein comprise administering an initial total oral daily dose of 10 mg for 3-14 days, followed by a total oral daily dose of 15 mg for 3-14 days, followed by a total oral daily dose of 20 mg, followed by a total maintenance oral dose of 30 mg.

[0068]

[0073] In other embodiments, the methods and uses of the invention described herein comprise administering to a patient an initial oral daily dose of 15 mg to 40 mg once daily, followed by a maintenance daily dose of 7.5 mg to 20 mg once daily if the patient experiences hypotension. In some embodiments, the maintenance dose continues indefinitely, as long as the patient continues to experience clinical benefit with minimal undesirable blood pressure-lowering effects. Thus, in some embodiments, the methods and uses of the invention described herein comprise administering to a patient an initial oral daily dose of 15 mg to 40 mg once daily, followed by a maintenance dose of 7.5 mg to 20 mg once daily if the patient experiences hypotension. In some embodiments, the maintenance dose continues indefinitely, as long as the patient continues to experience clinical benefit with minimal undesirable blood pressure-lowering effects.

[0069]

[0074] In some embodiments, when a patient is taking a strong CYP3A inhibitor concurrently with Compound I, the observed AUC and T 1 / 2 The AUC and T values ​​observed in patients not taking a strong CYP3A inhibitor concomitantly were 1 / 2 (See Clinical Trial Number NCT03499106, https: / / clinicalcentrals.gov). For these embodiments, the methods and uses of the invention described herein involve the use of a half dose of Compound I to achieve the same results as achieved with the full dose in patients not concurrently taking a strong CYP3A inhibitor.

[0070]

[0075] Examples of strong CYP3A inhibitors include, but are not limited to, azole antifungals, macrolide antibiotics, protease inhibitors, and diltiazem.

[0076] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient one or more (two, three, four, five, etc.) antihypertensive drugs. In one embodiment, the one or more antihypertensive drugs are each independently selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), an MR antagonist (MRA), an endothelin receptor antagonist (ERA), and a diuretic. In certain embodiments, the one or more antihypertensive drugs are each independently selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a diuretic, a calcium channel blocker, a beta-blocker, a vasodilator, a centrally acting agent, and an aldosterone antagonist. In one embodiment, at least one of the antihypertensive drugs is an ARB or an ACE inhibitor.

[0071]

[0077] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient one or more (two, three, four, five, etc.) antihypertensive drugs. In one embodiment, the one or more antihypertensive drugs are each independently selected from an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB). In another embodiment, the one or more antihypertensive drugs are each independently selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, benazepril, captopril, enalapril, candesartan, losartan, azilsartan, eprosartan, irbesartan, olmesartan, telmisartan, and valsartan. In another embodiment, the one or more antihypertensive drugs are each independently selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, losartan, metoprolol, and spironolactone. In another embodiment, the one or more antihypertensive drugs are each independently selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, and losartan. In one embodiment, at least one of the antihypertensive drugs is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). In another embodiment, at least one of the antihypertensive drugs is selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, and losartan.

[0072]

[0078] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient two or more (three, four, five, etc.) antihypertensive drugs. In certain embodiments, at least one of the antihypertensive drugs is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and at least one of the antihypertensive drugs is a diuretic. In certain embodiments, the diuretic is selected from chlorthalidone and hydrochlorothiazide.

[0073]

[0079] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient three or more (four, five, six, etc.) antihypertensive drugs. In certain embodiments, at least one of the antihypertensive drugs is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), at least one of the antihypertensive drugs is a diuretic, and at least one of the antihypertensive drugs is selected from a calcium channel blocker and a beta-blocker. In certain embodiments, the diuretic is selected from chlorthalidone and hydrochlorothiazide.

[0074]

[0080] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient four or more (five, six, etc.) antihypertensive drugs. In certain embodiments, at least one of the antihypertensive drugs is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), at least one of the antihypertensive drugs is a diuretic, at least one of the antihypertensive drugs is selected from a calcium channel blocker and a beta-blocker, and at least one of the antihypertensive drugs is selected from a vasodilator, a centrally acting agent, and an aldosterone antagonist. In certain embodiments, the diuretic is selected from chlorthalidone and hydrochlorothiazide. In certain embodiments, the vasodilator is selected from hydrazine and minoxidil. In certain embodiments, the centrally acting agent is clonidine. In certain embodiments, the aldosterone antagonist is selected from spironolactone and eplerenone.

[0075]

[0081] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient one or more (two, three, four, five, etc.) hypoglycemic agents (antihyperglycemic or antidiabetic agents). In one embodiment, the one or more hypoglycemic agents are independently selected from the group consisting of insulin, metformin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, canagliflozin, and dapagliflozin. In certain embodiments, insulin is not given or administered to a patient treated by a method described herein during treatment with Compound I. In some embodiments, the patient is being treated with an oral antihyperglycemic agent in addition to Compound I.

[0076]

[0082] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient an antihypertensive drug described herein and a hypoglycemic drug described herein. In one embodiment, the methods and uses further comprise administering to the patient one or more antihypertensive drugs independently selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, losartan, metoprolol, and spironolactone, and one or more hypoglycemic drugs independently selected from the group consisting of insulin, metformin, and glipizide. In one embodiment, at least one of the antihypertensive drugs is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). In another embodiment, at least one of the antihypertensive drugs is selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, and losartan.

[0077]

[0083] In certain embodiments, the methods of the present invention described herein further comprise administering to the patient one or more (two, three, four, five, etc.) antihyperlipidemic agents. In one embodiment, the one or more antihyperlipidemic agents are selected from cholesterol-lowering agents. In one embodiment, the one or more antihyperlipidemic agents are independently selected from the group consisting of atorvastatin, pravastatin, simvastatin, rosuvastatin, lovastatin, and nicotinic acid. In another embodiment, the one or more cholesterol-lowering agents are selected from the group consisting of atorvastatin, pravastatin, rosuvastatin, lovastatin, and simvastatin.

[0078]

[0084] In certain embodiments, the methods and uses of the present invention described herein further comprise administering to the patient one or more (two, three, four, five, etc.) neprilysin inhibitors. In one embodiment, the neprilysin inhibitor is sacubitril or a combination of sacubitril and valsartan.

[0079]

[0085] In certain embodiments, the methods and uses of the invention described herein are indicated for improving albuminuria in a patient. In some embodiments, improvement in albuminuria is measured by a decrease in the patient's UACR. In certain embodiments, the methods and uses of the invention described herein result in a decrease in UACR of 10% to 40%, 20% to 40%, 20% to 30%, or 30% to 40%. In certain embodiments, the patient has a decrease in UACR of 30 to 45 mL / min / 1.73 m 2 and the methods and uses of the invention described herein result in a reduction in UACR of 10% to 40%, 20% to 40%, 20% to 30% or 30% to 40%.

[0080]

[0086] In certain embodiments, the methods and uses of the present invention described herein are indicated for delaying or preventing clinical deterioration in a patient. In some embodiments, the methods and uses of the present invention described herein are indicated for delaying or preventing progression to ESKD or delaying or preventing the need for renal replacement therapy (dialysis or kidney transplant). In other embodiments, the methods and uses of the present invention described herein result in a reduction in hospitalizations due to renal causes. In some embodiments, the renal cause is uremia. In other embodiments, the methods and uses of the present invention described herein result in a delay or prevention of deterioration of renal function. In certain embodiments, deterioration of renal function is defined by a doubling of serum creatinine levels. In certain embodiments, deterioration of renal function is defined as a 40% or greater decline in eGFR over a period of 1 to 4 years. In some embodiments, the period is 1 year (fast deterioration). In other embodiments, the period of deterioration is 2 years. In other embodiments, the period of deterioration is 3 years. In other embodiments, the period of deterioration is 4 years (slow deterioration).

[0081]

[0087] In certain embodiments, the methods and uses of the invention described herein result in an increase in patient survival, while in other embodiments, they result in a delay in time to death.

