Phase 2b Study of KBP-5074 in Subjects With Uncontrolled Hypertension and Advanced Chronic Kidney Disease

The study will enroll approximately 240 patients, randomized in a 1:1:1 ratio to 1 of 3
treatment groups (80 patients in each group): KBP-5074 0.25 mg once daily (QD), KBP-5074 0.5
mg QD, or placebo QD. Randomization will be stratified to balance enrollment for key
variables that may influence safety and/or efficacy evaluations, including estimated
Glomerular Filtration Rate (eGFR) (30 versus 29 mL/min/1.73 m2) and Systolic Blood Pressure
(SBP) (160 versus <160 mmHg). The study will be approximately 5 months in duration with 84
days of double-blind treatment. The study will consist of an up to 4-week screening period;
2-week, open-label (placebo) run-in period; 84-day double-blind treatment period; and a
4-week post-treatment safety follow-up period. In total, a subset of 120 patients will be
sampled for plasma pharmacokinetics (PK) (40 per treatment group). Total KBP-5074 levels will
be assessed in 80 patients treated with active drug. A total of 4 PK samples will be
collected from each patient, including Day 1 (prior to discharge), Day 14 pre-dose, Day 28
pre-dose, and End of Study Visit (Day 98)/Early Termination Visit. The pre-dose samples
assume that patients will be dosed in the unit on those days above. If patients are not dosed
in the unit on those days, a flexible PK sample will be collected during each of these
visits.Safety will be assessed systematically, and an independent data monitoring committee
will perform cumulative reviews of safety data at regular intervals during the study. Serum
potassium levels, serum creatinine, and blood pressure will be closely monitored throughout
the study. At Screening, patients must have uncontrolled hypertension, defined as resting
trough cuff seated SBP 140 mmHg, based on the mean of the last 2 consecutive blood pressure
readings at Screening in the clinic. In all cases, dose and frequency of concurrent
antihypertensive medications are expected to be maintained without change for 30 days prior
to randomization in order to ensure that blood pressure is stable. In general, patients
should not add nor adjust dose and/or types of the antihypertensive medications they are
receiving during the screening period and throughout the duration of the study (unless they
develop hypertensive crisis or symptomatic hypotension). Patients will be advised to maintain
their normal diet and avoid alcohol or potassium-rich foods/drinks during the study period.
No potassium supplements are permitted, unless clinically indicated to treat hypokalemia
until serum potassium values are within the normal range. Potassium-sparing agents are not
permitted. After completion of the screening period and the qualifying Screening Visit,
patients who meet all eligibility criteria (except those criteria scheduled to be assessed
after the Screening Visit), will enter the 2-week, open-label (placebo) run-in period. At the
end of the run-in period, patients will be re-assessed for eligibility, including compliance
to study drug received during the run-in period, which must be >80% and 120% (ie, placebo and
stable antihypertensive medication, ie, no change in antihypertensive medication). If a
patient is found to be ineligible during Screening, a 1-time re-screening is allowed if the
Investigator believes that the patient's condition has changed and the patient may be
eligible before the re-screening tests. Please note that a new patient number should be
assigned to any re-screened patient, and all the procedures defined in the protocol for the
Screening Visit and during the run-in period must be repeated. Patients who meet all
eligibility criteria at the end of the screening period and run-in period will be randomized
(stratified based on eGFR 30 versus 29 mL/min/1.73 m2 and SBP 160 versus <160 mmHg) into the
study on Day 1. All randomized patients will receive double-blind treatment for 84 days.
Patients will be followed for 4 weeks for safety assessments after the last dose of study
drug. A subset of up to 40 patients per treatment group who still meet eligibility criteria
at the end of the run-in period (Visit 3) will undergo 24-hour ambulatory blood pressure
monitoring (ABPM) on Day 1, Day 40, and Day 82.

