RLY5016 in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN)

Inclusion Criteria:

1. 1. Age 30 - 80 years old at screening
2. Type 2 diabetes mellitus (T2DM) diagnosed after age 30 which has been treated with oral medications or insulin for at least one year prior to screening
3. Chronic kidney disease: eGFR 15 - < 60 mL/min/1.73m2 at screening based on central lab serum creatinine measurement (except for patients with hyperkalemia at S1, whose eligibility will be assessed based on local lab eGFR value)

4. 4. Urine ACR:

   1. Cohorts 1 and 2: urine ACR ≥ 30 mg/g at screening (S1) AND average urine ACR ≥ 30 mg/g at the beginning of Run-In Period (R0) based on up to 3 ACR values obtained starting at S1 and ending at the R0 Visit
   2. Cohort 3: not applicable

5. Local laboratory serum K+ values of:

   1. Cohorts 1 and 2: 4.3 - 5.0 mEq/L at S1; AND 4.5 - 5.0 mEq/L at R0; AND > 5.0 - < 6.0 mEq/L at randomization to RLY5016 (Baseline, T0 Visit)
   2. Cohort 3: > 5.0 - < 6.0 mEq/L at S1 OR at R0 after same day confirmation
6. Must be receiving an ACEI and/or ARB for at least 28 days prior to screening
7. Average SBP ≥ 140 - < 180 mmHg OR average DBP ≥ 90 - < 110 mmHg (sitting) at both screening and R0 (as applicable)
8. Females of child-bearing potential must be non-lactating, must have a negative serum pregnancy test at screening, and must have used a highly effective form of contraception for at least 3 months before RLY5016 administration, during the study, and for one month after study completion
9. Provide their written informed consent prior to participation in the study

Exclusion Criteria:

1. Type 1 diabetes mellitus
2. Central lab hemoglobin A1c > 12% at S1 (except for Cohort 3 patients who are hyperkalemic at S1)
3. Emergency treatment for T2DM within the last 3 months
4. Diabetic gastroparesis
5. Non-diabetic chronic kidney disease
6. History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery (e.g., cholectomy)
7. Current diagnosis of NYHA Class III or IV heart failure
8. Body mass index (BMI) ≥ 40 kg/m2
9. Any of the following events having occurred within 2 months prior to screening: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, cardiac arrest or clinically significant ventricular arrhythmias, transient ischemic attack or stroke, use of any intravenous cardiac medication
10. Prior kidney transplant, or anticipated need for transplant during study participation
11. Active cancer, currently on cancer treatment or history of cancer in the past two years except for non-melanocytic skin cancer which is considered cured
12. History of alcoholism or drug/chemical abuse within 1 year
13. Central lab liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] > 3 times upper limit of normal (except for Cohort 3 patients with hyperkalemia at S1, who will have local lab ALT and AST)
14. Loop and thiazide diuretics or other antihypertensive medications (calcium channel blocker, beta-blocker, alpha-blocker, or centrally acting agent) that have not been stable for at least 28 days prior to screening or not anticipated to remain stable during study participation
15. Current use of polymer-based drugs (e.g., sevelamer, sodium polystyrene sulfonate, colesevelam, colestipol, cholestyramine), phosphate binders (e.g., lanthanum carbonate), or other potassium binders, or their anticipated need during study participation
16. Current use of lithium
17. Use of potassium sparing medications, including aldosterone antagonists (e.g., spironolactone), drospirenone, potassium supplements, bicarbonate or baking soda in the last 7 days prior to screening
18. Use of any investigational product within 30 days or 5 half-lives, whichever is longer, prior to screening
19. Inability to consume the investigational product, or, in the opinion of the Investigator, inability to comply with the protocol
20. In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, or serious intercurrent illness that would significantly decrease study compliance or jeopardize the safety of the patient or affect the validity of the trial results