[0082]

[0088] In certain embodiments, the methods and uses of the present invention described herein are indicated for lowering blood pressure (BP) in diabetic patients. In certain embodiments, the methods and uses of the present invention described herein result in a reduction in the patient's MAP. In certain embodiments, the reduction in MAP is in the range of 1 mmHg to 10 mmHg, 1 mmHg to 6 mmHg, 2 mmHg to 6 mmHg, or 3 mmHg to 4 mmHg. In certain embodiments, the methods and uses of the present invention described herein result in a reduction in the patient's systolic blood pressure. In certain embodiments, the reduction in systolic blood pressure is in the range of 1 mmHg to 10 mmHg, 1 mmHg to 8 mmHg, 4 mmHg to 6 mmHg, or 4 mmHg to 5 mmHg. In certain embodiments, the BP measurement is a seated BP measurement. In one embodiment, the BP measurement is a seated BP measurement using an automated office device. In other embodiments, the BP measurement is a 24-hour average BP measurement using a portable monitoring device. In certain embodiments, the BP measurement is a BP measurement of systolic blood pressure, diastolic blood pressure, and / or MAP. In certain embodiments, the methods and uses of the present invention described herein result in a decrease in a patient's sitting BP (e.g., systolic blood pressure, diastolic blood pressure, and / or MAP). In certain embodiments, the decrease in sitting BP (e.g., systolic blood pressure, diastolic blood pressure, and / or MAP) is in the range of 1 mmHg to 10 mmHg, 1 mmHg to 8 mmHg, 1 mmHg to 6 mmHg, 2 mmHg to 6 mmHg, 4 mmHg to 6 mmHg, 4 mmHg to 5 mmHg, or 3 mmHg to 4 mmHg. In certain embodiments, the methods and uses of the present invention described herein decrease a patient's UACR as described above, and at least a portion of the observed decrease in UACR is independent of changes in the patient's blood pressure. In certain embodiments, the decrease in UACR is not associated with a significant decrease in the patient's MAP. In certain embodiments, the decrease in UACR is not associated with a significant decrease in the patient's diastolic blood pressure. In certain embodiments, the decrease in UACR is not associated with a significant decrease in the patient's systolic blood pressure. In certain embodiments, the decrease in UACR is not associated with a significant decrease in the patient's sitting BP (eg, systolic blood pressure, diastolic blood pressure and / or MAP).As used herein, a "significant" reduction refers to a reduction in blood pressure of more than 5 mmHg, more than 4 mmHg, more than 3 mmHg, more than 2 mmHg, or more than 1 mmHg.

[0083]

[0089] In certain embodiments, the methods and uses of the present invention described herein are indicated for improving a patient's metabolic outcomes, including reducing the risk of CV events. The likelihood of certain metabolic outcomes in a patient is known to be associated with elevated levels of various metabolic parameters, such as fasting plasma glucose, hemoglobin A1c (HbA1c), fasting plasma insulin, HOMA-IR, serum total cholesterol, LDL-cholesterol, and triglycerides. In some embodiments, the methods and uses of the present invention result in a reduction in one or more metabolic parameters. In some embodiments, the reduction is in one or more parameters selected from fasting plasma glucose, HbA1c, serum total cholesterol, and serum LDL-cholesterol. In certain embodiments, the reduction in a patient's fasting plasma glucose is in the range of 1% to 30%, 1% to 20%, 1% to 10%, or 1% to 5%. In certain embodiments, the reduction in HbA1c is in the range of 0.1% to 1%, 0.1% to 6%, 0.2% to 0.4%, or 0.3% to 0.4%. In certain embodiments, the reduction in serum total cholesterol is in the range of 1 mg / dL to 30 mg / dL, 1 mg / dL to 20 mg / dL, 1 mg / dL to 10 mg / dL, 1 mg / dL to 8 mg / dL, 3 mg / dL to 8 mg / dL, or 4 mg / dL to 6 mg / dL. In certain embodiments, the reduction in serum LDL-cholesterol is in the range of 1 mg / dL to 30 mg / dL, 1 mg / dL to 20 mg / dL, 1 mg / dL to 10 mg / dL, 1 mg / dL to 8 mg / dL, 3 mg / dL to 7 mg / dL, or 3 mg / dL to 6 mg / dL.

[0084]

[0090] In some embodiments, the methods and uses of the invention described herein are indicated for reducing the risk of CV events. In certain embodiments, the methods and uses of the invention described herein result in improved metabolic outcomes in patients.

[0085]

[0091] In certain embodiments, an improvement in the patient's albuminuria (e.g., a decrease in UACR), delay or prevention of clinical deterioration, a decrease in blood pressure (e.g., a decrease in MAP, a decrease in systolic blood pressure, a decrease in sitting BP), and / or an improvement in metabolic outcomes (e.g., a reduction in the risk of CV events, a decrease in fasting plasma glucose, hemoglobin A1c (HbA1c), fasting plasma insulin, HOMA-IR, serum total cholesterol, LDL-cholesterol, and / or triglycerides) is observed after the patient has been treated with the method for a period of time. In certain embodiments, an improvement in the patient's albuminuria (e.g., a decrease in UACR), delay or prevention of clinical deterioration, a decrease in blood pressure (e.g., a decrease in MAP, a decrease in systolic blood pressure, a decrease in sitting BP), and / or an improvement in metabolic outcomes (e.g., a reduction in the risk of CV events, a decrease in fasting plasma glucose, hemoglobin A1c (HbA1c), fasting plasma insulin, HOMA-IR, serum total cholesterol, LDL-cholesterol, and / or triglycerides) is observed after 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 6 months, 8 months, 12 months, or 24 months of treatment.

[0086] Combination Therapy

[0092] Treatment of DN and related symptoms with Compound I can be carried out using the compound alone or in combination with other therapeutic agents. In certain embodiments, Compound I can be used to treat DN in combination with one or more drugs independently selected from antihypertensive drugs, hypoglycemic drugs, antihyperlipidemic drugs, nephroprotective drugs, and neprilysin inhibitors.

[0087]

[0093] The sGC stimulator compound I can be used in combination therapy with one or more additional therapeutic agents (for example, the additional therapeutic agents described herein).For combination treatment with more than one therapeutic agent, where the therapeutic agents are in separate dosage formulations or dosage forms, the therapeutic agents can be administered separately or together (i.e., at the same time).In addition, when administered separately, the administration of one therapeutic agent can be before or after the administration of the other therapeutic agent.

[0088]

[0094] When Compound I is used in combination therapy with other therapeutic agents, the therapeutically effective amount of each of the other therapeutic agents depends on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by those skilled in the art according to the subject's condition, the type of condition being treated, and the amount of Compound I used. In one embodiment of the present invention, Compound I and the additional therapeutic agent are each administered in a therapeutically effective amount (i.e., an amount that is therapeutically effective when each is administered alone). In other embodiments, Compound I and the additional therapeutic agent are each administered in an amount that does not produce a therapeutic effect alone (a subtherapeutic dose). In yet another embodiment, Compound I can be administered in a therapeutically effective amount, and the additional therapeutic agent is administered in a subtherapeutic dose. In yet another embodiment, Compound I can be administered in a subtherapeutic dose, and the additional therapeutic agent is administered in a therapeutically effective amount.

[0089]

[0095] When co-administration comprises separate administration of a first amount of compound I and a second amount of additional therapeutic agent, the compounds are administered at a time close enough to achieve desired therapeutic effect.For example, the time between each administration that can bring about desired therapeutic effect can be in the range of several minutes to several hours, and can be determined by considering the properties of each compound, such as efficacy, solubility, bioavailability, plasma half-life and pharmacokinetic profile.For example, compound I and the second therapeutic agent can be administered simultaneously or simultaneously in any order within 24 hours, within 16 hours, within 8 hours, within 4 hours, within 1 hour, within 30 minutes, within 5 minutes.

[0090]

[0096] More specifically, the first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, or 12 hours before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours after) the administration of the second therapy to the subject.

[0091]

[0097] Examples of other therapeutic agents that may be combined with Compound I include, but are not limited to, those discussed below.

[0098] 1. Hypoglycemic agents (also called blood glucose control agents or antidiabetic agents) that may be used in combination with Compound I include, but are not limited to:

[0099] Biguanides. The biguanide metformin is typically the first drug prescribed for type 2 diabetes. It works by improving the body's tissue sensitivity to insulin, allowing the body to use insulin more efficiently. Metformin also reduces glucose production in the liver. Metformin may not adequately lower blood sugar on its own. If metformin and lifestyle changes are not enough to control blood sugar levels, other oral or injectable medications, such as the following types, may be added:

[0092]

[0100] Sulfonylureas. Examples of drugs in this class include glyburide, glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, atorvastatin calcium in combination with glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide and tolazamide. In certain embodiments, the sulfonylurea that can be used in combination with Compound I in the treatment of DN is selected from glyburide, glipizide and glimepiride.

