Safety, Tolerability and Pharmacokinetics of KBP-5074 in Healthy Subjects and Subjects With Renal Impairment

Study Overview
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Brief Summary
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This multiple ascending dose (MAD) study in healthy subjects and subjects with mild to moderate renal impairment will evaluate the safety, tolerability and pharmacokinetics of KBP-5074. Safety/tolerability data and Pharmacokinetics (PK)/Pharmacodynamics (PD) (plasma aldosterone, serum potassium, UACR and Blood Pressure) relationships will be explored to support the selection of dosing regimens of KBP-5074 that are suitable for the Phase II/III study.

Detailed Description
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This study consists of two parts: Part 1 is an open-label, multiple ascending dose (MAD) study to evaluate the safety, tolerability and pharmacokinetics of KBP-5074 in healthy subjects. The safety and tolerability will be assessed at each dose level before progressing to the next higher dose. Part 2 is an open label, randomized, parallel study to assess the safety and tolerability, the effect of renal dysfunction on the pharmacokinetics of KBP-5074, as well as the PK/PD relationship in subjects with mild to moderate renal impairment.

Official Title
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An Open-Label, Multiple Ascending Dose (MAD) Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KBP-5074 in Healthy Subjects With a Separate Panel in Subjects With Mild to Moderate Renal Impairment

Conditions
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Healthy, Renal Insufficiency

Intervention / Treatment
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* Drug: KBP-5074


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Part 1: Healthy male or female subject Are between the ages of 18 and 45 years (inclusive); Body mass index (BMI) of 19 to 30 kg/m2 inclusive and body weight not less than 50 kg. Exclusion Criteria for Part 1: Clinically significant history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity; Known or suspected malignancy; Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody; Positive pregnancy test result. Inclusion Criteria for Part 2: Are between the ages of 18 and 75 years (inclusive); Mild to moderate chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) > 30 and ≤89 mL/min/1.73 m2, using the modification of diet in renal disease (MDRD) formula, for > 3 months; Proteinuria (defined as urine albumin to creatinine ratio (UACR) ≥100 mg/g and ≤3,000 mg/g in two mid-morning urine specimens within a month interval); Subjects treated with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) Serum potassium≥3.3 mmol/L and ≤4.8 mmol/L; Body mass index (BMI) of 19 to 40 kg/m2 inclusive and body weight not less than 50 kg. Exclusion Criteria for Part 2: Severe uncontrolled hypertension (diastolic > 115 mmHg or systolic blood pressure > 180 mmHg) at either the Screening visit or the Study Check-in Visit; Type I diabetes mellitus or poorly controlled Type 2 diabetes mellitus (HbA1c > 10%) at the Screening visit; Prior kidney transplant, or anticipated need for transplant during study participation; Clinical diagnosis of heart failure and persistent symptoms (New York Heart Association [NYHA] Class II- IV) at either the Screening visit or the Study Check-in Visit; Known or suspected contraindications to study medications, including history of hypersensitivity or allergy to ACE inhibitors, ARBs, or aldosterone antagonists; Any clinically significant disorder, except for conditions associated with type 2 diabetes mellitus history, which in the investigators opinion could interfere with the results of the trial; Diabetic gastroparesis; Known bilateral clinically relevant renal artery stenosis (>75% reduction in artery diameter).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Healthy Volunteers will receive multiple dose of KBP-5074 | Drug: KBP-5074<br> <br> * Other names: mineralocorticoid receptor antagonist;|
| Experimental: Cohort 2<br>Healthy Volunteers will receive multiple dose of KBP-5074 | Drug: KBP-5074<br> <br> * Other names: mineralocorticoid receptor antagonist;|
| Experimental: Cohort 3<br>Healthy Volunteers will receive multiple dose of KBP-5074 | Drug: KBP-5074<br> <br> * Other names: mineralocorticoid receptor antagonist;|
| Experimental: Cohort 4<br>Healthy Volunteers will receive multiple dose of KBP-5074 | Drug: KBP-5074<br> <br> * Other names: mineralocorticoid receptor antagonist;|
| Experimental: Cohort 5<br>Subjects with mild to moderate renal impairment will receive multiple dose of KBP-5074 | Drug: KBP-5074<br> <br> * Other names: mineralocorticoid receptor antagonist;|
| Experimental: Cohort 6<br>Subjects with mild to moderate renal impairment will receive multiple dose of KBP-5074 | Drug: KBP-5074<br> <br> * Other names: mineralocorticoid receptor antagonist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Rate of adverse events | Up to 69 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) in healthy subjects | AUC 0-24 hours | pre-dose and 2, 4, 6, 8, 10, 12, 18, and 24 hours post dose on Day 1; pre-dose on Days 8, 11, 12, and 13; and pre-dose and 2, 4, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 168, 216, 264, and 312 hours post dose on Day 14 | 
| Area Under Curve (AUC) in subjects with mild to moderate renal impairment | AUC 0-24 hours | pre-dose and 2, 4, 6, 8, 10, 12, 18, and 24 hours post dose on Day 1; pre-dose on Days 8, 11, 12, and 13; pre-dose and 2, 4, 6, 8, 10, 12, 18, and 24 hours post dose on Day 14; pre-dose on Days 29 and 43; and pre-dose and 6, 12, and 24 hours on Day 56 | 
| The effect of mild to moderate renal impairment on the Area Under Curve (AUC) | AUC 0-24 hours | Up to 15 days | 
| Plasma aldosterone levels in healthy subjects | Plasma aldosterone level | Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Day 8; and 24 hours post last dose on Day 15 | 
| Serum potassium levels in healthy subjects | Serum potassium level | Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Day 8; and 24 hours post last dose on Day 15 | 
| Plasma aldosterone levels in subjects with mild to moderate renal impairment | Plasma aldosterone level | Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57 | 
| Serum potassium levels in subjects with mild to moderate renal impairment | Serum potassium level | Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57 | 
| Urinary Albumin to Creatinine Ratio (UACR) in subjects with mild to moderate renal impairment | Ratio of urinary albumin level to creatinine level | Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57 | 
| Blood Pressure in subjects with mild to moderate renal impairment | Systolic and diastolic seated blood pressure | Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57 |