VIR-2218 + Peginterferon Alfa-2a for Chronic Hepatitis B

Overseen By Cams Achondo

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Theophylline, Methadone

Disqualifiers: Pregnancy, HIV, Cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2223

Duration: 36 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Chronic hepatitis B virus (HBV) infection affects 292 million people worldwide; 887,000 die each year from cirrhosis, liver cancer, and related issues. Treatment options are limited. Objective: To test 2 drugs (VIR-2218 and peginterferon) in people with mild or inactive HBV infection. Eligibility: People aged 18 to 65 years with mild or inactive HBV infection. Design: Participants will be screened. They will have blood tests and an eye exam. They will have imaging scans of the liver to check the health of the liver. Participants will be in the study for over 2 years. VIR-2218 is an injection given under the skin of the stomach, upper arm, or thigh. Participants will come to the clinic to receive this injection once a month for 6 months. Peginterferon is also injected under the skin. Participants will have this shot once a week for 6 months. They may either inject themselves at home or come to the clinic to get the injections. Participants will get just the VIR-2218 for 3 months, then both shots for 3 months, then just the peginterferon for 3 months. Participants will have two 3-day stays in the hospital. Tests will include: Liver biopsy. A sample of tissue will be taken from their liver. After the procedure, participants will lie on their right side for 2 hours and then on their back for 4 hours. Fine needle aspiration. A small needle will be used to collect cells from the liver. After the last injection of peginterferon, follow-up visits will continue in the outpatient clinic every 4 to 12 weeks.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using oral theophylline, methadone, or have had any treatment for HBV in the last 24 weeks.

What data supports the effectiveness of the drug Peginterferon Alfa-2a for treating chronic hepatitis B?

Research shows that Peginterferon Alfa-2a can lead to seroconversion (a change from a negative to a positive blood test result) in up to 36% of patients with chronic hepatitis B, indicating its potential effectiveness in treating the condition. ^{1 2 3 4 5}

What is known about the safety of Peginterferon Alfa-2a in humans?

Peginterferon Alfa-2a has been studied for safety in patients with chronic hepatitis B and hepatitis C, showing it can be used safely, though the dose may affect the safety profile. It has been evaluated in various studies, including those with different doses, and is generally considered safe for human use in these conditions. ^{5 6 7 8 9}

How is the drug VIR-2218 + Peginterferon Alfa-2a unique for treating chronic hepatitis B?

The combination of VIR-2218 and Peginterferon Alfa-2a is unique because it combines a novel small interfering RNA (siRNA) therapy, VIR-2218, which targets the hepatitis B virus at the genetic level, with Peginterferon Alfa-2a, a long-used antiviral that boosts the immune response. This dual approach aims to enhance treatment effectiveness compared to using Peginterferon Alfa-2a alone. ^{1 3 10 11 12}

Research Team

Marc G Ghany, M.D.

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eligibility Criteria

Adults aged 18 to 65 with mild or inactive chronic hepatitis B can join this trial. They must have specific levels of HBV DNA and antigens, normal liver enzyme levels, and agree to use effective contraception. Those who are pregnant, breastfeeding, have other liver infections or diseases like cirrhosis or cancer, recent treatments for HBV, certain medical conditions or drug use that could interfere with the study cannot participate.

Inclusion Criteria

I am between 18 and 65 years old.

You have tested negative for the hepatitis B e antigen.

Your Hepatitis B Virus DNA levels have been less than 10,000 IU/mL on two separate occasions at least 24 weeks apart, with the second measurement taken at time of screening.

Exclusion Criteria

I do not have other liver conditions like hemochromatosis or alcoholic liver disease.

Presence of conditions that, in the opinion of the investigators, would not allow the patient to be followed in the current study

I am allergic to specific genetic therapies or interferon treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive VIR-2218 injections once a month for 3 months, followed by combination treatment with peginterferon alfa-2a weekly for 3 months, and then peginterferon alfa-2a alone weekly for another 3 months

36 weeks

Monthly visits for VIR-2218, weekly visits or self-administration for peginterferon

Follow-up

Participants are monitored for safety and effectiveness after treatment

84 weeks

Visits every 4 to 12 weeks

Treatment Details

Interventions

• Peginterferon Alfa-2a
• VIR-2218

Trial Overview The trial is testing VIR-2218 and peginterferon alfa-2a in people with chronic hepatitis B over a period of more than two years. Participants will receive monthly injections of VIR-2218 for six months and weekly shots of peginterferon for six months at home or in the clinic. The study includes hospital stays for liver biopsies and other tests.