[0093]

[0101] Alpha-glucosidase inhibitors, such as acarbose, epalrestat, voglibose, and miglitol.

[0102] Insulin secretagogues. Examples include repaglinide, mitiglinide and nateglinide. In certain embodiments, the insulin secretagogue that can be used in combination with Compound I in the treatment of DN is repaglinide or nateglinide.

[0094]

[0103] Thiazolidinediones such as rosiglitazone, troglitazone, ciglitazone, pioglitazone, englitazone, lobeglitazone sulfate, and balaglitazone.

[0104] DPP-4 inhibitors (or DPP-IV inhibitors). Examples of these drugs are sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alogliptin benzoate in combination with metformin or metformin hydrochloride, anagliptin, teneligliptin, atorvastatin calcium and glimepiride, empagliflozin in combination with linagliptin, gemigliptin, sitagliptin phosphate monohydrate in combination with pioglitazone hydrochloride, sitagliptin in combination with pioglitazone, sitagliptin in combination with atorvastatin calcium, and (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile (DBPR-108). In certain embodiments, the DPP-4 inhibitor that may be used in combination with Compound I in the treatment of DN is sitagliptin, saxagliptin, or linagliptin.

[0095]

[0105] GLP-1 receptor antagonist or incretin mimetic. Examples include exenatide, dulaglutide, liraglutide, semaglutide, lixisenatide, lixisenatide combined with insulin glargine, albiglutide and pegapamozutide (TT-401), LY3298176 (dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist). In certain embodiments, the GLP-1 receptor agonist that can be used in combination with Compound I in the treatment of DN is exenatide, semaglutide or liraglutide. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist is oral semaglutide.

[0096]

[0106] SGLT2 inhibitors (SGLT2i). Examples include empagliflozin, empagliflozin in combination with linagliptin, empagliflozin in combination with metformin, ipragliflozin, ipragliflozin L-proline, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, ertugliflozin in combination with sitagliptin, ertugliflozin in combination with metformin, sotagliflozin, canagliflozin, canagliflozin in combination with metformin or metformin hydrochloride, dapagliflozin, dapagliflozin and luseogliflozin in combination with metformin or metformin hydrochloride, dapagliflozin in combination with saxagliptin. In one embodiment, the SGLT2 inhibitor is empagliflozin, canagliflozin, or dapagliflozin, or a combination containing these agents. In another embodiment, the SGLT2 inhibitor is dapagliflozin. In another embodiment, the SGLT2 inhibitor is empagliflozin. In another embodiment, the SGLT2 inhibitor is canagliflozin. In certain embodiments, the SGLT2 inhibitor is canagliflozin or dapagliflozin.

[0097]

[0107] An SGLT1 inhibitor or a combination of an SGLT1 inhibitor and an SGLT2 inhibitor. Examples include sotagliflozin.

[0108] Insulin therapy. There are many types of insulin, each of which works in a different way. Options include insulin glulisine, insulin degludec, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane, insulin mixtard (human insulin containing both rapid-acting (soluble) and long-acting (isophane) insulin), insulin degludec combined with insulin aspart, insulin human (rDNA origin) inhalation powder, recombinant human insulin, hepatotropic vesicle insulin, insulin tregopir (IN-105), insulin degludec combined with liraglutide, insulin peglispro (LY-2605541), and nodulin.

[0098]

[0109] Trimidone (Lyn kinase activator)

[0110] 2. Blood pressure lowering agents (also known as antihypertensives) that may be used in combination with Compound I include, but are not limited to:

[0111] Diuretics. Diuretics, sometimes called water pills, are drugs that act on the kidneys to help the body excrete sodium and water and reduce blood volume. Diuretics, or calcium channel blockers, may be more effective than angiotensin-converting enzyme (ACE) inhibitors alone in blacks and the elderly. Thiazide diuretics are often the first choice for hypertension medication, but are not the only choice. Diuretics include, for example, chlorothiazide, chlorthalidone, hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xipamide, metolazone, indapamide, cicletanine, furosemide, torasemide, amiloride, spironolactone, canrenoate potassium, eplerenone, triamterene, acetazolamide, and carperitide. In certain embodiments, the diuretic that may be used in combination with Compound I to treat DN is spironolactone.

[0099]

[0112] Beta-blockers. These drugs reduce the heart's workload, open blood vessels, and make the heart beat slower and less forcefully. When prescribed alone, beta-blockers do not have the same effect, especially in blacks and the elderly, but can be effective when combined with other blood pressure-lowering drugs. Beta-blockers include, for example, acebutolol, antenolol, metoprolol, and nebivolol. In certain embodiments, the beta-blocker that can be used in combination with Compound I to treat DN is metoprolol.

[0100]

[0113] Angiotensin-converting enzyme (ACE) inhibitors. These drugs help relax blood vessels by blocking the formation of natural chemicals that constrict blood vessels. ACE inhibitors that can be combined with Compound I in the treatment of DN include, for example, sulfhydryl-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (e.g., enalapril, quinapril, ramipril, perindopril, lisinopril, and benazepril), phosphate-containing agents (e.g., fosinopril), naturally occurring ACE inhibitors (e.g., casokinin, lactokine, lactotripeptide Val-Pro-Pro, and Ile-Pro-Pro), alacepril, delapril, cilazapril, imidapril, temocapril, moexipril, lisinopril, a combination of lisinopril and hydrochlorothiazide, trandolapril, and spirapril. In certain embodiments, ACE inhibitors that may be used in combination with Compound I in the treatment of DN are selected from lisinopril, a combination of lisinopril and hydrochlorothiazide, benazepril, captopril, and enalapril.

[0101]

[0114] Angiotensin II receptor blockers (ARBs). These drugs help relax blood vessels by blocking the action of natural chemicals that narrow blood vessels, rather than their formation. ARBs include candesartan, losartan, losartan potassium-hydrochlorothiazide, valsartan, candesartan cilexetil, eprosartan, irbesartan, telmisartan, olmesartan medoxomil (or olmesartan), azilsartan medoxomil, azilsartan, amlodipine besylate in combination with irbesartan, azilsartan in combination with amlodipine besylate, cilnidipine in combination with valsartan, fimasartan, and atorvastatin. In certain embodiments, ARBs that may be used in combination with Compound I in the treatment of DN include candesartan, losartan, eprosartan, irbesartan, olmesartan, telmisartan, and valsartan.

[0102]

[0115] Endothelin receptor antagonists (ERAs), such as atrasentan, bosentan, sitaxsentan, ambrisentan, actelion-1 (macitentan), cyclo(D-trp-D-asp-L-pro-D-val-L-leu) (BQ-123), sparsentan, and tezosentan disodium. In some embodiments, the ERA is bosentan.

[0103]

[0116] Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, amiloride hydrochloride in combination with spironolactone, aparalenone or MT-3995, eplerenone, and finerenone (BAY-94-8862). In some embodiments, the MRA is finerenone.

[0104]

[0117] Calcium channel blockers. These drugs help relax the muscles in blood vessels. Calcium channel blockers may be more effective in blacks and the elderly than ACE inhibitors alone. Some lower heart rate. Calcium channel blockers that can be combined with Compound I to treat DN include, for example, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, diltiazem, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, isradipine, verapamil, gallopamil, diltiazem, mibefradil, bepridil, fluspirilene, and fendiline.

[0105]

[0118] Renin inhibitor. Aliskiren slows the production of renin, an enzyme produced in the kidneys that initiates a series of chemical steps that increase blood pressure. It works by reducing renin's ability to initiate this process. Due to the risk of serious complications, including stroke, aliskiren cannot be taken without an ACE inhibitor or ARB.

[0106]

[0119] Alpha-blockers. These drugs reduce nerve impulses to blood vessels, reducing the effects of natural chemicals that narrow blood vessels. Alpha-blockers include doxazosin and prazosin.

[0107]

[0120] Alpha-beta blockers. In addition to reducing nerve impulses to blood vessels, alpha-beta blockers slow the heart rate, reducing the amount of blood that must be pumped through the blood vessels. Alpha-beta blockers include carvedilol and labetalol.

[0108]

[0121] Centrally acting drugs. These drugs prevent the brain from sending signals to the nervous system to increase the heart rate and narrow blood vessels. Examples include clonidine, guanfacine, and methyldopa.

[0109]

[0122] Vasodilators. These drugs act directly on the muscles in the arterial walls to prevent muscle stiffening and narrowing of the arteries. Examples of vasodilators include NO-donors such as nitroglycerin, as well as hydralazine and minoxidil.

