Effect of Hepatic Impairment on the Pharmacokinetics and Safety of VIR-2218 and VIR-3434

Study Overview
=================
Brief Summary
-----------------
In this study, a single dose of VIR-2218 up to 200 mg SC or VIR-3434 at 300 mg SC monotherapy or a combination of VIR-2218 and VIR-3434 will be administered to assess the pharmacokinetic (PK) exposure, safety, and tolerability of VIR-2218 and VIR-3434 in participants with cirrhosis and Hepatic Impairment, defined using the Child-Pugh-Turcotte (CPT) categorization.

Detailed Description
-----------------
Participants may be enrolled in Cohorts 1, 2, 3, 4, 5, 6, 7, 8, and 9 in a non-randomized way.

Official Title
-----------------
A Phase 1 Open-Label, Single-Dose, Parallel-Group Study of the Pharmacokinetics and Safety of VIR-2218 and VIR-3434 Monotherapy and Combination Therapy in Adult Participants With Hepatic Impairment

Conditions
-----------------
Hepatic Impairment, Cirrhosis

Intervention / Treatment
-----------------
* Drug: VIR-2218
* Drug: VIR-3434


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must be ≥18 to ≤70 years of age at screening Must have a calculated BMI from 18.5 ≤ BMI ≤ 40 kg/m2 All participants must have an eGFR ≥ 60 mL/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation Inclusion criteria: Healthy matched participants Must in the opinion of the Investigator, be in good health based upon medical history, vital signs, physical examination, and screening laboratory evaluations Inclusion criteria: Hepatic impaired participants Apart from hepatic insufficiency, participants must, in the opinion of the Investigator be sufficiently healthy for study participation based on medical history, physical examination, vital signs, and screening laboratory evaluations Participant is considered to have chronic, stable moderate, severe, mild HI (of any etiology excluding chronic HBV and HDV) and has been clinically stable per Investigator assessment for at least 1 month prior to screening CPT score of 5 to 6 for mild HI at screening CPT score 7-9 for moderate HI at screening CPT score 10-15 severe HI at screening Exclusion Criteria: Participants with unstable cardiac function or evidence of previous myocardial infarction in the past 12 months or any clinically significant active cardiovascular disease that, in the opinion of the Investigator, could interfere with the safety of the participant Any clinically significant conduction abnormality or arrhythmia (including non-sustained or sustained ventricular tachycardia as per Investigator's assessment) Infection with human immunodeficiency virus (HIV), hepatitis A virus (HAV), HBV (positive HBsAg or positive hepatitis B core antibody with negative hepatitis B surface antibody), hepatitis C virus (HCV), HDV or hepatitis E virus (HEV). HCV antibody positive participants with a negative HCV RNA are eligible. HDV antibody positive participants with a negative HDV RNA are eligible Exclusion criteria: Healthy matched participants Systolic BP is outside the range of 90-160 mmHg, or diastolic BP is outside the range of 45-95 mmHg or heart rate is outside the range of 50-100 beats per minute (bpm) for female participants or 45-100 bpm for male participants at screening Use of any prescription medications or over-the-counter medications (with the exception of vitamins and/or hormonal contraceptive medication) within 30 days prior to D1 of study participation Exclusion criteria: Participants with Hepatic impairment Not on stable dose and regimen of any medication Acute or worsening chronic hepatitis Participants requiring paracentesis more than once a month Participants with refractory encephalopathy or significant Central Nervous System History of gastric or esophageal variceal bleeding within the past 6 months Participants with Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement Presence of hepatopulmonary or hepatorenal syndrome Presence of primarily cholestatic liver diseases History of or currently listed for liver transplantation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: CPT-B (moderate HI) participants and matched healthy participants will be evaluated first<br>All participants in Cohort 1 will be receiving VIR-2218 monotherapy. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection.<br>|
| Experimental: Cohort 2: CPT-C (severe HI) participants and matched healthy participants<br>This arm is optional based on Cohort 1. All participants in Cohort 2 will be receiving VIR-2218 monotherapy. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection.<br>|
| Experimental: Cohort 3: CPT-A (mild HI) participants and matched healthy participants<br>This cohort is optional. All participants in Cohort 3 will be receiving VIR-2218 monotherapy. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection.<br>|
| Experimental: Cohort 4: CPT-A (mild HI) participants and matched healthy participants<br>All participants in Cohort 4 will be receiving VIR-3434 monotherapy. | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection.<br>|
| Experimental: Cohort 5: CPT-B (moderate HI) participants and matched healthy participants<br>All participants in Cohort 5 will be receiving VIR-3434 monotherapy. | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection.<br>|
| Experimental: Cohort 6: CPT-C (severe HI) participants and matched healthy participants<br>This arm is optional based on Cohort 5. All participants in Cohort 6 will be receiving VIR-3434 monotherapy. | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection.<br>|
| Experimental: Cohort 7: CPT-A (mild HI) and matched healthy participants<br>All participants in Cohort 7 will be receiving VIR-3434 and VIR-2218 combination therapy. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection.<br>Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection.<br>|
| Experimental: Cohort 8: CPT-B (moderate HI) and matched healthy participants<br>All participants in Cohort 8 will be receiving VIR-3434 and VIR-2218 combination therapy. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection.<br>Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection.<br>|
| Experimental: Cohort 9: CPT-C (severe HI) and matched healthy participants<br>This arm is optional based on Cohort 8. All participants in Cohort 9 will be receiving VIR-3434 and VIR-2218 combination therapy. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection.<br>Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed Plasma concentration (Cmax) of VIR-2218 and metabolite AS(N-1)3'VIR2218 |  | 5 days | 
| Area Under The Plasma Concentration-time Curve from Time Zero to Time of Last Quantifiable Concentration (AUClast) of VIR-2218 and metabolite AS(N-1)3'VIR2218 |  | 5 days | 
| Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUCinf) of VIR-2218 metabolite AS(N-1)3'VIR2218 |  | 5 days | 
| Maximum observed Plasma concentration (Cmax) of VIR-3434 |  | 18 weeks | 
| Area Under The Plasma Concentration-time Curve from Time Zero to Time of Last Quantifiable Concentration (AUClast) of VIR-3434 |  | 18 weeks | 
| Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUCinf) of VIR-3434 |  | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) |  | Up to 18 Weeks | 
| Incidence of ADA and titers of ADA to VIR-3434 at each study visit for cohorts receiving VIR-3434 therapy |  | 18 Weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
siRNA, Monoclonal antibody, HDV, Compensated Cirrhosis, Decompensated Cirrhosis