Inclusion Criteria:

1. Male or female, between 18 and 79 years of age, inclusive. The lower age limit may be
higher if it is legally required in the participating country;

2. Body mass index between 19 and 45 kg/m2, inclusive;

3. Stage 3B/4 CKD (defined as eGFR 15 and 44 mL/min/1.73 m2, based on the isotope
dilution mass spectrometry traceable Modification of Diet in Renal Disease (MDRD)
equation version 4, according to central laboratory results at Screening [1-time
retest is allowed]);

o Approximately 30% of patients enrolled in the study should have eGFR in the range of
15 and 29 mL/min/1.73 m2;

4. Uncontrolled hypertension, defined as:

- Trough cuff seated SBP 140 mmHg based on a mean of the last 2 consecutive clinic
blood pressure readings at Screening; AND

- Currently on the maximally tolerated dose of 2 or more hypertension medications
with complementary mechanisms (such as diuretics, renin-angiotensin system
blockers, and/or calcium channel blockers, one of which must be a diuretic unless
not tolerated as the baseline medication), with no dose adjustment during the 30
days prior to randomization; OR

- History of documented intolerance or lack of efficacy while on multiple
hypertension medications;

5. Serum potassium 4.8 mmol/L at both Screening and the end of the placebo run-in period.
A 1-time retest is allowed to exclude laboratory error or hemolyzed samples;

6. Women of childbearing potential (WOCBP) must agree to use 2 medically accepted,
effective methods of birth control during the study and for 90 days after the end of
the study. Adequate methods of contraception are defined as those that result in a low
failure rate (<1% per year) when used consistently and correctly. Such methods include
the use of oral contraceptives, other hormonal contraceptives (vaginal products, skin
patches, or implanted or injectable products), or mechanical products (such as an
intrauterine diaphragm, condoms, or spermicides);

- WOCBP are defined as women who are not surgically or chemically sterilized,
including hysterectomy or bilateral oophorectomy (tubal ligation is not
acceptable), and who are between menarche and 1 year post-menopause; and

- Post-menopausal is defined as amenorrheic for at least 1 year, AND if aged under
60 years, have a serum follicle stimulating hormone (FSH) level >20 mIU/L. Women
who are taking hormone replacement therapy (HRT) do not have to have FSH
assessments, but the amenorrhea (before starting HRT) must have been naturally
(spontaneously) occurring and have been accompanied by an appropriate clinical
profile (eg, age appropriate and history of vasomotor symptoms);

7. Males with partners who are WOCBP must agree to use condoms plus spermicide and their
female partner must also be using contraception (eg, hormonal or intra-uterine
device). This double contraception must be used from the first dose of study drug
until at least 90 days after the last dose of study drug;

8. Males must also refrain from donating sperm during the study and for 90 days after the
last dose; and

9. Capable of understanding the written informed consent, provide signed and witnessed
written informed consent before any study-specific procedure, and agree to comply with
protocol requirements.

Exclusion Criteria:

1. Trough cuff seated SBP >180 mmHg, based on a mean of the last 2 consecutive clinic
blood pressure readings at Screening;

2. Compliance to medications (including both open-label placebo and current
antihypertensive medications) <80% and/or >120% during the run-in period (assessed at
Visit 3);

3. Currently on a mineralocorticoid receptor antagonist (MRA) or received any MRAs during
the last 3 months prior to Screening or currently on any potassium sparing diuretics
(eg, amiloride, triamterene) or potassium supplements;

4. History of known/suspected contraindications, allergy, or intolerance to MRAs (eg,
spironolactone, eplerenone) or has a known hypersensitivity to KBP-5074, other MRAs,
or related compounds;

5. History of clinically significant hyperkalemia while on an angiotensin converting
enzyme inhibitor, angiotensin receptor blocker, direct renin inhibitor, and/or MRA or
hospitalization for hyperkalemia during the 3 months prior to Screening or
hyperkalemia >5.5 mmol/L during the 2 weeks prior to Screening;

