Update on safety and efficacy in the REP 401 protocol: REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated Interferon alpha-2a in treatment naïve caucasian patients with chronic HBeAg negative HBV infection

Bazinet, Michel; Pântea, Victor; Plăcintă, Gheorghe; Moscalu, Iurie; Cebotarescu, Valentin; Cojuhari, Lilia; Jimbei, Pavlina; Iarovoi, Liviu; Smeşnoi, Valentina; Musteata, Tatiana; Jucov, Alina; Krawczyk, Adalbert; Vaillant, Andrew

doi:10.1016/s0168-8278(17)30821-8

Cited by 19 publications

(27 citation statements)

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“…The clearly reduced organ accumulation and trough plasma concentrations of REP 2165 with chronic exposure relative to REP 2139 demonstrated in this study are important performance improvements that could allow REP 2165 to be safely used in patients with heavy metal exposure because the reduced organ accumulation and plasma concentration observed with this NAP in cynomolgus monkeys is expected to translate well to humans 30 . Additionally, REP 2139 and REP 2165 were comparably well tolerated in cynomolgus monkeys with chronic exposure, consistent with the interim results of the REP 401 protocol recently presented 4 . Importantly, no effects on alanine transaminase (ALT) or aspartate transaminase (AST) were observed in monkeys, even at doses substantially higher than those used clinically, further supporting the observations that the transaminase flares observed with NAP therapy in HBV- or HBV/HDV-infected patients are therapeutic in nature and not directly caused by exposure to NAPs 2, 3, 4…”

Section: Discussionsupporting

confidence: 86%

“…Their activity is driven by interactions with large amphipathic protein domains important for viral replication and relies only on the length of the oligonucleotide (optimally 40-mer) and the presence of phosphorothioation 1 . The NAP REP 2139 is currently in clinical development for the treatment of chronic hepatitis B (HBV) infection and HBV/hepatitis delta (HDV) co-infection and has shown a unique ability to clear the HBV surface antigen (HBsAg) from the blood in clinical trials 2, 3, 4. This activity is driven by the ability of NAPs to block the release of HBsAg from infected hepatocytes, likely by interfering with the assembly of HBV subviral particles 5 by an as yet undefined mechanism.…”

Section: Introductionmentioning

confidence: 99%

“…The symptoms consistent with heavy metal intoxication occurring with REP 2139 in these patients are likely caused by liberation of heavy metals from the bones during the compensatory response to enhanced mineral elimination. These symptoms have been absent with chronic REP 2139 administration in recent clinical trials where patients had negligible heavy metal exposure 3, 4. Despite the obvious clinical benefits of REP 2139 therapy, the potential need to exclude patients with heavy metal exposure, as well as the likely significant mineral elimination, which could also affect immune function, suggests additional optimization of REP 2139 to reduce its systemic exposure with chronic dosing would be beneficial for patients in locales where heavy metal exposure is pervasive.…”

Section: Introductionmentioning

confidence: 99%

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Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy

Roehl¹,

Seiffert²,

Brikh

et al. 2017

Molecular Therapy - Nucleic Acids

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REP 2139 is a nucleic acid polymer (NAP) currently under clinical development for chronic hepatitis B (HBV) therapy. This preclinical study investigated different REP 2139 analogs that would display reduced accumulation in the serum and tissues, while retaining an antiviral effect against HBV infection. REP 2139 analogs were evaluated in human plasma, CD-1 mice, cynomolgus monkeys, and Pekin ducks. Discrete ribose transformation to 2′OH in selected riboadenosines resulted in a slow degradation in acidified human plasma that plateaued after 48 hr. REP 2165, a REP 2139 analog containing three unmodified riboadenosines equally spaced throughout the polymer, showed similar plasma clearance and tissue distribution as REP 2139 in mice and cynomolgus monkeys after a single dose. Interestingly, after repeated administration, accumulation of REP 2165 in plasma and organs was reduced, indicating a dramatically faster rate of clearance from organs after therapy was ended in both species. Both REP 2139 and REP 2165 were well tolerated at clinically relevant doses, with no alterations in liver, kidney, or hematological function. In chronic duck HBV (DHBV) infection, REP 2165 displayed significantly reduced liver accumulation after repeated dosing but retained antiviral activity similar to REP 2139. These results indicate the therapeutic potential of REP 2165 against chronic HBV infection in patients is similar to REP 2139, but with significantly reduced drug accumulation and improved tissue clearance.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy

