Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disorder which results in
frank proteinuria and progression to end-stage kidney disease (ESKD) over 5-10 years.
Proteinuria reduction is widely regarded to be beneficial, and is considered the primary goal
of treatment in FSGS and slowing its progressive course (D'Agati, et. al, 2011). Patients are
currently treated with steroids, calcineurin inhibitors, angiotensin receptor blockers (ARB)
and angiotensin converting inhibitors (ACE) to lower proteinuria (Cameron, 2003). Despite
these therapies, many patients have nephrotic range proteinuria and new therapeutic agents
are needed (Kiffel, et. al, 2011). Endothelin receptor antagonists (ERA) have been shown to
lower proteinuria in clinical trials of diabetic nephropathy (Kohan, et. al, 2011) (Mann, et.
al 2010) and have been speculated to be effective in FSGS (Barton, 2010).

Inclusion Criteria

1. Biopsy-proven primary FSGS (Primary FSGS confirmed by renal biopsy report) OR
documentation of a genetic mutation in a podocyte protein associated with the disease.

2. Urine protein/creatinine ratio (Up/C) at or above 1.0 g/g.

3. Estimated glomerular filtration rate (eGFR) >30.

4. Mean seated blood pressure (BP) >100/60 mmHg and <145/95 in patients >/= 18 years of
age. Mean seated BP for patients <18 years of age should be >90/60 mmHg and <95th
percentile for age, gender, and height.

5. If a patient is taking immunosuppressive medications (except for Rituximab or
cyclophosphamide), the dose and/or levels must be stable for 1 month prior to
randomization and the Investigator should not have plans to alter the regimen during
the first 8 weeks of treatment, except to stabilize levels. Patients on Rituximab or
cyclophosphamide will be eligible provided they have not been taking these medications
for 3 months prior to randomization.

6. US Sites: Males or females 8 to 75 years of age willing and able to provide written
informed consent and/or assent, with informed consent signed by patient or
parent/legal guardian.

7. EU Sites: Males or females 18 to 75 years of age willing and able to provide written
informed consent, with informed consent, signed by patient or legal guardian.

Exclusion Criteria

1. Patients with FSGS secondary to another condition.

2. Patients with history of type 1 diabetes mellitus, uncontrolled type 2 diabetes
mellitus (HBA1c>8%), or non-fasting blood glucose >180 mg/dL at screening.

3. Patients who have had any organ transplant.

4. Patients with a requirement for any of the medications indicated on the list of
Excluded Medications, with the exception of ACE and ARBs.

5. Patients with a documented history of heart failure (NYHA Class II-IV), and / or
previous hospitalization for heart failure or unexplained dyspnea, orthopnea,
paroxysmal nocturnal dyspnea, ascites and peripheral edema. Patients with clinically
significant cerebrovascular disease (transient ischemic attack or stroke) and/or
coronary artery disease (hospitalization for myocardial infarction or unstable angina,
new onset of angina with positive functional tests or coronary angiogram revealing
stenosis, coronary revascularization procedure) within 6 months before screening.

6. Patients with clinically significant cardiac conduction defects, including second or
third degree atrioventricular block, left bundle branch block, sick sinus syndrome,
atrial fibrillation, atrial flutter, an accessory bypass tract, or any arrhythmia
requiring medication.

7. Patients with jaundice, hepatitis, or known hepatobiliary disease (includes
asymptomatic cholelithiasis); alanine aminotransferase and/or aspartate
aminotransferase >2 times the upper limit of normal at Screening.

8. Patients positive for human immunodeficiency virus (HIV), and markers indicating acute
(positivity of at least one of the following: Hepatitis B surface antigen [HBsAg],
Hepatitis B "e" antigen [HBeAg], Hepatitis B virus [HBV] DNA in blood or liver,
Immunoglobulin M Hepatitis B core antibody) or chronic (HBsAg and/or HBeAg and/or
Hepatitis B virus [HBV] DNA positivity) HBV infection, or hepatitis C virus (HCV)
infection (reactive anti-HCV antibody and/or HCV RNA). Testing at screening is only
required for patients >/= 18 years of age.

9. History of malignancy other than adequately treated basal cell or squamous cell skin
cancer within the past 5 years.

10. Patients with hemodynamically significant valvular disease.

11. Hematocrit (HCT) <27 or hemoglobin (Hgb) <9.

12. Potassium >5.5 mEq/L.

13. Patients >18 years of age with Estimated Glomerular Filtration Rate (eGFR) ≥60 ml
mL/min who have N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥200
pg/mL (57.8 pmol/L). For patients >18 years of age with eGFR <60 mL/min, the following
parameters requiring echocardiography (ECHO) at screening should be used for
exclusion:

1. NT-proBNP ≥300 pg/mL in patients >18 years of age with eGFR 45 59.9 mL/min

2. NT-proBNP = 200-299 pg/mL in patients >18 years of age with eGFR 45 59.9 mL/min,
and abnormal ejection fraction (EF <55) and/or diastolic dysfunction on ECHO

3. NT-proBNP ≥400 pg/mL in patients >18 years of age with eGFR 30.0 44.9 mL/min

4. NT-proBNP = 200-399 pg/mL in patients >18 years of age with eGFR 30.0 44.9
mL/min, and abnormal ejection fraction (EF <55) and/or diastolic dysfunction on
ECHO.

14. Patients >/= 18 years of age with body mass index (BMI) >40. Patients <18 years of age
with a BMI in the 99% percentile plus 5 units.

15. Patients who have abnormal clinical laboratory values at Screening, which are
designated by the Principal Investigator as clinically significant.

16. Patients with a history of drug or alcohol abuse within the past two years.

17. Patients with a history of an allergic response to any angiotensin II antagonist or
endothelin receptor antagonist.

18. Women who are pregnant or breastfeeding.

19. Women of child-bearing potential (WOCBP) who are unwilling or unable to use two
reliable methods of contraception, with at least one being highly reliable (e.g. oral,
implanted or injected contraceptive hormones or an intrauterine device) and one being
a barrier method, in order to avoid pregnancy for the entire study period and for 90
days post study participation. WOCBP, defined as all women physiologically capable of
becoming pregnant, includes any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or
bilateral ovariectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive
months and for women on hormone replacement therapy, only with documented plasma
follicle stimulating hormone level greater than 35 mIU/mL). Women using oral,
implanted or injected contraceptive hormones, an intrauterine device, barrier methods
(diaphragm, condoms, spermicidal) to prevent pregnancy, practicing abstinence or where
the partner is sterile (e.g. vasectomy) As well as postmenopausal women who have
fertilized eggs implanted are also considered WOCBP.

20. Male patients and female spouse/partners who are of child-bearing potential must use
two reliable methods of contraception, with at least one being highly reliable (e.g.
including oral, implanted or injected contraceptive hormones or an intrauterine
device) and one being a barrier method, e.g. condom, to avoid pregnancy, for the
entire study period and for 90 days post study participation.

21. Patients who have participated in another investigational drug study within 28 days
prior to screening, or who will participate in another drug study during the course of
this study.

22. Prior exposure to Sparsentan, dual acting receptor antagonist (DARA), or PS433540.

23. Patients who are unable to comply with the study procedures and assessments, including
the ability swallow the study drug or control capsules.