Participant Groups

Group I: Single arm, open label Experimental Treatment 1 Intervention

open label

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

Findings from Research

In a study of 102 chronic hepatitis B patients treated with peginterferon-alpha 2a, both HBeAg-positive and HBeAg-negative groups showed similar rates of response to the therapy, indicating its efficacy across different patient types.

For HBeAg-positive patients, higher serum ALT levels (greater than 3 times the upper limit of normal) and more severe liver inflammation (grades G3 and G4) were associated with better therapeutic responses, suggesting these factors could help predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Responses of peginterferon-alpha 2a antiviral therapy in chronic hepatitis B patients]. Zhong, RX., Lai, CY., Liang, D., et al.[2018]

A new scoring system was developed to predict the likelihood of hepatitis B surface antigen (HBsAg) clearance in patients with chronic hepatitis B (CHB) treated with peginterferon alfa-2b, based on four key clinical variables: age, baseline HBsAg level, HBsAg level decline at week 12, and alanine aminotransferase ratio at week 12.

The scoring system demonstrated high sensitivity (86.49%) and specificity (72.16%), effectively categorizing patients into different likelihoods of achieving HBsAg clearance, which can aid in clinical decision-making for CHB treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A simple-to-use score system for predicting HBsAg clearance to peginterferon alfa-2b in nucleoside analogs-experienced chronic hepatitis B patients. Song, K., Zeng, D., Zheng, Y., et al.[2023]

In a study of 85 HBeAg-positive chronic hepatitis B patients with poor response to peginterferon alfa-2a, adding adefovir significantly improved sustained virological response rates from 31.4% to 73.5%.

Patients receiving adefovir also showed higher rates of HBeAg loss (55.9% vs. 19.6%) and seroconversion (41.2% vs. 13.7%), indicating that adefovir enhances the effectiveness of peginterferon therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained efficacy of adefovir add-on therapy in chronic hepatitis B patient with a poor virological response to peginterferon alfa. Wang, YX., Zheng, SM., Zhang, Y., et al.[2018]

In a study of 218 treatment-naive Chinese patients with HBeAg-positive chronic hepatitis B, the combination of pegylated interferon alfa-2a and entecavir did not show superior efficacy compared to peg-IFN monotherapy, with similar rates of HBeAg seroconversion across all treatment groups.

All treatment groups achieved significant reductions in HBeAg levels, but while the ETV add-on showed greater reductions in hepatitis B virus DNA during treatment, these effects were not sustained after treatment ended, indicating that the optimal treatment strategy remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B. Xie, Q., Zhou, H., Bai, X., et al.[2022]

In a study of 57 patients with chronic hepatitis B who did not achieve satisfactory results from entecavir treatment, those who received peginterferon alfa-2a therapy had significantly higher rates of HBeAg clearance (40.7% vs. 16.7%) and seroconversion (37.0% vs. 13.3%) after 48 weeks compared to those who continued on entecavir.

The peginterferon alfa-2a group also showed a significant reduction in HBsAg levels, indicating a potential benefit in managing chronic hepatitis B in patients who previously did not respond well to entecavir.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[HBeAg seroconversion achieved by sequential peginterferon alfa-2a therapy in chronic hepatitis B patients with unsatisfactory end point following entecavir treatment]. Chen, XF., Chen, XP., Ma, XJ., et al.[2018]

In a study of 43 HBeAg-positive chronic hepatitis B patients who had previously not responded to other treatments, peginterferon alpha-2a demonstrated efficacy with an HBeAg seroconversion rate increasing from 4.65% at the end of treatment to 11.62% after 24 weeks of follow-up.

The treatment also achieved viral suppression below 100,000 copies/mL in 23.25% of patients at the end of treatment, with ALT normalization occurring in 20.9% of patients, indicating that peginterferon alpha-2a can be a beneficial option for difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of peginterferon alpha-2a (40KD) in HBeAg-positive chronic hepatitis B patients. Caruntu, FA., Streinu-Cercel, A., Gheorghe, LS., et al.[2018]

In a study involving 2,940 patients with HCV, high-dose peginterferon alfa-2a (360 μg/week) did not significantly increase serious adverse events or treatment discontinuations compared to the standard dose (180 μg/week) during the first 12 weeks of treatment.