[0110]

[0123] Aldosterone antagonists. These drugs block the effects of natural chemicals that can lead to salt and fluid retention, which can contribute to high blood pressure. Examples include finerenone, spironolactone, and eplerenone.

[0111]

[0124] 3. Antihyperlipidemic agents that may be used in combination with Compound I include, but are not limited to:

[0125] Statins. Examples of statins include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Combinations of statins with other drugs can also be used. Examples include, but are not limited to, amlodipine / atorvastatin, aspirin / pravastatin, ezetimibe / simvastatin, niacin / simvastatin, lovastatin / niacin, simvastatin / sitagliptin, and atorvastatin / ezetimibe. In certain embodiments, the statin is atorvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin.

[0112]

[0126] Fibrate or fibric acid derivatives. Examples include, but are not limited to, fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate, and clofibrate.

[0113]

[0127] Niacin (or nicotinic acid).

[0128] Bile acid sequestrants. Examples include, but are not limited to, cholestyramine, colesevelam, colestilan, and colestipol.

[0114]

[0129] Ezetimibe, lomitapide, phytosterols, or orlistat.

[0130] PCSK9 inhibitors. Examples include, but are not limited to, alirocumab and evolocumab.

[0115]

[0131] 4. Neprilysin inhibitors (also known as endopeptidase inhibitors, NEP inhibitors, or enkephalinase inhibitors). For example, Sacubitril, or a combination of Sacubitril and Valsartan. Other neprilysin inhibitors under development that can be combined with Compound I include TD-1439 and TD-0714. In some embodiments, the neprilysin inhibitor is Sacubitril or a combination of Sacubitril and another drug.

[0116]

[0132] 5. Nephroprotective drugs. Examples include, but are not limited to, bardoxolone, ACE inhibitors (such as captopril), ARBs (such as losartan or irbesartan), SGLT2 inhibitors (such as canagliflozin), GLP1 receptor agonists, MRAs (such as finerenone), ERAs (such as atrasentan), and apoptosis signal-regulating kinase 1 (ASK1) inhibitors (such as selonsertib). [Example]

[0117]

[0133] In order that the present invention may be better understood, the following examples are set forth. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. All references provided in the examples are incorporated herein by reference.

[0118] Example 1

[0134] A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of IW-1973 in Type 2 Diabetic Patients with Albuminuria Treated with Renin-Angiotensin System Inhibitors List of term abbreviations and definitions ABPM Ambulatory Blood Pressure Monitoring ACEi angiotensin-converting enzyme inhibitors AE Adverse Event ALT alanine aminotransferase AOBP Automated Office Blood Pressure ARB angiotensin receptor blockers AST aspartate aminotransferase AUC Area under the plasma concentration time curve BID twice a day BMI Body Mass Index (kg / m 2 ) BP blood pressure BUN Blood urea nitrogen CBC complete blood count cGMP cyclic guanosine 3',5'-monophosphate CKD-EPI Chronic Kidney Disease Epidemiology Collaborative Study CL / F Apparent total body clearance after oral administration CMH Cochran-Mantel-Haenszel CYP3A cytochrome P450 3A DBP Diastolic Blood Pressure DMC Data Monitoring Committee DN Diabetic Nephropathy DNA deoxyribonucleic acid ECG electrocardiogram eCRF Electronic Case Report Form EDC Electronic Data Capture eGFR Estimated glomerular filtration rate (mL / min / 1.73m 2 ) eNOS endothelial nitric oxide synthase EQ-5D-5L EuroQOL 5-dimensional questionnaire ESRD End Stage Renal Disease FDA Food and Drug Administration FPG fasting plasma glucose FPI fasting plasma insulin GCP Good Clinical Practice Standards GGT gamma-glutamyltransferase GI gastrointestinal GLP Good Laboratory Practice h time HbA1c Hemoglobin A1c (glycated hemoglobin) HBsAG Hepatitis B surface antigen HCV Hepatitis C virus HDPE High Density Polyethylene hERG (ether-a-go-go related gene) HIV human immunodeficiency virus HOMA-IR Homeostasis Model Assessment for Quantifying Insulin Resistance HPF high magnification field of view HR heart rate I C 50 Half the maximum inhibitory concentration ICF Informed Consent Form ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IRB Institutional Review Board ITT Intent to Treat IUD (intrauterine contraceptive device) IWRS Interactive Web Auto Response System KDIGO Kidney Disease: Improving Global Outcomes KDQOL-SF Kidney Disease Quality of Life - Short Form kg kilogram kg / m 2 kilograms per square meter (body mass index) LDH lactate dehydrogenase L-NAME L-nitroarginine methyl ester LS Least Squares m minutes MAD Multiple Ascending Dose MAP Mean Arterial Pressure MCH Mean corpuscular hemoglobin MCHC Mean corpuscular hemoglobin concentration MCV mean corpuscular volume MedDRA Drug Regulatory Information MEMS Drug Event Monitoring System mg milligram MI myocardial infarction mL milliliter mmHg millimeters of mercury MMRM Mixed Effects Model Repeated Measures MPV mean platelet volume msec milliseconds NO Nitric oxide NT-proBNP N-terminal pro-B-type natriuretic peptide NYHA New York Heart Association PEG polyethylene glycol After pd administration PD Pharmacodynamics PDE phosphodiesterase Assessment of global changes in PGIC patients Assessment of global severity in patients with PGIS PID patient identification PK Pharmacokinetics PKG Protein kinase G Per PP protocol PRN When needed [i.e., as needed] PT preferred term QD Once a day QTcF: QT interval corrected by the Fridericia formula RAAS renin-angiotensin-aldosterone system SAE serious adverse event SBP systolic blood pressure Scr serum creatinine sGC soluble guanylate cyclase SOC major classification by organ Tau administration interval TEAE Treatment-emergent adverse events UACR Urinary albumin to creatinine ratio

[0119] Outcome measures

[0135] The primary objective of this clinical study (Clinical Trials.gov Identifier NCT03217591) was to evaluate the safety and tolerability of oral IW-1973 and to assess its effect on renal function when administered daily for approximately 12 weeks in adult patients with type 2 diabetes mellitus and albuminuria receiving a stable regimen of renin-angiotensin system inhibitors (ERA or ARB).

[0120]

[0136] The primary safety and tolerability measures were the incidence of treatment-emergent adverse events (TEAEs) and TEAEs related to the study drug.

[0137] The primary efficacy endpoint of this study was the change from baseline in urinary albumin-to-creatinine ratio (UARC) at weeks 8 and 12. UARC was determined as the concentration of urinary albumin (mg / dL) divided by the concentration of urinary creatinine (g / dL) from a urinalysis. First-morning urine specimens were collected. To reduce variability, UARC measurements were the average of two first-morning urine tests at each time point.

[0121]

[0138] Other secondary objectives of this clinical study included assessing the pharmacokinetic (PK) concentrations of oral IW-1973 and exploring the effects of oral IW-1973 on hemodynamic and metabolic effects when administered daily for approximately 12 weeks to adult patients with type 2 diabetes mellitus (i.e., DN patients) with albuminuria receiving a stable regimen of renin-angiotensin system inhibitors (RAAS inhibitors, i.e., ACEi and ARB).

[0122]

[0139] Clinical laboratory evaluations obtained during the conduct of this clinical trial included complete blood count, serum chemistry panel, urinalysis, coagulation panel, estimated glomerular filtration rate (eGFR; determined by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula), hemoglobin Alc (HbAlc), homeostasis model assessment to estimate insulin resistance (HOMA-IR), platelet function testing (using VerifyNow® at some sites), urine pregnancy test, and screening for hepatitis, human immunodeficiency virus, and drugs of abuse.

[0123]

[0140] Hemodynamic and vital signs measured included sitting and standing BP (systolic and diastolic) and pulse measurements by automated office blood pressure (AOBP), ambulatory BP (systolic and diastolic) and pulse monitoring, respiratory rate, and oral temperature. Orthostatic (standing minus sitting) measurements of BP and pulse were calculated.

[0124]

[0141] Biomarkers measured included plasma and / or serum blood and urine levels of signaling molecules, which were assessed by either LC-MS / MS, ELISA, or MSD multiplex assays.

[0125]

[0142] Other measurements taken during the conduct of the study included recording of adverse events, electrocardiogram (ECG), physical examination, and recording of concurrent medications.

