Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

Abstract

Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2–7 log reductions of serum HBsAg, 3–9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10–1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which may improve the effect of immunotherapy. NAPs may be a potentially useful component of future combination therapies for the treatment of chronic hepatitis B.Trial Registration: ClinicalTrials.gov NCT02646163 and NCT02646189

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

“…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.…”

“…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.…”

“…Although inflammatory responses were observed early in vivo experiments with degenerate NAPs (i.e. REP 2006), consistent with activation of the innate response212 the antiviral activities of NAPs containing sequences and naturally occurring nucleotide modifications designed to block recognition by pattern receptors13141516171819, persist and are not accompanied by pro-inflammatory effects in vivo or in human patients351220. However since many of the antiviral effects of NAP therapy in HBV infection are similar to those observed with immunotherapy, a more rigorous examination of immunostimulatory effects of NAPs optimized for therapeutic use was conducted in primary cultures of human parenchymal and non-parenchymal liver cells and peripheral blood mononuclear cells.…”

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…The success rate of these treatments is low. Several candidates are being evaluated in clinical trials mainly in combination with PegIFNa and/or NA including HBV/HDV entry inhibitors (Myrcludex-B), 244,245 drugs inhibiting the release of HBsAg (nucleic acid polymers), 246 and inhibitors of the prenylation of the large HDV antigen. 243,247 Whenever possible, enrollment in these new clinical trials should be considered, either as a rescue of PegIFNa failure or to improve treatment success rate in naïve patients.…”

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

“…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.…”