REP 2165-Mg / Replicor - LARVOL DELTA

Compassionate use of REP 2165-Mg in chronic HBV/HDV patients with progressive liver disease and failure to previous pegIFN therapy (EASL-ILC 2024) - "Background and Aims: REP 2165 is an analog of REP 2139 no longer in development with identical activity to REP 2139 in HBV and HDV in clinical studies (achieving HBV functional cure and HDV cure) but with weaker liver accumulation. Although REP 2165-Mg is no longer in clinical development, it demonstrates excellent safety and efficacy against HBV and HDV infection in patients with advanced liver disease with prior pegIFN failure. These results confirm previous clinical data, expand the database of NAP compassionate use and inform on the design of upcoming phase IIA studies."

Clinical • Fibrosis • Hepatitis B • Hepatology • Immunology

An in vivo duck hepatitis B virus model recapitulates key aspects of nucleic acid polymer treatment outcomes in chronic hepatitis B patients. (PubMed, Antiviral Res) - "Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients...REP2139 add-on to entecavir treatment induced a deeper and more sustained virological response compared to entecavir monotherapy...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."

Journal • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

An in vivo duck hepatitis B virus model recapitulates key aspects of nucleic acid polymer treatment outcomes in chronic hepatitis B patients (EASL-ILC 2023) - "Background and Aims: Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients. Subcutaneous administration of NAPs in the DHBV duck model provides a useful tool for in vivo evaluation of NAPs, recapitulating many aspects of this class of compound’s efficacy in CHB patients."

Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

[VIRTUAL] HBsAg, anti-HBs and ALT kinetic characterization during NAP-based combination therapy of HBeAg negative chronic hepatitis B infection (EASL-ILC 2021) - "Background and aims: The interplay among serum hepatitis B surface Antigen (HBsAg), anti-HBs, and alanine aminotransferase (ALT) during combination therapy with REP 2139-Mg or REP 2165- Mg, pegylated interferon alpha-2a (IFN) and tenofovir disoproxil fumarate (TDF) has not been analyzed in detail. Longer (>6 weeks) delay in HBsAg decline may predict non-responders to combination therapy. Concomitant ALT flare and anti-HBs seroconversion with a rapid decline in HBsAg suggest that NAP-based therapy leads to specific anti-HBV immune responses yet to be identified."

Combination therapy • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Establishment of high rates of functional cure of HBeAg negative chronic HBV infection with REP 2139-Mg based combination therapy: Ongoing follow-up results from the REP 401 study (EASL-ILC 2019) - P2; "Background and aims: The REP 401 study (NCT02565719) is assessing the safety and efficacy of REP 2139-Mg (clinical lead) or REP 2165-Mg combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon (pegIFN) in Caucasian patients with HBeAg negative chronic HBV infection. Lead-in TDF therapy in 40 patients was followed by randomization into an experimental group (48 weeks of TDF, pegIFN and REP 2139-Mg or REP 2165-Mg) or an adaptive control group (24 weeks of TDF + pegIFN followed by cross over to 48 weeks of experimental therapy). A finite REP 2139-Mg based combination therapy with TDF and pegIFN is well tolerated and results in a high proportion of patients achieving control of infection not requiring further therapy under current guidelines. Transaminase flares appear therapeutic in nature and may reflect an immune mediated clearance of infected hepatocytes essential in establishing persistent control of chronic HBV infection."

Combination therapy

[VIRTUAL] RAPID MONOPHASIC HBsAg DECLINE DURING NAP-BASED THERAPY PREDICTS FUNCTIONAL CURE (AASLD 2021) - "Background: The interplay among serum HBsAg, anti-HBs, and ALT during combination therapy with the nucleic acid polymers (NAPs) REP 2139-Mg or REP 2165-Mg, pegylated interferon alpha-2a (pegIFN) and tenofovir disoproxil fumarate (TDF) and their association with treatment outcome have not been analyzed in detail . Rapid monophasic HBsAg decline may predict functional cure with NAP-based therapy. Non-monophasic HBsAg kinetic pattern was associated with 100% NPV for achieving functional cure ."