[0143] Plasma concentrations of IW-1973 were measured for pharmacokinetic determinations. Plasma concentrations were consistent with previous studies, demonstrating dose-proportional exposure and reaching steady state within 4 weeks of treatment.

[0126]

[0144] A population PK approach based on sparse PK data was used to determine the exposure (AUC) and oral clearance (CL / F) of IW-1973. The effect of patient demographics (e.g., age, race) on exposure was assessed. In addition, exposure-effect relationships (e.g., hemodynamics, exploratory biomarkers, efficacy, and safety parameters) were explored. The effect of concomitant medications on IW-1973 PK was also assessed.

[0127]

[0145] Praliciguat concentrations were measured using a previously described, validated liquid chromatography-tandem mass spectrometry method (Hanrahan JP et al., "A Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects," Clin Pharmacol Drug Dev. 2019, 8(5):564–575). Population PK analyses were performed using NONMEM 7.4 (Icon Development Solutions, Ellicott City, MD) to update existing models established with data from three Phase 1 studies in healthy subjects and two Phase 2a studies in patients with stable type 2 diabetes mellitus (T2D) and hypertension. The effects of patient demographics, renal function, and concomitant medications on exposure were assessed, and estimates of exposure (AUC) and oral clearance (CL / F) were determined.

[0128] research design

[0146] This multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluated two dose levels of IW-1973 versus placebo. The study population consisted of adult patients with type 2 diabetes mellitus, albuminuria, and impaired renal function. Patients must have been taking antihyperglycemic medications for at least 12 weeks, and their regimen (i.e., drug and dose) must have been stable for at least 28 days prior to the randomization visit. In addition, patients must have been receiving a stable regimen of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) for at least 28 days prior to the randomization visit. For further details, see the inclusion criteria below. A total of 156 patients (approximately 50 patients per group) were stratified into three groups by baseline estimated glomerular filtration rate (eGFR) (30–45, >45–60, and >60–75 mL / min / 1.73 m).2 Patients were randomized approximately 1:1:1 to receive a total of 20 mg IW-1973, 40 mg IW-1973, or placebo daily.

[0129]

[0147] The study consisted of three periods (see study schematic below).

[0148] Screening Period: The screening period began with the signing of the Informed Consent Form (ICF) at the screening visit and lasted up to 45 days. At the screening visit (which could occur on days -45 to -15), patients underwent a pre-screening procedure to determine their eligibility. Eligible patients returned to the clinic for a baseline visit (day 7 ± 3) for baseline and eligibility assessment, including 24-hour ambulatory blood pressure monitoring (ABPM). The end of the screening period coincided with the start of the treatment period.

[0130]

[0149] Treatment Period: The treatment period began on randomization day 1 (there was no day 0) and ended after the end of the treatment visit on day 87 (±3). Patients were stratified into one of three groups by baseline eGFR (i.e., 30–45, >45–60, and >60–75 mL / min / 1.73 m). 2 Patients were randomized in an approximately 1:1:1 ratio to receive 20 mg of IW-1973, 40 mg of IW-1973, or placebo for approximately 12 weeks.

[0131]

[0150] On days 1 through 7 (±1), dosing was BID (twice daily), morning and evening. From day 8 (±1) onward, dosing was QD (two tablets per day), morning. At the randomization visit on day 1, patients received their morning dose of study medication in the clinic and underwent safety, efficacy, and pharmacokinetic (PK) assessments, including timed blood and urine collections. Patients remained in the clinic for at least 6 hours after dosing and were allowed to leave the clinic at the investigator's discretion after all study procedures. At the week 1 visit on day 8 (±1), patients returned to the clinic and received their first QD dose of study medication in the clinic. Patients underwent safety, efficacy, and PK assessments, including timed blood and urine collections. Patients remained in the clinic for at least 6 hours after dosing and were allowed to leave the clinic at the investigator's discretion after all study procedures. At the Week 4 (Day 29 ± 3), Week 8 (Day 57 ± 3), and End of Treatment (Day 87 ± 3) visits, patients returned to the clinic for administration of study medication; safety, efficacy, and PK assessments; and study medication supplies, if applicable.

[0132]

[0151] Follow-up Period: The follow-up period began immediately after the end of the treatment visit and lasted for 28 (± 3) days. At the follow-up visit on day 115 (± 3), patients returned to the clinic for their final study evaluation.

[0133] [ka]

[0134] Stopping criteria

[0152] If any event included in the table below was reported during the study and determined to be both a study drug-related adverse event and a serious adverse event, individual stopping criteria or Data Monitoring Committee (DMC) review was invoked as described below. The inclusion of these AEs was based on clinical experience with IW-1973, the prescribing information for riociguat (an FDA-approved sGC stimulant), and the patient population of this study.

[0135] [Table 1]

[0136]

[0153] On an individual basis, patients were discontinued from the study drug if one or more of the SAEs in the table were reported. At the discretion of the investigator or sponsor, any AE of concern could also be a basis for discontinuing the patient from the study. At the study level, an independent DMC reviewed the study safety data. The committee reviewed the accumulated AE data and could recommend continuation, continuation with modifications, or termination of the study. The DMC was also required to perform a special review of whether the SAEs were from the same category in the table above.

[0137] Medication regimen

[0154] Two dosing regimens were studied (see table below summarizing weekly dosing regimens):

[0155] 10 mg BID for 1 week, then 20 mg QD for the remainder of the trial, i.e., a total daily dosage of 20 mg; or

[0156] 20 mg BID for 1 week, then 40 mg QD for the remainder of the trial, for a total daily dosage of 40 mg.

[0138] [Table 2]

[0139]

[0157] Based on the judgment of the investigator, the dose for each patient could be reduced by half, i.e., from two tablets per day to one tablet per day (in the morning). Each patient's dose could only be reduced once and could not be increased after a reduction.

[0140] Study Drug Compound I was administered as a multiple of 10 mg oral tablet form (10 mg dose) or a multiple of 20 mg oral tablet form (40 mg dose). Placebo was administered as a multiple of matching placebo tablets. Compound I was formulated as a spray-dried dispersion tablet as described in WO2017095697.

[0141] Study drug administration

[0158] Patients received study medication daily for up to 90 days. Total patient participation ranged from 131 to 163 days, including screening, treatment, and follow-up. During Week 1, patients took study medication BID (2x / day), one tablet in the morning and one tablet approximately 12 hours later in the evening, preferably at approximately the same time each day. From the Week 1 visit (Day 8 ± 1), patients took study medication QD (1x / day), two tablets in the morning, preferably at approximately the same time each day. Patients were instructed to take study medication with water, with or without food.

[0142] Inclusion criteria

[0159] Patients had to meet all of the following criteria to be eligible for enrollment in the study:

[0160] 1. Patients signed an Informed Consent Form (ICF) before undergoing any study-specific procedures.

[0143]

[0161] 2. The patient is an outpatient male or female between 25 and 75 years of age at the time of the screening visit.

[0162] 3. Patients had type 2 diabetes diagnosed by a physician or nurse practitioner ≥6 months prior to the screening visit, had been receiving ≥1 antihyperglycemic medication for ≥12 weeks prior to the randomization visit, and had been receiving a stable regimen (i.e., same medication and same dose) of ≥1 antihyperglycemic medication for ≥28 days prior to the randomization visit. (Changes in short-acting insulins throughout the screening period did not affect eligibility.)

[0163] 4. Patients were receiving a stable regimen (i.e., same drug and dose) of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for ≥ 28 days prior to the randomization visit and were expected to continue that regimen during the follow-up visit (Note: these drugs could be changed during the study if medically necessary).

[0144]

[0164] 5. If the patient was receiving medication for hypertension, the regimen (drug and dose) must have been stable for ≥ 28 days prior to the randomization visit and was expected to remain stable until the follow-up visit (Note: Antihypertensive medications could be changed during the study if medically necessary).

[0145]

[0165] 6. Patient has:

[0166] a. At screening and baseline visits, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine formula of 30-75 mL / min / 1.73 m 2 Estimated glomerular filtration rate (eGFR).

[0146]

[0167] b. Urinary albumin creatinine ratio (UACR) of >200 mg / g and <5000 mg / g at screening and baseline visits (the average of two first-morning urine tests at the baseline visit will be used to determine eligibility).

[0147]

[0168] c. Serum albumin >3.0 g / dL at screening and baseline visits.

[0169] d. Hemoglobin Alc (HbAlc) of ≤12% at screening and baseline visits.