While more patients on the high-dose experienced weight loss as an adverse event (7.7% vs. 3.3%), the overall safety profile was similar, indicating that high doses can be managed effectively without increasing safety risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies. Marcellin, P., Roberts, SK., Reddy, KR., et al.[2018]

In a study of 298 inactive hepatitis B virus carriers, peginterferon alpha (peg-IFN-α) monotherapy led to a high rate of hepatitis B surface antigen (HBsAg) clearance at 72 weeks, with 47.9% achieving clearance compared to only 1.9% in the control group.

The treatment was generally well tolerated, with only five participants discontinuing due to adverse events, indicating that peg-IFN-α is a safe option for managing inactive HBV carriers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers. Wu, F., Lu, R., Liu, Y., et al.[2021]

In a study of 72 patients with chronic hepatitis B, PEG-IFN alpha-2a demonstrated significantly higher rates of HBeAg negative cases and lower HBV DNA levels compared to the control group receiving standard interferon alpha after 48 weeks of treatment.

PEG-IFN alpha-2a not only effectively inhibited HBV replication but also showed lasting effects after treatment, with no significant changes in liver inflammation or fibrosis, and was well tolerated by patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pegylated interferon alpha 2a in treating chronic hepatitis B patients]. Tian, YL., Zhao, W., Shen, L., et al.[2018]

In a study of 160 HBeAg-negative chronic hepatitis B patients treated with pegylated interferons, 25% achieved a sustained virologic response (SVR), indicating the treatment's efficacy.

Key predictors for achieving SVR included a decline of 1 log10 IU/mL in viral load after the first month and a serum HBV DNA level below 2,000 IU/mL by the third month of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of response to pegylated interferon treatment in HBeAg-negative patients with chronic hepatitis B. Guclu, E., Tuna, N., Karabay, O., et al.[2018]

In a study of 205 HBeAg-positive chronic hepatitis B patients treated with peginterferon alfa, specific IL28B genotypes were found to significantly influence the likelihood of achieving HBeAg seroconversion, with an odds ratio of 3.16 for the AA genotype compared to AG/GG.

The IL28B genotype was also associated with long-term outcomes, showing a 2.14 times higher probability of HBeAg seroconversion and a 3.47 times higher chance of hepatitis B surface antigen clearance for the AA genotype, indicating its potential role as a biomarker for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Sonneveld, MJ., Wong, VW., Woltman, AM., et al.[2023]

In a study of 35 HBeAg-negative, genotype D-naive patients treated with PEG-IFN α-2a for 48 weeks, a sustained virologic response (SVR) was achieved in 23% of patients at a HBV DNA cutoff of <400 copies/ml, and in 57% at a more sensitive cutoff of <20,000 copies/ml.

Key predictors for achieving SVR included low body weight, high alanine aminotransferase (ALT) levels, low HBV DNA, and low triglyceride levels, suggesting that these factors could help identify patients more likely to respond to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of peginterferon α-2a and predictors of response in HBeAg-negative, genotype D-naive patients. Al-Ashgar, HI., Khan, MQ., Aljumah, A., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

[Responses of peginterferon-alpha 2a antiviral therapy in chronic hepatitis B patients]. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A simple-to-use score system for predicting HBsAg clearance to peginterferon alfa-2b in nucleoside analogs-experienced chronic hepatitis B patients. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Sustained efficacy of adefovir add-on therapy in chronic hepatitis B patient with a poor virological response to peginterferon alfa. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[HBeAg seroconversion achieved by sequential peginterferon alfa-2a therapy in chronic hepatitis B patients with unsatisfactory end point following entecavir treatment]. [2018]

6. Romania pubmed.ncbi.nlm.nih.gov

Efficacy and safety of peginterferon alpha-2a (40KD) in HBeAg-positive chronic hepatitis B patients. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers. [2021]

9. China pubmed.ncbi.nlm.nih.gov

[Pegylated interferon alpha 2a in treating chronic hepatitis B patients]. [2018]

10. Italy pubmed.ncbi.nlm.nih.gov

Predictors of response to pegylated interferon treatment in HBeAg-negative patients with chronic hepatitis B. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Efficacy of peginterferon α-2a and predictors of response in HBeAg-negative, genotype D-naive patients. [2021]