Study of VIR-2218 in Healthy Subjects and Patients With Chronic Hepatitis B

Study Overview
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Brief Summary
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This is a phase 1/2 study in which healthy adult subjects and subjects with chronic hepatitis B virus (HBV) infection will receive VIR-2218 or placebo and will be assessed for safety, tolerability, pharmacokinetics, and antiviral activity (only in subjects with chronic HBV). In the single ascending dose (SAD) part, Part A, healthy adult subjects will receive one dose of VIR-2218 or placebo, administered subcutaneously (SC). In the multiple ascending dose (MAD) parts, Part B & Part C, subjects with chronic HBV infection will receive two doses of VIR-2218 or placebo every 4 weeks administered SC.

Official Title
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A Phase 1/2, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of VIR-2218

Conditions
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Chronic Hepatitis B

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


Participation Criteria
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Eligibility Criteria
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Part A SAD: Inclusion Criteria: Male or female age 18 - 55 BMI 18 - 32 kg/m^2 Exclusion Criteria: Any clinically significant chronic or acute medical condition that makes the volunteer unsuitable for participation History or evidence of drug or alcohol abuse History of intolerance to SC injection Parts B/C MAD: Inclusion Criteria: Male or female age 18 - 65 BMI 18 - 32 kg/m^2 Chronic HBV infection for >/= 6 months Exclusion Criteria: Any clinically significant chronic or acute medical condition that makes the volunteer unsuitable for participation Significant fibrosis or cirrhosis History or evidence of drug or alcohol abuse History of intolerance to SC injection History of chronic liver disease from any cause other than chronic HBV infection History of hepatic decompensation

