Combination Treatment With REP 2139-Ca and Pegasys in Patients With Chronic Hepatitis B

Phase 2

Completed

• Conditions: Hepatitis B, Chronic
• Interventions: Drug: REP 2139-Ca; Drug: pegylated interferon; Drug: entecavir

• Registration Number: NCT02726789
• Lead Sponsor: Replicor Inc.

Brief Summary

The REP 201 protocol is a small exploratory study assessing the antiviral effects and tolerability of REP 2139-Ca when used with a full course of pegylated interferon (48 weeks) in treatment naive patients or in patients already receiving entecavir and continuing entecavir with treatment.

Detailed Description

Chronic hepatitis B is a long term condition caused by infection of the body with the hepatitis B virus (HBV). This infection often results in inflammation or scarring of the liver and can eventually lead to liver cirrhosis and liver failure. These infections are also one of the major causes of the development of hepatocellular carcinoma (liver cancer).

Although some drugs have been approved to treat chronic hepatitis B infections, they do not provide a complete cure except in rare cases (a cure generally means that a person loses the hepatitis B virus from the blood and the liver and develops a durable immunological control of subsequent HBV infection). However, these drugs do significantly decrease the risk of liver damage and liver cancer arising from the presence of a chronic liver infection by slowing or stopping the production of infectious virus. Thus the primary problem associated with currently available drugs is the lack of clearance of the virus from the hepatocytes which necessitates long term treatment with these drugs. There is clearly a need to identify new drugs that can benefit patients with chronic hepatitis B infections. Nucleic acid-based polymers (NAPs) are a new class of broad-spectrum antiviral compounds which act against HBV infection by blocking the release of the surface antigen protein (HBsAg) from infected hepatocytes.

Current interim data analysis from the REP 102 assessing the activity of the NAP REP 9AC' (REP 2139, given as a calcium chelate complex \[REP 2139-Ca\]) in patients with chronic HBV infection indicates the following:

1. REP 2139-Ca is generally well tolerated and patients tolerate short term combined treatment (13-26 weeks) of pegylated interferon and / or thymosin alpha

2. REP 2139-Ca has achieved serum HBsAg reduction or clearance 9 of 9 patients receiving combined therapy.

3. Appearance of substantial titers of serum anti-HBs occur with the addition of immunotherapy.

4. After all treatment is withdrawn, 8 / 9 patients achieved HBV DNA \< 116 copies / ml (LLOQ of the Roche Cobas platform) and sustained suppression of viremia (HBV DNA \< 1000 cpm, HBsAg \< 1 IU / ml) for a period of greater than 1 year was observed in four patients.

This exploratory study is designed to examine if REP 2139-Ca can be safely combined with a full course of pegylated interferon in treatment naive patients and in patients with previous and continuing therapy with entecavir and that similar antiviral effects can be observed as in the previous REP 101 and 102 protocols.

Study Timeline

• Study Start: 2012-10
• Study First Submitted: 2016-03-18
• Study First Submitted QC: 2016-03-29
• Study First Posted: 2016-04-04
• Primary Completion: 2016-09
• Study Completion: 2016-12
• Status Verified: 2017-02
• Results First Submitted: 2018-08-27
• Results First Submitted QC: 2019-04-17
• Last Update Submitted: 2019-04-17
• Results First Posted: 2019-05-08
• Last Update Posted: 2019-05-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 5

Inclusion Criteria

• Age between 18 and 55
• HBsAg+
• Anti-HBs negative
• Patients currently receiving nucleoside based HBV polymerase inhibitors may be included in the study at the discretion of the Principle Investigator.
• HIV / hepatitis C / hepatitis delta virus negative
• Fibrosis with compensation (as determined by Fibroscan and liver enzymes)
• Non cirrhotic
• No known active cytomegalovirus infection
• Willingness to utilize adequate contraception while being treated with REP 9AC' and for 6 months following the end of treatment
• Adequate venous access allowing weekly intravenous therapies and blood tests

Exclusion Criteria

• Evidence of cardiovascular disease
• Autoimmune hepatitis
• Presence of Wilson's disease
• Presence of severe NAFLD
• Evidence of any other co-existent liver disease
• Anti-nuclear antibody positive
• Ultrasonograph of hepato-biliary system: positive for cirrhosis of liver
• A history of ascites, hepatic encephalopathy or variceal hemorrhage
• Body weight > 100 kg
• Platelet count < 75,000, polymorphonuclear cell count < 1,500 or hematocrit < 33%
• alpha feto protein > 100 ng/ml or the presence of a hepatic mass suggestive of hepatocellular carcinoma .
• Bilirubin > 2.5 mg/dl
• Creatinine > 1.5 mg/dl
• Platelet count < 75,000 / cmm
• Serum albumin < 35 mg/ml
• Poorly controlled diabetes mellitus
• Another serious medical disorder
• A serious psychiatric disorder
• Uncontrolled hypertension
• A history of alcohol abuse within the last year
• The use of illicit drugs within the past two years
• Inability to provide informed consent
• Positive pregnancy test
• Breastfeeding
• Inability or unwillingness to provide weekly blood samples
• Poor venous access making IV infusion too difficult

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental	REP 2139-Ca	Patients either treatment naive or with HBV DNA controlled with entecavir receive REP 2139-Ca in combination with pegylated interferon. Only patients receiving entecavir at enrollment continue to receive entecavir during treatment in the study.
Experimental	pegylated interferon	Patients either treatment naive or with HBV DNA controlled with entecavir receive REP 2139-Ca in combination with pegylated interferon. Only patients receiving entecavir at enrollment continue to receive entecavir during treatment in the study.
Experimental	entecavir	Patients either treatment naive or with HBV DNA controlled with entecavir receive REP 2139-Ca in combination with pegylated interferon. Only patients receiving entecavir at enrollment continue to receive entecavir during treatment in the study.

Primary Outcome Measures

Name	Time	Method
Number of Patients Experiencing Treatment Emergent Laboratory Test Abnormalities or Adverse Events.	48 weeks (treatment)	To record side effects, symptoms and adverse effects of exposure to REP 2139-Ca when combined pegylated interferon.

Secondary Outcome Measures

Name	Time	Method
Number of Patients Experiencing Reductions in Serum HBsAg	48 weeks (treatment)	To assess antiviral activity of REP 2139-Ca when combined with pegylated interferon on serum HBsAg.
Number of Patients Experiencing Reductions in Serum HBV DNA	48 weeks (treatment)	To assess antiviral activity of REP 2139-Ca when combined with pegylated interferon on serum HBV DNA.
Number of Patients Experiencing Serum Anti-HBs > 10 mIU / ml	48 weeks (treatment)	To assess antiviral activity of REP 2139-Ca when combined with pegylated interferon on anti-HBsAg antibody titer.