A Study to Evaluate ALN-AGT01 in Patients With Hypertension

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of subcutaneous (SC) ALN-AGT01 (zilebesiran) in participants with hypertension. The study will be conducted in 4 parts: Part A will be a single ascending dose (SAD) phase in hypertensive participants, Part B will be a single dose (SD) phase in hypertensive participants with controlled salt intake, Part D will be a MD phase in hypertensive participants who are obese, and Part E will be an open-label SD phase with co-administration of irbesartan in hypertensive patients.

Official Title
-----------------
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Dose and Active Comparator-Controlled Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered ALN-AGT01 in Patients With Hypertension

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: ALN-AGT01
* Drug: ALN-AGT01-Matching Placebo
* Drug: Irbesartan
* Drug: Irbesartan-Matching Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has mild to moderate hypertension with mean sitting systolic blood pressure (SBP) of >130 and ≤165 mmHg without hypertensive medication for Parts A, B and D, and >135 and ≤165 mmHg without hypertensive medication for Part E Parts A and B: Has body mass index (BMI) ≥18 and ≤35 kg/m^2; Part D: Has BMI >35 and ≤50 kg/m^2; Part E: Has BMI ≥18 kg/m^2 and ≤50 kg/m^2 Has a normal 12-lead electrocardiogram (ECG) Is a nonsmoker Exclusion Criteria: Has secondary hypertension Has orthostatic hypotension Has estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m^2 Recently received an investigational agent Has diabetes mellitus Has history of any cardiovascular event Has history of intolerance to SC injection(s)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: SAD: ALN-AGT01<br>Participants will be administered a single dose of ALN-AGT01. | Drug: ALN-AGT01<br>* ALN-AGT01 will be administered by subcutaneous (SC) injection.<br>* Other names: Zilebesiran;|
| Placebo Comparator: Part A: SAD: ALN-AGT01-Matching Placebo<br>Participants will be administered a single dose of ALN-AGT01-matching placebo. | Drug: ALN-AGT01-Matching Placebo<br>* Normal saline (0.9% NaCl) matching volume of ALN-AGT01 doses will be administered SC.<br>|
| Experimental: Part B: SD: ALN-AGT01<br>Participants with controlled salt intake will be administered a single dose of ALN-AGT01. | Drug: ALN-AGT01<br>* ALN-AGT01 will be administered by subcutaneous (SC) injection.<br>* Other names: Zilebesiran;|
| Placebo Comparator: Part B: SD: ALN-AGT01-Matching Placebo<br>Participants with controlled salt intake will be administered a single dose of ALN-AGT01-matching placebo. | Drug: ALN-AGT01-Matching Placebo<br>* Normal saline (0.9% NaCl) matching volume of ALN-AGT01 doses will be administered SC.<br>|
| Experimental: Part D: MD: ALN-AGT01 + Irbesartan-Matching Placebo<br>Participants, who are obese, will be administered multiple doses of ALN-AGT01 and irbesartan-matching placebo. | Drug: ALN-AGT01<br>* ALN-AGT01 will be administered by subcutaneous (SC) injection.<br>* Other names: Zilebesiran;Drug: Irbesartan-Matching Placebo<br>* Irbesartan-matching placebo will be administered orally.<br>|
| Active Comparator: Part D: MD: ALN-AGT01-Matching Placebo + Irbesartan<br>Participants, who are obese, will be administered multiple doses of ALN-AGT01-matching placebo and irbesartan. | Drug: ALN-AGT01-Matching Placebo<br>* Normal saline (0.9% NaCl) matching volume of ALN-AGT01 doses will be administered SC.<br>Drug: Irbesartan<br>* Irbesartan will be administered orally.<br>|
| Experimental: Part E: Open Label: ALN-AGT01 + Irbesartan<br>Participants will be administered a single dose of ALN-AGT01 and multiple doses of irbesartan. | Drug: ALN-AGT01<br>* ALN-AGT01 will be administered by subcutaneous (SC) injection.<br>* Other names: Zilebesiran;Drug: Irbesartan<br>* Irbesartan will be administered orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) |  | Parts A, B and E: each up to approximately 12 months; Part D: up to approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Blood Angiotensinogen (AGT) Level |  | Parts A, B and E: each up to approximately 12 months; Part D: up to approximately 18 months | 
| Maximum Observed Plasma Concentration (Cmax) of ALN-AGT01 and of Potential Metabolites |  | Parts A, B and E: Up to Day 15; Part D: Up to Day 99 | 
| Area Under the Concentration-time Curve (AUC) of ALN-AGT01 and of Potential Metabolites |  | Parts A, B and E: Up to Day 15; Part D: Up to Day 99 |