[0148]

[0170] e. Systolic blood pressure (BP) of 110-160 mmHg based on the average of three seated automated office blood pressure (AOBP) measurements at screening and baseline visits.

[0171] 7. Female patients must be postmenopausal (no menstrual periods for ≥ 12 consecutive months); surgically sterile (i.e., bilateral oophorectomy, hysterectomy, or tubal sterilization [ligation, clips, bands, or cauterization]); agree to abstain completely from heterosexual intercourse; or, if sexually active with the opposite sex, agree to use one of the proposed methods of contraception from the date of signature.

[0149]

[0172] 8. Male patients must be surgically sterile by vasectomy (performed ≥ 60 days prior to the screening visit or confirmed by sperm analysis) and agree to abstain completely from heterosexual intercourse, or, if sexually active, agree to use a combination of two highly effective methods of contraception from the screening visit until 60 days after the last dose of study drug.

[0150]

[0173] 9. Patients must agree not to change any major lifestyle habits (e.g., diet, exercise) from the screening visit to the follow-up visit.

[0151] Exclusion criteria:

[0174] Patients who met any of the following criteria were ineligible to participate in the study.

[0152]

[0175] 1. The patient has a history of secondary hypertension (i.e., renal arteriosclerosis, primary aldosteronism, or pheochromocytoma).

[0176] 2. Patients have a CI of <20 or >45 kg / m at the screening visit. 2 have a body mass index (BMI) of

[0153]

[0177] 3. Patient has elevated (>1.5x the laboratory-defined upper limit of normal) levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at the screening or baseline visit.

[0154]

[0178] 4. Patient has a hemoglobin level of <9 g / dL at the screening or baseline visit.

[0179] 5. Patients have a 12-lead electrocardiogram (ECG) showing severe bradycardia (heart rate <50 beats per minute) or a QTcF of ≥450 msec for male patients or ≥470 msec for female patients at the screening or baseline visit. (Note: If the QTcF was above the limit on the initial ECG, the ECG was repeated at least twice, and the average of the three QTcF values ​​was used to determine patient eligibility at the screening and baseline visits.)

[0155]

[0180] 6. The patient has significant non-traumatic bleeding episodes such as platelet dysfunction, hemophilia, von Willebrand's disease, coagulopathy, other bleeding diathesis, or gastrointestinal (GI) origin.

[0156]

[0181] 7. The patient has liver dysfunction defined as Child-Pugh A, B, or C.

[0182] 8. The patient has a significant comorbidity (e.g., malignancy, advanced liver disease, pulmonary hypertension, pulmonary fibrosis, lung disease requiring supplemental oxygen) or other significant condition, including clinically significant abnormalities in laboratory values, that, in the opinion of the investigator, limits the patient's ability to complete or participate in this clinical study, or has been hospitalized for cardiovascular, renal, or metabolic causes within the 3 months prior to the screening visit, or has a life expectancy of less than 1 year.

[0157]

[0183] 9. The patient has a history of chronic GI disease that, in the opinion of the investigator, may cause significant GI malabsorption.

[0184] 10. Patients with known non-diabetic kidney disease (e.g., known polycystic kidney disease, focal segmental glomerulosclerosis, or FSGS) or non-diabetic etiology of renal decline. Concurrent hypertension-related nephrosclerosis associated with diabetic nephropathy is permitted.

[0158]

[0185] 11. Patient has had prior dialysis, kidney transplant, or is scheduled for kidney transplant. (Prior dialysis does not include transient, short-term dialysis indicated for illness or emergency hospitalization. This "transient" dialysis must have occurred >3 months prior to randomization, lasted <7 days, and have a current stable eGFR within the eligibility range [>30 mL / min / 1.73 m].) 2 ] must be .)

[0186] 12. The patient has clinically active, symptomatic, or unstable coronary artery disease or heart disease within 3 months prior to the screening visit, defined as one of the following: a. Myocardial infarction (MI), unstable angina, or hospitalization for heart failure. b. Coronary angiogram showing new-onset angina or stenosis with positive functional tests. c. Coronary revascularization.

[0159]

[0187] 13. Patient has a documented history of New York Heart Association (NYHA) Class III or IV heart failure, although the preceding simplified / transitional NYHA Class III or IV designation is not exclusive, provided that at the time of randomization, the condition is Class II or better and has been stable for ≥ 3 months without progression to a more severe class.

[0160]

[0188] 14. Patient has a positive hepatitis panel (hepatitis B surface antigen [HBsAg] and anti-hepatitis C virus [HCV]) or human immunodeficiency virus (HIV) antibodies at the screening visit.

[0161]

[0189] 15. Patient has a history of viral or bacterial infection within 4 weeks of the screening visit.

[0190] 16. Patient has undergone surgery under general anesthesia in the 12 weeks prior to the screening visit or is scheduled or planned to undergo surgery under general anesthesia during the study.

[0162]

[0191] 17. The patient has a history of active alcoholism or drug addiction in the year prior to the screening visit, or has a positive drug screen for a drug not legally prescribed at the time of the screening visit.

[0163]

[0192] 18. Patients are taking specific inhibitors of phosphodiesterase type 5 (PDE5), nonspecific inhibitors of PDE5 (including dipyridamole and theophylline), any supplements for the treatment of erectile dysfunction, riociguat, or any form of nitrate or nitric oxide (NO) donor. These medications and supplements are prohibited from 7 days prior to randomization and throughout the study period.

[0164]

[0193] Patients taking strong cytochrome P450 3A (CYP3A) inhibitors, including azole antifungals, macrolide antibiotics, protease inhibitors, and diltiazem, are prohibited from taking these medications and from consuming excessive grapefruit for 14 days prior to randomization and throughout the study.

[0165]

[0194] 19. Female patients who may wish to conceive and / or plan to undergo egg donation or egg retrieval for current or future in vitro fertilization during the study and for at least 60 days after the last dose of study drug.

[0166]

[0195] 20. Male patients unwilling to abstain from sperm donation during the study and for at least 60 days after the last dose of study medication.

[0196] 21. Patient has a history of clinically significant hypersensitivity or allergy to any of the inactive ingredients contained in the active or placebo drug product.

[0167]

[0197] 22. Patient has previously received Compound I in the study, or has received an investigational drug within 30 days or 5 half-lives of that investigational drug (whichever is longer) prior to the screening visit, or is planning to receive another investigational drug at any time during the study.

[0168]

[0198] 23. Female patients are pregnant or breastfeeding at the time of the screening visit. Breastfeeding is not permitted between the screening and follow-up visits.

[0199] 24. The patient is unable to adhere to the study assessment schedule or, in the clinical judgment of the investigator, the patient is otherwise unsuitable for the study.

[0169] Study population / demographics

[0200] A total of 156 patients were enrolled in the study: 54 received placebo, 50 received a 20 mg total oral daily dose, and 52 received a 40 mg total oral daily dose. Overall, 81% to 94% of patients completed the study, depending on the group. The median age of patients receiving the drug was 66 years. Approximately 65% ​​of patients receiving the drug were male. Approximately 70% of patients receiving the drug were white, and 30% were black. Approximately 60% of white patients were Latino. The median BMI of patients receiving the drug was 32.5.

[0170]

[0201] Table 1 below summarizes the study population by race, ethnicity, BMI, and weight. The study population was significantly represented among Black / African Americans, a population disproportionately affected by type 2 diabetes mellitus and nephropathy compared to the general population. Latino participants were also significantly represented. The population had a median age in the mid-60s, was predominantly male, and had a median BMI in the early 30s, characteristics typical of large DKD populations and other Phase 2 studies for this indication.

[0171]

[0202]

[0172] [Table 3]

[0173]

[0203] The remaining baseline demographic characteristics of the population enrolled in the trial are summarized in the table below.

[0174] [Table 4]

[0175] Concurrent / Combination Therapy

[0204] At baseline, per protocol, all participants were receiving a stable regimen of an ACEi or ARB and at least one antihyperglycemic agent. In addition, most participants were also receiving a stable medical regimen for blood pressure and lipid control consistent with current standard of care. These participants were representative of a real-world population, with >71% of participants receiving ≥5 of these standard medications. The table below provides an overview of the concomitant medications patients were receiving at baseline.