Roehl¹,

Seiffert²,

Brikh

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Based on the chemical modifications present in REP 2006 and REP 2055 their intermediate stability relative to REP 2139 and REP 216525 will result in liver accumulation for these NAPs within the limits observed for REP 2139 and REP 2165 but will have the same rapid clearance characteristics from the plasma. In all clinical assessments of REP 2055, REP 2139 and REP 2165 performed to date, substantial HBsAg reductions and or clearance is achieved well within 3 months52829 well before any immunostimulatory or pro-inflammatory activity would be predicted to occur based on pharmacokinetics in non-human primates and the weak pro-inflammatory and immunostimulatory properties of NAPs observed in this study.…”

Section: Discussionmentioning

confidence: 70%

“…Here slight but significant induction of IFNA4 and IFNL2 gene expression was observed that did not result in interferon secretion. The antiviral effects of NAPs, namely the reduction of serum HBV surface antigen in HBV-infected patients are very similar for REP 2055, REP 2139 and REP 216552829 despite the absence (REP 2055) or presence (REP 2139 and REP 2165) of 2′OMe and 5MeC modifications. It should be noted that although an increase in inflammatory cytokine gene expression in PBMCs is significant for all NAPs, cytokine secretion was only weakly stimulated for REP 2055 and REP 2139 (and not with REP 2165) and was only observed with NAP concentrations about 5-fold greater than their C max in cymologus monkeys, which is short lived.…”

Section: Discussionmentioning

confidence: 96%

Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

Real

Werner

Paul

et al. 2017

Sci Rep

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Nucleic acid polymers (NAPs) block the release of subviral particles from hepatocytes, a mechanism consistent with their antiviral activity against hepatitis B virus (HBV) in patients. Analysis of immunostimulatory properties of NAPs were conducted with several NAP species: REP 2006, the prototypic degenerate NAP [dN]40, containing TLR9-stimulatory CpG; REP 2055 a clinically active NAP with a sequence [dAdC]20 devoid of CpG content; REP 2139 (also clinically active) and REP 2165 (REP 2055 analogues further rendered immunologically inactive by replacing cytidine with 5-methylcytidine and incorporating 2′-O methylation of riboses). These analyses revealed pro-inflammatory responses in human peripheral blood mononuclear cells with REP 2006 and with REP 2139 and REP 2165 only at high dose but displayed no significant antiviral activity. In primary isolated human hepatocytes and liver sinusoidal endothelial cells no significant inflammatory or antiviral responses were detected for any NAPs. In human Kupffer cells pro-inflammatory activity was observed with REP 2006 and REP 2055, whereas a weak but significant induction of interferon genes was only observed with REP 2006 at the highest concentration. We therefore hypothesize that the antiviral activity of NAPs optimized to treat HBV infection in patients cannot be explained by direct induction of innate antiviral responses.

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Hepatitis B cure: From discovery to regulatory approval

et al. 2017

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The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly or secretion, and immune-modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments, and definitions of new or additional endpoints to inform clinical trials. To move the field forward, and to expedite the pathway from discovery to regulatory approval, a workshop with key stake holders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure i.e. viral eradication from the host is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of HBsAg with or without anti-HBs seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers towards better defining HBV cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional HBV cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues.

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Update on safety and efficacy in the REP 401 protocol: REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated Interferon alpha-2a in treatment naïve caucasian patients with chronic HBeAg negative HBV infection

Cited by 19 publications

References 0 publications

Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy

Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy

Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

Hepatitis B cure: From discovery to regulatory approval

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