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

• ClinicalTrials.gov Identifier: NCT03672188
• Recruitment Status: Completed
• First Posted: September 14, 2018
• Results First Posted: December 13, 2021
• Last Update Posted: December 13, 2021
• Sponsor: Vir Biotechnology, Inc.
• Collaborator: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Vir Biotechnology, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Hepatitis B	Drug: VIR-2218; Drug: Placebo	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of VIR-2218
• Actual Study Start Date: November 14, 2018
• Actual Primary Completion Date: September 3, 2020
• Actual Study Completion Date: September 3, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: SAD VIR-2218 50 mg; Healthy subjects received a single dose of VIR-2218 of 50 mg administered SC	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part A: SAD VIR-2218 100 mg; Healthy subjects received a single dose of VIR-2218 of 100 mg administered SC	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part A: SAD VIR-2218 200 mg; Healthy subjects received a single dose of VIR-2218 of 200 mg administered SC	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part A: SAD VIR-2218 400 mg; Healthy subjects received a single dose of VIR-2218 of 400 mg administered SC	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part A: SAD VIR-2218 600 mg; Healthy subjects received a single dose of VIR-2218 of 600 mg administered SC	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part A: SAD VIR-2218 900 mg; Healthy subjects received a single dose of VIR-2218 of 900 mg administered SC	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Placebo Comparator: Part A: SAD Placebo; Healthy subjects received a single dose of placebo administered SC	Drug: Placebo; Sterile normal saline (0.9% NaCl) given by subcutaneous injection
Experimental: Part B: MAD VIR-2218 20 mg; Chronic HBV, HBeAg negative, subjects received 2 SC doses of 20 mg VIR-2218 administered 4 weeks apart.	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part B: MAD VIR-2218 50 mg; Chronic HBV, HBeAg negative, subjects received 2 SC doses of 50 mg VIR-2218 administered 4 weeks apart.	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part B: MAD VIR-2218 100 mg; Chronic HBV, HBeAg negative, subjects received 2 SC doses of 100 mg VIR-2218 administered 4 weeks apart.	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part B: MAD VIR-2218 200 mg; Chronic HBV, HBeAg negative, subjects received 2 SC doses of 200 mg VIR-2218 administered 4 weeks apart.	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part C: MAD VIR-2218 50 mg; Chronic HBV, HBeAg positive, subjects received 2 SC doses of 50 mg VIR-2218 administered 4 weeks apart.	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Experimental: Part C: MAD VIR-2218 200 mg; Chronic HBV, HBeAg positive, subjects received 2 SC doses of 200 mg VIR-2218 administered 4 weeks apart.	Drug: VIR-2218; VIR-2218 given by subcutaneous injection
Placebo Comparator: Part B: MAD Placebo; Chronic HBV, HBeAg negative, subjects received 2 SC doses of placebo administered 4 weeks apart.	Drug: Placebo; Sterile normal saline (0.9% NaCl) given by subcutaneous injection
Placebo Comparator: Part C: MAD Placebo; Chronic HBV, HBeAg positive, subjects received 2 SC doses of placebo administered 4 weeks apart.	Drug: Placebo; Sterile normal saline (0.9% NaCl) given by subcutaneous injection

Outcome Measures

Primary Outcome Measures :

1. Incidence of Adverse Events (AEs) [ Time Frame: Up to 364 days ]
   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.
2. Clinical Assessments Including But Not Limited to Laboratory Test Results [ Time Frame: Up to 336 days ]
   Number of participants with clinically significant abnormalities in vital signs, electrocardiogram (ECG), and laboratory parameters graded by CTCAE v5.0.