[0176]

[0205] Concomitant medications at baseline

[0177] [Table 5]

[0178] Top-line evaluation / results A) Intention-to-treat (ITT) population

[0206] Primary efficacy endpoint:

[0207] For the primary efficacy endpoint, there was a trend for praliciguat to reduce UACR over 12 weeks, with a 28% reduction from baseline in the praliciguat combination group and a 15% placebo-adjusted reduction from baseline. The trend vs. placebo did not achieve statistical significance. Similar reductions in UACR were seen in the praliciguat 20 mg and 40 mg dose groups. The effect on albuminuria, as measured by change in UACR, is summarized in the table below (combination results at weeks 8-12).

[0179] [Table 6]

[0180]

[0208] The table below summarizes the results for change at 12 weeks.

[0181] [Table 7]

[0182]

[0209] Figures 1A and 1B show the results for the primary efficacy outcome measure (change in UACR) in the two populations. Figure 1A shows the results for the 30–45 mL / min / 1.73 m 2 Figure 1B shows the results for the subpopulation of patients with an eGFR of 0.05 mg / kg / day, while Figure 1B shows the results for all patients. As can be seen from comparing the two figures, at 12 weeks, the group of patients with lower levels of eGFR (i.e., patients with severely impaired renal function) shows a more pronounced effect both versus baseline and compared to placebo.

[0183]

[0210] Other subgroups of the population that showed a trend toward improved response in the responder analysis included men, patients of non-Hispanic ethnicity, patients with a BMI < 30, and patients with a mean arterial pressure (MAP) below the median for the particular cohort.

[0184]

[0211] Blood pressure / hemodynamic effects:

[0212] Treatment with praliciguat was associated with a consistent reduction in 24-hour mean blood pressure after 12 weeks of treatment. Mean changes in MAP of -3.2 to -4.0 mmHg relative to placebo were observed in the various cohorts in the study. Mean changes in systolic blood pressure of -4.0 to -4.4 mmHg were observed in the various cohorts in the study. These differences were statistically significant. These results are summarized in the two tables below.

[0185] [Table 8]

[0186] [Table 9]

[0187]

[0213] Mediation analyses suggested that approximately two-thirds or more of the observed effect on UACR was independent of and could not be explained by changes in blood pressure.

[0214] Metabolic outcomes:

[0215] Improvements in several metabolic parameters were observed in this trial. Praliciguat treatment for 12 weeks was associated with a reduction in mean HbAlc levels of approximately 0.3% compared with placebo, suggesting improved glycemic control in patients with type 2 diabetes and diabetic kidney disease. Praliciguat treatment was also associated with modest reductions in mean serum cholesterol and LDL cholesterol over 12 weeks compared with placebo. Overall, positive metabolic outcomes included reductions in fasting plasma glucose, HbAlc, total serum cholesterol, and serum LDL cholesterol. These results are summarized in the table below.

[0188] [Table 10]

[0189] [Table 11]

[0190] [Table 12]

[0191] [Table 13]

[0192] B) Identification of the mITT population

[0216] During routine data review, one site (including 23 randomized study participants) was flagged for multiple abnormalities.

[0193]

[0217] First, as predefined in the statistical analysis plan (SAP), plasma BQL (lower limit of quantification level) values ​​of praliciguat at weeks 8 to 12 in participants treated with praliciguat were flagged as a large protocol deviation, and the center was identified as having the highest incidence of such cases.

[0194]

[0218] Second, during data examination, examination of the interaction between treatment, visit, and geographic region indicated that the southeastern US was distinct from the remaining regions, and furthermore, this regional difference was entirely driven by data from this facility.

[0195]

[0219] Third, during quality checks of the topline data, increased variability in the data at subsequent study visits was noted, and further investigation revealed that this facility was the main contributor to this variability.

[0196]

[0220] Participants from this center had an unlikely frequency of high-responders. There were 13 high-responders throughout the study. Of these 13 high-responders, 9 were from this center, and although 6 of them received praliciguat, only 2 had the expected drug concentrations. In contrast, 4 other high-responders were from the remaining 42 centers in the study. The likelihood that such an excessive occurrence of high-responders could occur by chance among the 23 center participants is less than 1 in 10,000.

[0197]

[0221] Based on the much higher than expected proportion of high-responders from this center, combined with plasma drug concentrations at or near zero, an analysis based on the ITT population that excluded participants from this center, referred to herein as the mITT population (or modified intention-to-treat population), was thought to provide a better estimate of the effect of praliciguat in this study. Analyses of both the mITT and ITT populations show a reduction in UACR and improvements in important cardiovascular risk factors.

[0198]

[0222] UACR: Mean percent change from baseline from weeks 8 to 12 (mITT and ITT populations)

[0223] The primary efficacy analysis of mean percent change from baseline in UACR from weeks 8 to 12 for the mITT and ITT populations is summarized in the table below. In the mITT population, the placebo-adjusted mean percent decrease from baseline for the praliciguat combination treatment group was 20%, with a nominal p-value of 0.030. In the ITT population, the placebo-adjusted mean percent decrease from baseline for the praliciguat combination treatment group was 15%, with a p-value of 0.174.

[0199] [Table 14]

[0200]

[0224] UACR: Mean percent change from baseline at week 12 (mITT population)

[0225] For UACR at week 12, the placebo-adjusted mean percent reduction in the praliciguat combination treatment group was 23%, with a nominal p-value of 0.07. See table below.

[0201] [Table 15]

[0202]

[0226] One subgroup of particular interest is patients with significantly reduced eGFR, as these patients are at increased risk of progression to ESRD. We determined the mean percent change from baseline in UACR over the 12-week treatment period for participants in the mITT population stratified by baseline level of eGFR. 2 eGFR) and less severe (>45 mL / min / 1.73 m 2All participants with reduced eGFR had a significant mean decrease from baseline in UACR. Interestingly, the magnitude of the placebo-corrected mean decrease (30-40%) was greater in participants with a higher degree of renal decline at baseline, suggesting that praliciguat may provide meaningful clinical benefit even in more advanced stages of DKD. Importantly, praliciguat is metabolized in the liver with negligible renal excretion, and the lack of renal metabolism may be particularly advantageous for this subgroup of DKD patients.

[0203]

[0227] Mediation analyses determined that for the mITT population, only 4-17% of the total treatment effect on change in UACR was mediated by change in systolic blood pressure. Similarly, for the ITT population, only 8-25% of the total change in UACR was mediated by change in systolic blood pressure. When trough cuff systolic blood pressure at week 12, a common but less comprehensive measure of blood pressure, was used as the mediator, only 3% of the total change in UACR was mediated by change in SBP.

[0204]

[0228] Metabolic outcomes

[0229] Consistent placebo-adjusted reductions in cholesterol and LDL cholesterol were also observed across praliciguat dose groups in the mITT population. Notably, these improvements were evident even though approximately 75% of study participants were on a standard-of-care lipid-lowering regimen and had a median baseline total cholesterol level of <170 mg / dL.

[0205]

[0230]

[0206] [Table 16]

Claims

1. 1. A pharmaceutical composition for treating a human patient with diabetic nephropathy (DN), comprising: Compound I in a total oral daily dose of 10 mg to 40 mg: 【Chemical 1】 The pharmaceutical composition comprising:

2. The pharmaceutical composition according to claim 1, i) the pharmaceutical composition reduces the urinary albumin to creatinine ratio (UACR) in the patient; ii) the pharmaceutical composition reduces blood pressure in the patient; iii) the pharmaceutical composition reduces mean arterial pressure (MAP) in the patient; iv) the pharmaceutical composition reduces the systolic blood pressure of the patient; v) the pharmaceutical composition does not result in a significant decrease in the patient's blood pressure; vi) the pharmaceutical composition improves one or more metabolic parameters in the patient; preferably, the one or more metabolic parameters are selected from fasting plasma glucose, hemoglobin A1c (HbA1c), fasting plasma insulin, HOMA-IR, serum total cholesterol, and LDL-cholesterol; vii) the pharmaceutical composition reduces the patient's risk of a cardiovascular event; or viii) the pharmaceutical composition improves a metabolic outcome in the patient; The pharmaceutical composition.

