An Open-label, Randomized, Active Controlled, Parallel Comparison Study of the Safety and Efficacy of REP 2139-Mg in Combination With Pegasys® and Viread® and REP 2165-Mg in Combination With Pegasys® and Viread® in Patients With HBeAg Negative Chronic Hepatitis B

NAPs have been previously shown to clear serum hepatitis B virus surface antigen (HBsAg) both preclinically (in duck HBV infected ducks) and in human patients. REP 2139-Ca mediated HBsAg clearance acts synergistically with immunotherapeutic agent pegylated interferon-alpha 2a to restore host immunological control of HBV infection. REP 2165 is a version of REP 2139 which has been shown preclinically to retain antiviral activity with lower accumulation in the liver.
Both REP 2139 and REP 2165 used in this protocol are formulated as magnesium chelate complexes, which improve their administration tolerability. This open label, randomized and controlled study will examine the safety and efficacy of REP 2139-Mg and REP 2165-Mg therapy in patients with HBeAg negative chronic hepatitis B when used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha-2a.

Start Date01 Mar 2016

Sponsor / Collaborator

Replicor, Inc.

100 Clinical Results associated with REP-2165

100 Translational Medicine associated with REP-2165

100 Patents (Medical) associated with REP-2165

Literatures (Medical) associated with REP-2165

01 Apr 2024·Antiviral Research

An in vivo duck hepatitis B virus model recapitulates key aspects of nucleic acid polymer treatment outcomes in chronic hepatitis B patients

Article

Author: Symons, Julian A ; Gohil, Vikrant ; Acosta Sanchez, Abel ; Chanda, Sushmita ; Debing, Yannick ; Lin, Tse-I ; Kum, Dieudonné Buh ; Paeshuyse, Jan ; Blatt, Lawrence M ; Jekle, Andreas ; Vanrusselt, Hannah ; Rajwanshi, Vivek ; Ebwanga, Ebanja Joseph ; Silva de Oliveira, Daniel Apolônio ; Smith, David B ; Thatikonda, Santhosh Kumar ; Hong, Jin ; Merckx, Wouter ; Kariuki, Christopher Kinyanjui ; Bashir, Shahbaz ; Degrauwe, Lars ; Beigelman, Leonid ; Raboisson, Pierre

Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients. A subset of patients achieve functional cure, whereas the others exhibit a moderate response or are non-responders. NAP efficacy has been difficult to recapitulate in animal models, with the duck hepatitis B virus (DHBV) model showing some promise but remaining underexplored for NAP efficacy testing. Here we report on an optimized in vivo DHBV duck model and explore several characteristics of NAP treatment. REP2139 was efficacious in reducing DHBV DNA and DHBsAg levels in approximately half of the treated ducks, whether administered intraperitoneally or subcutaneously. Intrahepatic or serum NAP concentrations did not correlate with efficacy, nor did the appearance of anti-DHBsAg antibodies. Furthermore, NAP efficacy was only observed in experimentally infected ducks, not in endogenously infected ducks (vertical transmission). REP2139 add-on to entecavir treatment induced a deeper and more sustained virological response compared to entecavir monotherapy. Destabilized REP2165 showed a different activity profile with a more homogenous antiviral response followed by a faster rebound. In conclusion, subcutaneous administration of NAPs in the DHBV duck model provides a useful tool for in vivo evaluation of NAPs. It recapitulates many aspects of this class of compound's efficacy in CHB patients, most notably the clear division between responders and non-responders.

01 Mar 2021·Gastroenterology

Clarifying the Chemistry, Activity, and Safety of Nucleic Acid Polymers

Letter

Author: Vaillant, Andrew

In the editorial entitled ''Nucleic Acid Polymers are Effective in Targeting Hepatitis B Surface Antigen, But More Trials Are Needed'' commenting on the recent publication of the REP 401 study in Gastroenterol., ''Safety and Efficacy of 48 Wk REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy,'' it is important to clarify several statements that are at opposition to or inconsistent with the large body of published data on nucleic acid polymers (NAPs) to date.The target(s) of NAPs driving their activity are of great interest but a NAP-hepatitis B surface antigen (HBsAg) interaction as suggested in the editorial has been excluded.

01 Jun 2020·GastroenterologyQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Bazinet, Michel ; Pântea, Victor ; Dittmer, Ulf ; Moscalu, Iurie ; Placinta, Gheorghe ; Iarovoi, Liviu ; Krawczyk, Adalbert ; Cebotarescu, Valentin ; Cojuhari, Lilia ; Jimbei, Pavlina ; Smesnoi, Valentina ; Musteata, Tatiana ; Jucov, Alina ; Vaillant, Andrew

BACKGROUND & AIMSNucleic 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.METHODSFollowing 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.RESULTSLevels 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.CONCLUSIONSIn 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.

100 Deals associated with REP-2165

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B, Chronic	Phase 2	MD	Replicor, Inc.	01 Mar 2016
Hepatitis D	Phase 2	CA	Replicor, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02565719 (Pubmed) Manual	Phase 2	Hepatitis B	40	TDF + pegIFN + REP 2139-Mg or REP 2165-Mg (NAP groups)	(mhgjsgncok) = 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. pfvcmzffdh (avmyyrvvzx ) View more	Positive	06 Mar 2020
				TDF + pegIFN

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