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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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 VIR-2218 50 mg<br>Healthy subjects received a single dose of VIR-2218 of 50 mg administered SC | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part A: SAD VIR-2218 100 mg<br>Healthy subjects received a single dose of VIR-2218 of 100 mg administered SC | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part A: SAD VIR-2218 200 mg<br>Healthy subjects received a single dose of VIR-2218 of 200 mg administered SC | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part A: SAD VIR-2218 400 mg<br>Healthy subjects received a single dose of VIR-2218 of 400 mg administered SC | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part A: SAD VIR-2218 600 mg<br>Healthy subjects received a single dose of VIR-2218 of 600 mg administered SC | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part A: SAD VIR-2218 900 mg<br>Healthy subjects received a single dose of VIR-2218 of 900 mg administered SC | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Placebo Comparator: Part A: SAD Placebo<br>Healthy subjects received a single dose of placebo administered SC | Drug: Placebo<br>* Sterile normal saline (0.9% NaCl) given by subcutaneous injection<br>|
| Experimental: Part B: MAD VIR-2218 20 mg<br>Chronic HBV, HBeAg negative, subjects received 2 SC doses of 20 mg VIR-2218 administered 4 weeks apart. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part B: MAD VIR-2218 50 mg<br>Chronic HBV, HBeAg negative, subjects received 2 SC doses of 50 mg VIR-2218 administered 4 weeks apart. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part B: MAD VIR-2218 100 mg<br>Chronic HBV, HBeAg negative, subjects received 2 SC doses of 100 mg VIR-2218 administered 4 weeks apart. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part B: MAD VIR-2218 200 mg<br>Chronic HBV, HBeAg negative, subjects received 2 SC doses of 200 mg VIR-2218 administered 4 weeks apart. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part C: MAD VIR-2218 50 mg<br>Chronic HBV, HBeAg positive, subjects received 2 SC doses of 50 mg VIR-2218 administered 4 weeks apart. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Experimental: Part C: MAD VIR-2218 200 mg<br>Chronic HBV, HBeAg positive, subjects received 2 SC doses of 200 mg VIR-2218 administered 4 weeks apart. | Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>|
| Placebo Comparator: Part B: MAD Placebo<br>Chronic HBV, HBeAg negative, subjects received 2 SC doses of placebo administered 4 weeks apart. | Drug: Placebo<br>* Sterile normal saline (0.9% NaCl) given by subcutaneous injection<br>|
| Placebo Comparator: Part C: MAD Placebo<br>Chronic HBV, HBeAg positive, subjects received 2 SC doses of placebo administered 4 weeks apart. | Drug: Placebo<br>* Sterile normal saline (0.9% NaCl) given by subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) | Number of Subjects with Adverse Events as assessed by CTCAE v5.0. In our planned analysis for this outcome measure, incidence is defined as the number of participants with treatment emergent AEs (TEAEs) in relation to the total number of participants in the cohort. | Up to 364 days | 
| Clinical Assessments Including But Not Limited to Laboratory Test Results | Number of participants with clinically significant abnormalities in vital signs, electrocardiogram (ECG), and laboratory parameters graded by CTCAE v5.0. | Up to 336 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (ng/mL) | VIR-2218 and metabolite Maximum Concentration in Plasma | Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose and Week 1; Part B/C: predose on Day 1 and at 1h, 2h, 4h, 8h, 24h postdose, Week 1, predose on Week 4 and at 1h, 2h, 4h, 8h, 24h postdose, and Week 5 | 
| Time to Reach Maximum Plasma Concentration (h) | VIR-2218 and metabolite time of Cmax in Plasma: Median (Inter-Quartile Range Q1-Q3) | Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose and Week 1; Part B/C: predose on Day 1 and at 1h, 2h, 4h, 8h, 24h postdose, Week 1, predose on Week 4 and at 1h, 2h, 4h, 8h, 24h postdose, and Week 5 | 
| Area Under the Plasma Concentration Versus Time Curve (ng*h/mL) | VIR-2218 and metabolite Area under the curve from time 0 to last measurable Time | Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose and Week 1; Part B/C: predose on Day 1 and at 1h, 2h, 4h, 8h, 24h postdose, Week 1, predose on Week 4 and at 1h, 2h, 4h, 8h, 24h postdose, and Week 5 | 
| Apparent Terminal Elimination Half-life (h) | VIR-2218 Apparent Elimination Half-life t1/2 in Plasma: Median (Inter-Quartile Range Q1-Q3) | Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose and Week 1 | 
| Apparent Plasma Clearance (L/h) | VIR-2218 CL/F Apparent plasma clearance | Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose, and Week 1 | 
| Apparent Volume of Distribution (L) | VIR-2218 VZ/F apparent volume of distribution | Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose, and Week 1 | 
| Urine %fe 0-24h | VIR-2218 and metabolite: Fraction excreted in the urine from time 0 to 24 h. Pooled Urine PK samples was collected at pre-specified intervals in the single ascending dose study of VIR-2218. Therefore, the following PK parameter, fraction excreted in the urine ( %fe 0-24h ) was only calculated in healthy subjects who participated in Part A of the study. This parameter was not listed as a secondary endpoint for parts B/C in the submitted protocol, and as such was not reported in this secondary outcome measures. | Pooled urine was collected at time interval D1 (0-4 hrs) (4-8 hrs) (8-12 hrs) and (12-24 hrs) | 
| Apparent Renal Clearance (CLR/F) | VIR-2218 Apparent renal clearance from 0 to 24 h. Pooled Urine PK samples was collected at pre-specified intervals in the single ascending dose study of VIR-2218. Therefore, the following PK parameter, apparent renal clearance (CLR/F) was only calculated in healthy subjects who participated in Part A of the study. This parameter was not listed as a secondary endpoint for parts B/C in the submitted protocol, and as such was not reported in this secondary outcome measures. | Pooled Urine was collected at time interval D1 (0-4 hrs) (4-8 hrs) (8-12 hrs) and (12-24 hrs) | 
| Maximum Reduction of Serum HBsAg From Baseline | Maximum reduction of serum HBsAg from Day 1 until Week 16. | Up to 112 days | 
| Number of Subjects With Serum HBsAg Loss at Any Time Point | Serum HBsAg loss is defined as quantitative HBsAg < 0.05 IU/mL at two or more consecutive measurements | Up to 336 days | 
| Number of Subjects With Sustained Serum HBsAg Loss for >/= 6 Months | Serum HBsAg loss is defined as quantitative HBsAg < 0.05 IU/mL at two or more consecutive measurements | Up to 336 days | 
| Number of Subjects With Anti-HBs Seroconversion at Any Timepoint | Anti-HBs seroconversion is defined as anti-HBs positivity at two or more consecutive measurements | Up to 336 days | 
| Number of Subjects With HBeAg Loss and/or Anti-HBe Seroconversion at Any Timepoint | HBeAg loss is defined as quantitative HBeAg < 0.11 IU/mL at two or more consecutive measurements. anti-HBe seroconversion is defined as anti-HBe positivity at two or more consecutive measurements | Up to 336 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HBV, Hepatitis B Virus, Chronic Hepatitis B, Hepatitis