6. History/diagnosis of renal artery stenosis or history/diagnosis of renovascular
hypertension;

7. Currently receiving hemodialysis/peritoneal dialysis or plan to start hemodialysis or
peritoneal dialysis within 3 months prior to Screening or history of acute kidney
injury that required dialysis;

8. Kidney transplant, or on a list for a kidney transplant. Patients with a medical
history of kidney transplant will also be excluded;

9. Acute decompensated heart failure including exacerbation of chronic heart failure
manifested by signs and symptoms that may require intravenous diuretic therapy (New
York Heart Association Class III to IV) within 3 months prior to Screening, or
presence of hemodynamically significant valve diseases and/or other hemodynamically
significant obstructive lesions of left ventricular outflow tract;

10. Major cardiac, cerebral, and/or carotid artery diseases, including, but not limited
to, acute coronary syndrome, myocardial infarction, stroke, and/or transient ischemic
attack, cardiovascular surgery, coronary revascularization, and/or carotid angioplasty
within 6 months prior to Screening; OR

o Any of those conditions that are likely to require surgical or percutaneous
intervention within 3 months from Screening;

11. History of clinically significant arrhythmia, including, but not limited to any of the
following:

- Symptomatic bradycardia and/or symptomatic ventricular arrhythmia within 3 months
prior to Screening; or

- Second or third degree heart block without a pacemaker;

12. History of cardiac transplant, on a heart transplant list, or has a left ventricular
assistance device;

13. Has diagnosed or suspected sleep apnea;

14. History of clinically significant acute or chronic hepatitis (including infectious,
metabolic, autoimmune, genetic, ischemic, or other forms), hepatocirrhosis, or hepatic
tumors;

15. History of gastrointestinal surgery that might affect absorption/oral bioavailability
of oral antihypertensive therapies including KBP-5074;

16. Clinically significant abnormal liver function test at Screening or the end of the
run-in period, defined as aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) >3 × the upper limit of normal (ULN) or total bilirubin >2 × ULN;

o Note: Patients with total bilirubin >2 × ULN and history of Gilbert's syndrome may
be included.

17. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface
antigen (HbsAg), or hepatitis C virus (HCV) antibody;

18. History of prescription drug abuse, illicit drug use, or alcohol abuse according to
medical history within 6 months prior to Screening;

19. Positive screen for drugs of abuse (except for patients with a positive drug screen
test as a result of a prescribed medication from their physician) at Screening and the
end of the run-in period;

20. Female patients who are known to be pregnant or breastfeeding;

21. Previously enrolled in any KBP-5074 study;

22. Receipt of any other investigational product within 30 days or 5 half-lives (whichever
is longer) prior to Screening;

23. Use of any nutrients known to modulate cytochrome P450 (CYP)3A activity (based on the
KBP-5074 metabolic pathway) or any strong or moderate inhibitors or inducers of
CYP3A4, starting from 14 days prior to the first dose of study drug at Day 1 until the
end of study assessments, including, but not limited to the following: inhibitors such
as ketoconazole, miconazole, itraconazole, fluconazole, atazanavir, erythromycin,
clarithromycin, ranitidine, cimetidine, verapamil, and diltiazem, and inducers such as
rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, and
St. John's wort;

24. Has donated or lost a significant volume (>500 mL) of blood or plasma within 30 days
prior to Screening;

25. An employee or family member of the Investigator or study site personnel;

26. Unlikely to comply with the protocol requirements, instructions, and/or study-related
restrictions (eg, uncooperative attitude, unavailable for follow up call, and/or
improbability of completing the clinical study); or

27. History of any other prior or concomitant clinical condition or acute and/or unstable
systemic disease not listed above that, in the opinion of the Investigator,
compromises patient inclusion; such as a history or presence of clinically
decompensated or unstable cardiovascular, pulmonary, hepatic, gallbladder or biliary
tract, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,
neurologic, or psychiatric disease, or concomitant morbidity of such severity that the
patient is likely to die within 1 year from Screening.