A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group, Dose-Ranging Study to Evaluate CIN-107 for the Treatment of Patients With Uncontrolled Hypertension and Chronic Kidney Disease

Inclusion Criteria:

• Is an adult male or female patient ≥18 years of age;

• Has a mean seated SBP ≥140 mmHg at Screening (Visit 1) and Visit 2; Note: Patients with mean seated SBP ≥130 mmHg may be eligible if diabetic. Note: Mean seated SBP is defined as the average of 3 seated SBP measurements at any single clinical site visit.

• Has a prior diagnosis of mild-to-severe CKD, defined as eGFR (based on the CKD-EPI equation) of 25 to 75 mL/min/1.73 m2 , inclusive, presumed to be diabetic nephropathy or hypertensive nephrosclerosis at Visit 1; Note: All other types of CKD and known overlapping kidney diseases are exclusionary. To ensure patients with moderate and severe renal impairment will be represented, the number of patients with an eGFR ≥ 60 and < 75 mL/min/1.73 m2 will be capped at 45 (approximately 15% of the total population.)

• Has a UACR ≥ 200 mg/g (≥ 22.6 mg/mmol) in at least 2 out of 3 measurements based on first urine collected in the morning on consecutive days during the Screening Period;

• Is currently taking an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) at the maximum tolerated daily dose, based on Investigator judgment, for >4 weeks prior to Visit 1;

• If taking a sodium-glucose cotransporter-2 (SGLT2) inhibitor at Screening (Visit 1), the regimen must be stable for a period of at least 8 weeks before Visit 1 and be expected to remain at a stable dose over the study period; Note: It is expected that patients not currently taking an SGLT2 inhibitor at Screening (Visit 1) will not initiate this class of medication during the entire Study Period.

• Is willing to be compliant with the contraception and reproduction restrictions of the study as follows:

• Female patients of childbearing potential (ie, ovulating, pre-menopausal, and not surgically sterile) must have a documented negative pregnancy test at Visit 1 and the Randomization Visit (Visit 3); and

• Female patients of childbearing potential must use a highly effective method of contraception (ie, <1% failure rate) from Day 1 through 30 days after the last administration of study drug.

• Note: Acceptable methods of contraception for female patients of childbearing potential enrolled in the study include the following:

• Surgical sterilization (tubal ligation);

• Intrauterine device for at least 12 weeks before Visit 1;

• Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks before Visit 1; or

• Diaphragm used in combination with spermicide

• Post-menopausal women must have not had menstrual bleeding for at least 1 year before initial dosing and either be >60 years or have an elevated follicle-stimulating hormone level >40 mIU/mL at Visit 1;

• Is able and willing to give informed consent for participation in the study. After the run-in period of 2 to 4 weeks, all patients must confirm the BP and UACR measurements still meet the eligibility criteria.

Exclusion Criteria:

• Have a documented diagnosis of type 1 diabetes;

• Are not willing or not able to discontinue a mineralocorticoid receptor antagonist (MRA) or a potassium sparing diuretic as part of an existing antihypertensive regimen;

• Note: Patients taking an MRA or a potassium sparing diuretic (eg, triamterene, amiloride, etc) as an antihypertensive agent must be willing to discontinue this agent for study eligibility. The potassium sparing diuretic may be discontinued and replaced with a non-potassium sparing diuretic. All patients who remain on a stable regimen of antihypertensive agents, including a non-potassium sparing diuretic, for at least six weeks, will be eligible to enter the single blind Run In.

• Have a single occurrence of mean seated SBP >180 mmHg or DBP >110 mmHg during the Screening Period (if such a BP is recorded during the Screening Period, the patient may attend an Interim Visit for an additional BP measurement and reassessment of Inclusion/Exclusion Criteria);

• Note: Mean seated BP is defined as the average of 3 measurements obtained at any 1 clinical site visit. If the patient missed the regularly scheduled antihypertensive medication(s) prior to the visit (Visits 1 or 2), 1 BP re-test is allowed ≥2 hours after taking the medication(s), on the following day, or later after reestablishing the regularly scheduled antihypertensive regimen.

• Has a body mass index (BMI) >45 kg/m2 at Visit 1;

• Has documented bilateral clinically relevant renal artery stenosis of ≥70%;

• Has had dialysis for acute kidney injury/acute renal failure within 12 weeks prior to the Screening Period, or has a planned dialysis or kidney transplantation during the course of the study;

• Has known documented chronic heart failure New York Heart Association class III or IV and/or hospitalization for heart failure within 6 months of Visit 1;

• Has had a stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months of Visit 1;

• Has known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and/or severe aortic valvular disease, diagnosed from a prior echocardiogram or another imaging study;

• Has a planned coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) or any major surgical procedure during the study;

• Has had PCI, CABG, other major cardiac surgery (eg, valve replacement), or peripheral arterial bypass surgery within 6 months of Visit 1;

• Has had a prior solid organ transplant or cell transplant;

• Is expected to receive or is receiving any of the exclusionary drugs such as strong inducers of cytochrome P450 3A, chronic use of non-steroidal anti-inflammatory drugs, spironolactone/ eplerenone, and/or chronic use of steroids;

• Has a known hypersensitivity to any of the following:

• vCIN-107 or drugs of the same class; or

• vExcipients in CIN-107 or drugs of the same classes

• Has received immunotherapy for treatment of CKD within 6 months of Visit 1 or expects to receive immunotherapy for treatment of CKD during participation in the study;

• Has any clinically relevant medical or surgical conditions including unstable conditions and/or conditions requiring regular transfusion or treatment with systemic immunosuppressants, including corticosteroids that, in the opinion of the Investigator, would put the patient at risk by participating in the study;

• Has evidence of any of the following at Visit 1 or the Randomization Visit (1 retest is allowed):

• White blood cell count >15 × 109 /L or absolute neutrophil count

• Serum potassium <3.5 mEq/L;

• Note: Patients with a serum potassium level below normal range may continue in the study if the Investigator elects to correct the serum potassium level with supplementation and offers to manage the condition

• Serum potassium >5.0 mEq/L;

• Serum sodium <135 mEq/L;

• Serum aspartate aminotransferase or alanine aminotransferase >3 × upper limit of normal (ULN); or

• Total bilirubin >2 × ULN, unless due to Gilbert’s syndrome

• Has uncontrolled diabetes with glycosylated hemoglobin >10.5% at Visit 1.

• Is positive for HIV antibody, hepatitis B surface antigen, or hepatitis C virus RNA;

• Has typical consumption of >14 alcoholic drinks weekly; Note: 1 drink of alcohol is equivalent to ½ pint of beer (285 mL), 1 glass of spirits (25 mL), or 1 glass of wine (125 mL).

• Has participated in another clinical study involving any investigational drug within 30 days prior to Visit 1, or plans to participate in another clinical study within 30 days of discontinuation of study drug;

• Has received experimental therapy for disease intervention with a small molecule within 30 days of Visit 1 or 5 half-lives, whichever is longer, or received experimental therapy with a large molecule within 90 days of the Visit 1 or 5 half-lives, whichever is longer; Note: Vaccinations, including those for Coronavirus Disease 2019 (COVID-19), will not be exclusionary if administered during the Screening Period.

• Is pregnant, breastfeeding, or planning to become pregnant during the study; or

• Is considered by the Investigator, after reviewing medical and psychiatric history, physical examination, and laboratory evaluations, to be unsuitable for any other reason that may either place the patient at increased risk during participation or interfere with the interpretation of the study outcomes.