Hepatitis B • Infectious Disease

[VIRTUAL] INTERFERON FREE CLEARANCE OF HDV RNA AND HBsAg SEROCONVERSION IN A CIRRHOTIC SUBJECT WITH CHRONIC HBV / HDV CO-INFECTION WITH TDF AND REP 2165-MG (AASLD 2020) - "The magnesium chelate complex of REP 2165 (REP 2165-Mg) has similar asymptomatic administration and potent antiviral effect as REP 2139-Mg in HBV infection but with reduced accumulation in organs and blood...HDV RNA has been target not detected since Nov 12, 2019 (baseline 11400 IU/mL), HBsAg is currently 1.01 IU/mL (baseline 657 IU/mL) with HBsAg seroconversion (11 mIU/mL)... TDF, REP 2165-Mg and the accompanying transaminase flare were well tolerated in this cirrhotic subject and accompanied by simultaneous clearance of HDV RNA, ~3 log10 reduction of HBsAg with accompanying HBsAg seroconversion. This interferon free regimen may be safe and effective for the treatment of HBV / HDV co-infection in patients with advanced cirrhosis."

Clinical • Cardiovascular • Fibrosis • Gastroenterology • Hepatitis B • Hepatology • Hypertension • Immunology • Infectious Disease • Pneumonia • Portal Hypertension • Respiratory Diseases

Hot News: Hepatitis B Gene Therapy Coming to Age. (PubMed, AIDS Rev) - "...Third, the specificity against HBV is higher than for other experimental agents, as immune modulators that enhance innate immunity, such as TLR agonists (i.e., GS-9620) or checkpoint inhibitors (i.e., nivolumab). Fourth, significant declines in serum hepatitis B surface antigen (HBsAg) are demonstrated during gene therapy, which have never been seen using the most potent polymerase inhibitors (i.e., tenofovir or entecavir)...Exp Op Biol Ther, in press), including ARB-1467 and AB-729 (Arbutus), ARO-HBV (Arrowhead), ALN-HBV (Alnylam), and IONIS-HBVRx (Ionis)...In a pilot study with intravenous REP-2139, investigators from Replicor demonstrated strong reductions in HBV-DNA along with significant drops in HBsAg and seroconversion in some patients...EASL, Paris 2018; abstract FRI-343). An improved NAP, named REP-2165 and subcutaneous administration are currently being tested."

Journal • PD(L)-1 Biomarker • Biosimilar • Gene Therapies • Hepatitis C Virus • Immune Modulation • Immunology • Inflammation

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. (PubMed, Gastroenterology) - P2; "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."

Clinical • Journal

REP 2139-Mg and REP 2165-Mg Combination Therapy in Chronic Hepatitis B Infection (clinicaltrials.gov) - P2; N=40; Completed; Sponsor: Replicor Inc.; Active, not recruiting ➔ Completed; Trial completion date: Aug 2019 ➔ May 2019

Clinical • Combination therapy • Trial completion • Trial completion date

REP 2139-Mg and REP 2165-Mg Combination Therapy in Chronic Hepatitis B Infection (clinicaltrials.gov) - P2; N=40; Active, not recruiting; Sponsor: Replicor Inc.; Trial completion date: Mar 2019 ➔ Aug 2019; Trial primary completion date: Sep 2018 ➔ Jun 2019

Clinical • Combination therapy • Trial completion date • Trial primary completion date

Establishment of High Rates of Functional cure of HBeAg negative chronic HBV with REP 2139-Mg Based Combination Therapy (APASL 2019) - P2; "Introduction: The REP 401 study (NCT02565719) is assessing the safety and efficacy of REP 2139-Mg (clinical lead) or REP 2165-Mg combined with TDF and pegIFN in HBeAg negative chronic HBV infection. A finite REP 2139-Mg based therapy with TDF and pegIFN is well tolerated and restores control of infection requiring no further treatment in 85% of patients and is accompanied by normalization of liver function and reversal of liver inflammation."

Combination therapy