3. A pharmaceutical composition for improving albuminuria in a diabetic human patient, comprising: Compound I at a total oral daily dose of 10 mg to 40 mg; 【Chemistry 2】 The pharmaceutical composition comprising:

4. The pharmaceutical composition according to claim 3, i) the pharmaceutical composition reduces the urinary albumin to creatinine ratio (UACR) in the patient; ii) the pharmaceutical composition does not result in a significant decrease in the patient's blood pressure; iii) the patient has an eGFR value of 30-45 mL / min / 1.73 m 2 at the start of treatment; iv) the patient has an eGFR value of 45-60 mL / min / 1.73 m 2 at the start of treatment; or v) the patient is taking a GLP-1 inhibitor for glycemic control; The pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, i) the pharmaceutical composition preserves renal function in a patient; ii) the pharmaceutical composition delays or prevents clinical deterioration in the patient; or iii) the pharmaceutical composition increases survival of the patient; The pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, i) a daily oral dose of 10 mg to 20 mg of Compound I is administered to said patient; ii) a total oral daily dose of Compound I of 20 mg to 40 mg is administered to said patient; iii) a total oral daily dose of Compound I of 15 mg to 30 mg is administered to said patient; iv) a total oral daily dose of Compound I of 20 mg to 30 mg is administered to said patient; or v) a daily oral dose of 30 mg to 40 mg of Compound I is administered to said patient; The pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, i) a patient is administered a single oral daily dose of 10 mg of Compound I; ii) the patient is administered a single oral daily dose of 15 mg of Compound I; iii) the patient is administered a single oral daily dose of 20 mg of Compound I; iv) the patient is administered a single oral daily dose of 25 mg of Compound I; v) the patient is administered a single oral daily dose of 30 mg of Compound I; or vi) the patient is administered a single oral daily dose of 40 mg of Compound I; The pharmaceutical composition.

8. The pharmaceutical composition according to any one of claims 1 to 6, i) the patient is administered a 5 mg oral dose of Compound I twice daily; preferably, the patient is administered a first oral dose of Compound I of 5 mg and a second oral dose of Compound I of 5 mg, said first dose and said second dose being 5 to 15 hours apart; ii) the patient is administered a 7.5 mg oral dose of Compound I twice daily; preferably, the patient is administered a first oral dose of 7.5 mg of Compound I and a second oral dose of 7.5 mg of Compound I, said first dose and said second dose being 5 to 15 hours apart; iii) the patient is administered a 10 mg oral dose of Compound I twice daily; preferably, the patient is administered a first oral dose of Compound I of 10 mg and a second oral dose of Compound I of 10 mg, said first dose and said second dose being 5 to 15 hours apart; iv) the patient is administered a 12.5 mg oral dose of Compound I twice daily; preferably, the patient is administered a first oral dose of Compound I of 12.5 mg and a second oral dose of Compound I of 12.5 mg, said first dose and said second dose being 5 to 15 hours apart; v) the patient is administered a 15 mg oral dose of Compound I twice daily; preferably, the patient is administered a first oral dose of Compound I of 15 mg and a second oral dose of Compound I of 15 mg, said first dose and said second dose being 5 to 15 hours apart; or vi) the patient is administered a 20 mg oral dose of Compound I twice daily; preferably, the patient is administered a first oral dose of Compound I of 20 mg and a second oral dose of Compound I of 20 mg, said first dose and said second dose being 5 to 15 hours apart; The pharmaceutical composition.

9. The pharmaceutical composition according to claim 1, i) administering to a patient an initial oral dose of 5 mg to 20 mg twice daily for 7 to 14 days, after which said patient is administered a maintenance dose of 10 mg to 40 mg once daily; ii) a patient is administered an initial oral dose of 5 mg twice daily for 7 to 14 days, after which said patient is administered a maintenance dose of 10 mg once daily; iii) a patient is administered an initial oral dose of 7.5 mg twice daily for 7 to 14 days, after which said patient is administered a maintenance dose of 15 mg once daily; iv) a patient is administered an initial oral dose of 10 mg twice daily for 7 to 14 days, after which said patient is administered a maintenance dose of 20 mg once daily; v) a patient is administered an initial oral dose of 12.5 mg twice daily for 7 to 14 days, after which said patient is administered a maintenance dose of 25 mg once daily; vi) administering to a patient an initial oral dose of 15 mg twice daily for 7 to 14 days, after which said patient receives a maintenance dose of 30 mg once daily; or vii) administering to a patient an initial oral dose of 20 mg twice daily for 7 to 14 days, after which said patient receives a maintenance dose of 40 mg once daily; The pharmaceutical composition.

10. The pharmaceutical composition according to claim 1, i) the patient is further administered one or more antihypertensive drugs; preferably, the one or more antihypertensive drugs are independently selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a diuretic, a calcium channel blocker, a beta-blocker, a vasodilator, a centrally acting agent, and an aldosterone antagonist; at least one of the antihypertensive drugs is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB); at least one of the antihypertensive drugs is selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, and losartan; at least one of the antihypertensive drugs is a diuretic; the diuretic is selected from chlorthalidone and hydrochlorothiazide; or ii) the patient is further administered two or more antihypertensive drugs, wherein at least one of the antihypertensive drugs is selected from an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB), and at least one of the antihypertensive drugs is a diuretic; the diuretic is selected from chlorthalidone and hydrochlorothiazide; The pharmaceutical composition.

11. The pharmaceutical composition according to any one of claims 1 to 10, The patient is further administered one or more hypoglycemic agents; preferably i) the one or more hypoglycemic agents are independently selected from biguanides, GLP-1 receptor agonists, SGLT2 inhibitors (alone or in combination with SGLT1 inhibitors), and insulin therapy; ii) at least one of the hypoglycemic agents is a GLP-1 receptor agonist; preferably, the GLP-1 receptor agonist is semaglutide or the GLP-1 receptor agonist is oral semaglutide; iii) the one or more hypoglycemic agents are independently selected from the group consisting of insulin, metformin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, empagliflozin, canagliflozin, and dapagliflozin; or iv) at least one of the hypoglycemic agents is an SGLT2 inhibitor; preferably, the SGLT2 inhibitor is selected from the group consisting of empagliflozin, canagliflozin and dapagliflozin; The pharmaceutical composition.

12. The pharmaceutical composition according to claim 1, i) the patient is further administered one or more antihypertensive agents and one or more hypoglycemic agents; or ii) the patient is further administered one or more antihypertensive agents independently selected from the group consisting of lisinopril, a combination of lisinopril and hydrochlorothiazide, enalapril, losartan, chlorthalidone, metoprolol, and spironolactone, and one or more hypoglycemic agents independently selected from the group consisting of insulin, metformin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, empagliflozin, canagliflozin, and dapagliflozin; The pharmaceutical composition.

13. The pharmaceutical composition according to any one of claims 1 to 12, The patient is further administered one or more antihyperlipidemic drugs; preferably i) the one or more antihyperlipidemic agents are cholesterol-lowering agents; preferably, the one or more cholesterol-lowering agents are independently selected from the group consisting of atorvastatin, pravastatin, rosuvastatin, lovastatin, and simvastatin, or ii) the one or more antihyperlipidemic agents are independently selected from the group consisting of atorvastatin, pravastatin, simvastatin, rosuvastatin, lovastatin, and nicotinic acid; The pharmaceutical composition.

14. The pharmaceutical composition according to any one of claims 1 to 13, i) the patient is further administered one or more neprilysin inhibitors; preferably, the neprilysin inhibitor is sacubitril or a combination of sacubitril and valsartan; or ii) the patient is further administered one or more nephroprotective drugs; preferably, the nephroprotective drugs are selected from the group consisting of bardoxolone, irbesartan, losartan, captopril, finerenone, canagliflozin and atrasentan; The pharmaceutical composition.

15. The pharmaceutical composition according to any one of claims 1 to 14, i) the patient has a urinary albumin-to-creatinine ratio (UACR) greater than 200 mg / g and less than 5000 mg / g at the start of treatment; ii) the patient has a urinary albumin-to-creatinine ratio (UACR) of 30-300 mg / g; iii) the patient has a urinary albumin-to-creatinine ratio (UACR) of 30-200 mg / g; iv) the patient has an estimated glomerular filtration rate (eGFR) of 30-75 mL / min / 1.73 m 2 at the start of treatment; v) the patient has an eGFR of 30-45 mL / min / 1.73 m 2 at the start of treatment; vi) the patient has an eGFR of 45-60 mL / min / 1.73 m 2 at the start of treatment; vii) the patient has an eGFR of 60-75 mL / min / 1.73 m 2 at the start of treatment; viii) the patient has an eGFR of 75-90 mL / min / 1.73 m 2 at the start of treatment; ix) the patient has a systolic blood pressure of 110-160 mmHg at the start of treatment; x) the patient has a hemoglobin A1c level of 6.5% to 12% at the start of treatment; or xi) the patient has a serum albumin level greater than 3.0 g / dL at the start of treatment; The pharmaceutical composition.

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