An 8-Week Study to Evaluate Tenapanor in the Treatment of Hyperphosphatemia in End-Stage Renal Disease Patients on Hemodialysis (ESRD-HD)

The study consists of a screening visit, a wash out period of up to 3 weeks, when existing
phosphate lowering medication is withheld, an 8-week treatment period, in which all groups
receive tenapanor, and a 4-week placebo-controlled, randomized withdrawal period, during
which patients are re-randomized 1:1 to either remain on their current tenapanor treatment
or placebo.

Depending on the increase in serum phosphate levels, subjects can be randomized 1,2, or 3
weeks after being taken off their phosphate lowering medication.

Inclusion Criteria:

- 18 to 80 years old

- Females must be non-pregnant, non-lactating, and either be post-menopausal for at
least 12 months, have documentation of irreversible surgical sterilization, or
confirm the use of one of the acceptable contraceptive methods.

- Males must agree to avoid fathering a child and agree to use an appropriate method of
contraception

- Chronic maintenance hemodialysis 3x/week for at least 3 months

- Kt/V ≥ 1.3 at most recent measurement prior to screening

- Prescribed and taking at least 3 doses of phosphate binder per day

- Serum phosphate levels should be between 4.0 and 7.0 mg/dL (inclusive) at screening

- For randomization in the study, after 1 week wash-out of phosphate binders, subjects
must have serum phosphate level of at least 9 mg/dL but below 10 mg/dL and have had
an increase of at least 1.5 mg/dL versus pre-wash out value

- For randomization in the study, after 2 or 3 weeks wash-out of phosphate binders,
subjects must have serum phosphate level of at least 6 mg/dL but below 10 mg/dL and
have had an increase of at least 1.5 mg/dL versus pre-wash out value

Exclusion Criteria:

- Severe hyperphosphatemia defined as >10 mg/dL on Phosphate-binders at any time point
during clinical routine monitoring for the 3 preceding months before screening

- Serum parathyroid hormone >1200 pg/mL

- Persistent metabolic acidosis defined as serum carbon dioxide <18 mmol/L from two
consecutive measurements during screening and washout periods

- Clinical signs of hypovolemia at randomization

- History of inflammatory bowel disease (IBD) or diarrhea predominant irritable bowel
syndrome (IBS-D)

- Scheduled for living donor kidney transplant, change to peritoneal dialysis, home HD
or plans to relocate to another center during the study period

- Diarrhea or loose stools during the week before randomization defined as BSFS ≥ 6 and
frequency ≥ 3 for 2 or more days

- Any evidence of or treatment of malignancy within one year, excluding
non-melanomatous malignancies of the skin

- Positive serology with evidence of significant hepatic impairment or WBC elevation
according to the Investigator

- Life expectancy < 6 months