Secondary Outcome Measures :

1. Maximum Plasma Concentration (ng/mL) [ Time Frame: 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 ]
   VIR-2218 and metabolite Maximum Concentration in Plasma
2. Time to Reach Maximum Plasma Concentration (h) [ Time Frame: 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 ]
   VIR-2218 and metabolite time of Cmax in Plasma: Median (Inter-Quartile Range Q1-Q3)
3. Area Under the Plasma Concentration Versus Time Curve (ng*h/mL) [ Time Frame: 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 ]
   VIR-2218 and metabolite Area under the curve from time 0 to last measurable Time
4. Apparent Terminal Elimination Half-life (h) [ Time Frame: Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose and Week 1 ]
   VIR-2218 Apparent Elimination Half-life t1/2 in Plasma: Median (Inter-Quartile Range Q1-Q3)
5. Apparent Plasma Clearance (L/h) [ Time Frame: Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose, and Week 1 ]
   VIR-2218 CL/F Apparent plasma clearance
6. Apparent Volume of Distribution (L) [ Time Frame: Part A: predose on Day 1 and at 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h postdose, and Week 1 ]
   VIR-2218 VZ/F apparent volume of distribution
7. Urine %fe 0-24h [ Time Frame: Pooled urine was collected at time interval D1 (0-4 hrs) (4-8 hrs) (8-12 hrs) and (12-24 hrs) ]
   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.
8. Apparent Renal Clearance (CLR/F) [ Time Frame: Pooled Urine was collected at time interval D1 (0-4 hrs) (4-8 hrs) (8-12 hrs) and (12-24 hrs) ]
   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.
9. Maximum Reduction of Serum HBsAg From Baseline [ Time Frame: Up to 112 days ]
   Maximum reduction of serum HBsAg from Day 1 until Week 16.
10. Number of Subjects With Serum HBsAg Loss at Any Time Point [ Time Frame: Up to 336 days ]
    Serum HBsAg loss is defined as quantitative HBsAg < 0.05 IU/mL at two or more consecutive measurements
11. Number of Subjects With Sustained Serum HBsAg Loss for >/= 6 Months [ Time Frame: Up to 336 days ]
    Serum HBsAg loss is defined as quantitative HBsAg < 0.05 IU/mL at two or more consecutive measurements
12. Number of Subjects With Anti-HBs Seroconversion at Any Timepoint [ Time Frame: Up to 336 days ]
    Anti-HBs seroconversion is defined as anti-HBs positivity at two or more consecutive measurements
13. Number of Subjects With HBeAg Loss and/or Anti-HBe Seroconversion at Any Timepoint [ Time Frame: Up to 336 days ]
    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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

Australia, Queensland

Investigative Site

Birtinya, Queensland, Australia, 4575

Australia, Victoria

Investigative Site

Clayton, Victoria, Australia, 3168

Investigative Site

Fitzroy, Victoria, Australia, 3065

Hong Kong

Investigative Site

Hong Kong, Hong Kong

Korea, Republic of

Investigative Site

Busan, Korea, Republic of, 49241

Investigative Site

Seoul, Korea, Republic of, 03080

Investigative Site

Seoul, Korea, Republic of, 05505

New Zealand

Investigative Site

Auckland, New Zealand, 1010

Investigative Site

Auckland, New Zealand, 2025

Thailand

Investigative Site

Bangkok, Thailand, 10330

Investigative Site

Bangkok, Thailand, 10400

Investigative Site

Bangkok, Thailand, 10700

Investigative Site

Hat Yai, Thailand, 90110

Investigative Site

Khon Kaen, Thailand, 40002

Sponsors and Collaborators

Vir Biotechnology, Inc.

Alnylam Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Vir Biotechnology, Inc.:

Study Protocol  [PDF] March 27, 2019

Statistical Analysis Plan  [PDF] December 22, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gupta SV, Fanget MC, MacLauchlin C, Clausen VA, Li J, Cloutier D, Shen L, Robbie GJ, Mogalian E. Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection. Drugs R D. 2021 Dec;21(4):455-465. doi: 10.1007/s40268-021-00369-w. Epub 2021 Nov 6.

• Responsible Party: Vir Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT03672188
• Other Study ID Numbers: VIR-2218-1001
• First Posted: September 14, 2018
• Results First Posted: December 13, 2021
• Last Update Posted: December 13, 2021
• Last Verified: December 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Vir Biotechnology, Inc.:

Hepatitis B Virus; Chronic Hepatitis B; HBV; Hepatitis

Additional relevant MeSH terms:

Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Hepadnaviridae Infections; DNA Virus Infections; Chronic Disease; Disease Attributes; Pathologic Processes