Inclusion Criteria:

• The patient or parent/legal guardian (as appropriate) is willing and able to provide signed informed consent, and where required, the patient is willing to provide assent, prior to any screening procedures.
• The patient has biopsy-proven FSGS lesion(s) or documentation of a genetic mutation in a podocyte protein associated with FSGS. The biopsy may have been performed at any time in the past. The patient will be enrolled based on light microscopy diagnosis of FSGS and supportive findings on either electron microscopy (EM) or immunofluorescence (IF) analysis (preferably both). In exceptional cases, the patient may be enrolled based on light microscopy diagnosis of FSGS lesion(s) in the absence of EM and/or IF analysis, provided the history and/or the course of the disease are indicative of primary FSGS and the case has been reviewed by the Medical Monitor and Investigator.
• Sites within the US and UK: The patient is male or female aged 8 to 75 years, inclusive, weighing ≥ 20 kg, at screening. Sites outside the US and UK: The patient is male or female aged 18 to 75 years, inclusive, weighing ≥ 20 kg, at screening.
• The patient has a UP/C ≥1.5 g/g (170 mg/mmol) at screening. 5. The patient has an eGFR ≥ 30 mL/min/1.73 m^2 at screening. 6. The patient has a mean seated blood pressure ≥100/60 mmHg and ≤ 160/100 mmHg (patients ≥18 years of age) or between the 5th and 95th percentile for age, sex, and height (patients < 18 years of age; Banker 2016).
• Women of childbearing potential (WOCBP), beginning at menarche, must agree to the use of 1 highly reliable (ie, can achieve a failure rate of < 1% per year) method of contraception from 7 days prior to the first dose of study medication until 90 days after the last dose of study medication. Examples of highly reliable contraception methods include stable oral, implanted, transdermal, or injected contraceptive hormones associated with inhibition of ovulation, or an intrauterine device in place for at least 3 months. One additional barrier method must also be used during sexual activity, such as a diaphragm or diaphragm with spermicide (preferred) or male partner’s use of male condom or male condom with spermicide (preferred) from Day 1/Randomization until 90 days after the last dose of study medication. Women of childbearing potential are defined as those who are fertile, following menarche and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea for more than 24 consecutive months without an alternative medical cause; women on hormone replacement therapy must have a documented plasma follicle-stimulating hormone level > 40 mIU/mL. All WOCBP must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test, with positive results confirmed by serum, at every study visit from Randomization (Visit 3) and after.
  • NOTE: Prior to menarche, pregnancy testing and contraceptive use are not required. However, the patient and their parent/guardian must be advised that, immediately upon menarche, the patient will be required to begin pregnancy testing and initiate contraceptive use. This requirement cannot be avoided.

Exclusion Criteria:

• The patient has FSGS secondary to another condition.
• The patient is ≥18 years of age and has positive findings on serological tests that, in the Investigator’s opinion, are diagnostic of another primary or secondary glomerular disease. These may include antinuclear antibody, anti-double stranded deoxyribonucleic acid (DNA) antibodies, complement C3 and C4, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-glomerular basement membrane antibodies, any clinically significant abnormalities identified by serum and urine protein electrophoresis or immunofixation, or serum kappa and lambda free light chains. At the Investigator’s discretion, these tests may be performed in patients <18 years of age under clinically relevant circumstances.
• The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] > 8%), or nonfasting blood glucose > 180 mg/dL (10.0 mmol/L) at screening.
• The patient has undergone any organ transplantation, with the exception of corneal transplants.
• The patient requires any of the prohibited concomitant medications.
• The patient has been treated with rituximab, cyclophosphamide, or abatacept within ≤ 3 months prior to screening. If a patient is taking other chronic immunosuppressive medications, the dosage must be stable for ≥ 1 month prior to screening and during the screening period.
• The patient has a documented history of heart failure (New York Heart Association Class II-IV) and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
• The patient has 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, coronary angiogram revealing stenosis, or a coronary revascularization procedure) within 6 months prior to screening.
• The patient has hemodynamically significant valvular disease.
• The patient has jaundice, hepatitis, or known hepatobiliary disease (excluding asymptomatic cholelithiasis), or alanine aminotransferase and/or aspartate aminotransferase > 2 times the upper limit of the normal range at screening.
• The patient is positive at screening for the human immunodeficiency virus or markers indicating acute or chronic hepatitis B virus (HBV) infection (acute HBV is defined as a positive hepatitis B surface antigen [HBsAg], hepatitis B “e” antigen [HBeAg], HBV DNA in blood or liver, or immunoglobulin M hepatitis B core antibody; chronic HBV is defined as a positive HBsAg and/or HBeAg and/or HBV DNA) or hepatitis C virus (HCV) infection (defined as reactive anti-HCV antibody and HCV RNA).
• The patient has a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years.
• The patient has a screening hematocrit value 5.5 mEq/L (5.5 mmol/L).
• The patient is extremely obese (i.e., ≥ 18 years of age with a body mass index [BMI] > 40 kg/m^2 or < 18 years of age with a BMI in the 99th percentile plus 5 units at screening), in whom, in the Investigator’s opinion, there is a causal relationship between obesity and development of the FSGS lesion. For patients with moderate or severe edema, BMI will be calculated based on remission or premorbid weight measured within 3 months prior to screening, if available. If not available, BMI will be calculated based on the estimated dry weight, based on the Investigator’s clinical judgment.
• The patient has a history of alcohol or illicit drug use disorder (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), or a reported habitual alcohol intake greater than 21 units/week within 2 years prior to screening.
• The patient has a history of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan or irbesartan, or has a hypersensitivity to any of the excipients in the study medications.
• The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
• The patient has participated in a study of another investigational product within 28 days prior to screening or plans to participate in such a study during the course of this study.
• The patient has had prior exposure to sparsentan.
• The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study, including the ability to swallow the study medication capsules whole.
• Patients with a medical condition or abnormal clinically significant laboratory screening value not listed above that may interfere with the evaluation of sparsentan efficacy or safety will be reviewed with the Medical Monitor before consideration of the patient for enrollment. Patients who fail screening may be re-screened up to 2 additional times. Patients who are re-screened will undergo all screening procedures and will be assigned a new patient number. Patients will also repeat the informed consent procedure each time they are re-screened.