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.

Tracking Information

• First Submitted Date: September 11, 2018
• First Posted Date: September 14, 2018
• Results First Submitted Date: October 20, 2021
• Results First Posted Date: December 13, 2021
• Last Update Posted Date: December 13, 2021
• Actual Study Start Date: November 14, 2018
• Actual Primary Completion Date: September 3, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 9, 2021)

• 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.
• 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.

Original Primary Outcome Measures (submitted: September 13, 2018)

• Number of subjects with Adverse Events as assessed by CTCAE v5.0 [ Time Frame: Up to 364 days ]
• Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings [ Time Frame: Up to 112 days post-dose ]

Current Secondary Outcome Measures (submitted: December 9, 2021)

• 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
• 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)
• 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
• 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)
• 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
• 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
• 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.
• 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.
• Maximum Reduction of Serum HBsAg From Baseline [ Time Frame: Up to 112 days ]
  Maximum reduction of serum HBsAg from Day 1 until Week 16.
• 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
• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: September 13, 2018)

• PK: maximum plasma concentration (ng/mL) [ Time Frame: Up to 7 days post-dose ]
• PK: time to reach maximum plasma concentration (h) [ Time Frame: Up to 7 days post-dose ]
• PK: area under the plasma concentration versus time curve (ng*h/mL) [ Time Frame: Up to 7 days post-dose ]
• PK: percent of area extrapolated from AUC last to infinity (%) [ Time Frame: Up to 7 days post-dose ]
• PK: apparent terminal elimination half-life (h) [ Time Frame: Up to 7 days post-dose ]
• PK: apparent plasma clearance (L/h) [ Time Frame: Up to 7 days post-dose ]
• PK: apparent volume of distribution (L) [ Time Frame: Up to 7 days post-dose ]
• PK (healthy volunteers): fraction eliminated in the urine (mg) [ Time Frame: Up to 7 days post-dose ]
• PK (healthy volunteers): renal clearance (L/h) [ Time Frame: Up to 7 days post-dose ]
• CHB: Maximum reduction of serum HBsAg from baseline [ Time Frame: Up to 336 days ]
• CHB: Number of subjects with serum HBsAg loss at any time point [ Time Frame: Up to 336 days ]
• CHB: Number of subjects with sustained serum HBsAg loss for >/= 6 months [ Time Frame: Up to 336 days ]
• CHB: Number of subjects with anti-HBs seroconversion at any timepoint [ Time Frame: Up to 336 days ]
• CHB: Number of subjects with HBeAg loss and/or anti-HBe seroconversion at any timepoint [ Time Frame: Up to 336 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of VIR-2218 in Healthy Subjects and Patients With Chronic Hepatitis B
• Official Title: A Phase 1/2, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of VIR-2218

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Hepatitis B

Intervention

• Drug: VIR-2218
  VIR-2218 given by subcutaneous injection
• Drug: Placebo
  Sterile normal saline (0.9% NaCl) given by subcutaneous injection

Study Arms

• Experimental: Part A: SAD VIR-2218 50 mg
  Healthy subjects received a single dose of VIR-2218 of 50 mg administered SC
  Intervention: Drug: VIR-2218
• Experimental: Part A: SAD VIR-2218 100 mg
  Healthy subjects received a single dose of VIR-2218 of 100 mg administered SC
  Intervention: Drug: VIR-2218
• Experimental: Part A: SAD VIR-2218 200 mg
  Healthy subjects received a single dose of VIR-2218 of 200 mg administered SC
  Intervention: Drug: VIR-2218
• Experimental: Part A: SAD VIR-2218 400 mg
  Healthy subjects received a single dose of VIR-2218 of 400 mg administered SC
  Intervention: Drug: VIR-2218
• Experimental: Part A: SAD VIR-2218 600 mg
  Healthy subjects received a single dose of VIR-2218 of 600 mg administered SC
  Intervention: Drug: VIR-2218
• Experimental: Part A: SAD VIR-2218 900 mg
  Healthy subjects received a single dose of VIR-2218 of 900 mg administered SC
  Intervention: Drug: VIR-2218
• Placebo Comparator: Part A: SAD Placebo
  Healthy subjects received a single dose of placebo administered SC
  Intervention: Drug: Placebo
• 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.
  Intervention: Drug: VIR-2218
• 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.
  Intervention: Drug: VIR-2218
• 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.
  Intervention: Drug: VIR-2218
• 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.
  Intervention: Drug: VIR-2218
• 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.
  Intervention: Drug: VIR-2218
• 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.
  Intervention: Drug: VIR-2218
• Placebo Comparator: Part B: MAD Placebo
  Chronic HBV, HBeAg negative, subjects received 2 SC doses of placebo administered 4 weeks apart.
  Intervention: Drug: Placebo
• Placebo Comparator: Part C: MAD Placebo
  Chronic HBV, HBeAg positive, subjects received 2 SC doses of placebo administered 4 weeks apart.
  Intervention: Drug: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 17, 2021): 82
• Original Estimated Enrollment (submitted: September 13, 2018): 104
• Actual Study Completion Date: September 3, 2020
• Actual Primary Completion Date: September 3, 2020 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Hong Kong, Korea, Republic of, New Zealand, Thailand

Administrative Information

• NCT Number: NCT03672188
• Other Study ID Numbers: VIR-2218-1001
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Vir Biotechnology, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Vir Biotechnology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Alnylam Pharmaceuticals
• Investigators: Not Provided
• PRS Account: Vir Biotechnology, Inc.
• Verification Date: December 2021