Gastroenterology

Gastroenterology

Volume 158, Issue 8, June 2020, Pages 2180-2194
Gastroenterology

Original Research
Full Report: Clinical—Liver
Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

https://doi.org/10.1053/j.gastro.2020.02.058Get rights and content

Background & Aims

Nucleic acid polymers (NAPs) inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles. We performed an open-label, phase 2 study of the safety and efficacy of the NAPs REP 2139 or REP 2165 combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (pegIFN) in patients with chronic HBV infection who were negative for hepatitis B e antigen.

Methods

Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF + pegIFN + REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF + pegIFN) followed by 48 weeks of experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. Primary outcomes were the safety and tolerability of REP 2139-Mg or REP 2165-Mg in combination with TDF + pegIFN compared with TDF + pegIFN alone through the first 48 weeks of therapy and subsequently throughout 48 weeks of NAP-based combination therapy (treatment weeks 24–72 in the experimental group and weeks 48–96 in the control group). Secondary outcomes were reductions in hepatitis B surface antigen (HBsAg) in control and experimental groups over the first 48 weeks of the study and throughout 48 weeks of combination therapy and virologic control (HBsAg positive, HBV DNA below 2000 IU/mL, normal level of alanine aminotransferase) or functional cure (HBsAg below 0.05 IU/mL, HBV DNA target not detected, normal level of alanine aminotransferase) after removal of all therapy.

Results

Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. PegIFN-induced thrombocytopenia (P = .299 vs controls) and neutropenia (P = .112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P < .001 vs controls) and greater (P = .002 vs controls) in the NAP groups (but did not produce symptoms), correlated with initial decrease in HBsAg, and normalized during therapy and follow-up. During the first 24 weeks of TDF and pegIFN administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P < .001 vs control) and HBsAg seroconversion (P = .046 vs control). At the time patients completed the TDF + pegIFN + NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants (all with seroconversion up to 233,055 mIU/mL). During 48 weeks of treatment-free follow-up, virologic control persisted in 13 of 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion. One participant had a viral rebound during follow-up with hepatic decompensation and was placed on TDF therapy.

Conclusions

In a phase 2 randomized trial, we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy. Clinicaltrials.gov no: NCT02565719.

Section snippets

Study Design

The REP 401 study is an open-label, randomized, controlled, phase 2 study assessing the safety and efficacy of addition of either REP 2139-Mg or REP 2165-Mg (250-mg intravenous infusion every week) to a backbone therapy of TDF (Viread, 300 mg oral every day) and pegIFN (Pegasys, 180 μg subcutaneous every week). Calculation of statistical power in the REP 401 study was based on historical HBsAg response observed in previous trials with NAPs vs HBsAg response observed with pegIFN or pegIFN + NUCs

Participants

Forty noncirrhotic participants with chronic HBeAg-negative HBV infection (HBsAg >1000 IU/mL and HBV DNA >2000 IU/mL) were enrolled between September 2015 and June 2016 with complete results available in April 2019. Group characteristics at baseline and at randomization are shown in Table 1 and disposition of participants from recruitment to the end of follow-up is presented in Supplementary Figure 1.

Adverse Events During the Conduct of the Study

Unrelated serious adverse events (AEs) included 1 case of pneumonia, which resolved within 2

Discussion

Administration tolerability of REP 2139-Mg and REP 2165-Mg in the REP 401 study was improved over REP 2139-Ca from previous studies,9,12 indicating that subcutaneous administration of REP 2139-Mg or REP 2165-Mg will also be well tolerated. Delivery of NAPs to the liver occurs with subcutaneous administration in vivo22 and the safety and efficacy of subcutaneous administration of REP 2139-Mg will be examined in future studies.

All PS-ONs are accompanied by mild but stable depression of platelet

Acknowledgments

The conduct of the study was supported by Replicor Inc. The authors thank Dr Sergiu Merioara for his assistance during the study.

CRediT Authorship Contributions

Michel Bazinet, MD (Conceptualization: Equal; Methodology: Supporting); Victor Pântea, MD (Investigation: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting); Gheorghe Placinta, MD (Investigation: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting); Iurie Moscalu, MD (Investigation: Lead; Writing –

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    Conflict of interest These authors disclose the following: Michel Bazinet and Andrew Vaillant are employees and shareholders of Replicor Inc. and inventors of patents assigned to Replicor. The Institute for Virology received compensation from Replicor for performing virologic diagnostics. The remaining authors disclose no conflicts.

    Funding Supported by Replicor Inc.

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