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EP-4444311-B1 - GINSENOSIDES FOR TREATMENT OF CHRONIC HEPATITIS B VIRUS INFECTIONS

EP4444311B1EP 4444311 B1EP4444311 B1EP 4444311B1EP-4444311-B1

Inventors

  • MILLER, ANDREW DAVID
  • Ruzek, Daniel
  • Duraisamy, Ganesh Selvaraj
  • ADAM, Vojtech
  • Heger, Zbynek

Dates

Publication Date
20260506
Application Date
20221212

Claims (11)

  1. A ginsenoside selected from Rg6, Rh4, Rb3 and mixtures thereof for use in the treatment or prophylaxis of chronic hepatitis B virus infections.
  2. A combination of at least one ginsenoside selected from Rg6, Rh4, Rb3 and at least one nucleoside/nucleotide analogue selected from lamivudine, telbivudine, entecavir, adefovir, adefovir dipivoxil, tenofovir, tenofovir disoproxil fumarate, clevudine, lagociclovir valactate, besifovir, tenofovir alafenamide, HDP-tenofovir (CMX157), and AGX-1009 for use in the treatment or prophylaxis of chronic hepatitis B virus infections.
  3. The combination for use according to claim 2 wherein the molar ratio of the at least one ginsenoside to the at least one nucleoside/nucleotide analogue is at least 1000: 1.
  4. The combination for use according to claim 2 wherein the molar ratio of the at least one ginsenoside to the at least one nucleoside/nucleotide analogue is at least 100:1.
  5. The combination for use according to claim 2 wherein the molar ratio of the at least one ginsenoside to the at least one nucleoside/nucleotide analogue is at least 10:1.
  6. The combination for use according to any one of claims 2 to 5 wherein the at least one ginsenoside is administered simultaneously with the at least one nucleoside/nucleotide analogue.
  7. The combination for use according to any one of claims 2 to 5 wherein the at least one ginsenoside and the at least one nucleoside/nucleotide analogue are administered sequentially.
  8. The combination for use according to any one of claims 2 to 7 wherein the ginsenoside is Rh4 and the nucleoside/nucleotide analogue is lamivudine.
  9. A pharmaceutical composition comprising at least one ginsenoside selected from Rg6, Rh4, Rb3 and at least one nucleoside/nucleotide analogue selected from lamivudine, telbivudine, entecavir, adefovir, adefovir dipivoxil, tenofovir, tenofovir disoproxil fumarate, clevudine, lagociclovir valactate, besifovir, tenofovir alafenamide, HDP-tenofovir (CMX157), and AGX-1009 as active ingredients, and optionally further at least one pharmaceutically acceptable excipient and/or drug delivery system.
  10. The pharmaceutical composition according to claim 9 wherein the ginsenoside is selected from Rg6, Rh4 and Rb3, and/or the nucleoside/nucleotide analogue is lamivudine.
  11. The pharmaceutical composition according to claim 9, wherein the ginsenoside is Rh4 and the nucleoside/nucleotide analogue is lamivudine.

Description

The present invention relates to ginsenosides for use in the treatment of chronic hepatitis B virus infections. Background Art Ginsenosides are a class of natural product steroid glycosides and triterpene saponins found in Panax ginseng. Individual ginsenosides appear to exhibit a variety of biological effects, but these are often subtle and difficult to characterize in isolation [Attele, A.S; Wu, J.A; Yuan, C.S. Ginseng pharmacology: multiple constituents and multiple actions. Biochem. Pharmacol. 1999, 58, 1685-93]. Many studies suggest that ginsenosides have antioxidant properties, including free radical scavenging. Accordingly, ginsenosides have been suggested to be anti-proliferative with respect to cancer development and potentially neuroprotective with respect to Alzheimer's and Parkinson's diseases. Chronic hepatitis B virus (HBV) infection remains a worldwide public health concern given its impact on the formation of severe liver diseases such as hepatocellular carcinoma. The hepatitis B virus is herein abbreviated as HBV. Currently, nucleoside/nucleotide analogue therapies, including treatment with lamivudine, telbivudine, entecavir, adefovir, or tenofovir, are approved for treatment of chronic HBV infection. However, nucleoside/nucleotide analogue treatments are not sufficient to achieve a functional cure, hence new active pharmaceutical ingredients are required. Kang et al: Int. J. Biochem. Cell Biol. 2013, 45(11), 2612 suggest that ginsenoside Rg3 may be a promising candidate for the treatment of liver diseases caused by HBV infection. CN104644661 discloses 20(R)-ginsenoside Rg3s for use in the treatment of chronic HBV infection. CN1795893 discloses ginsenoside Rg1 for use in the treatment of hepatitis infections. Xu et al.: Biomed. Pharmacother. 2021-139, 111612 disclose a herbal preparation which contains, inter alia, ginsenoside Rh4, for treatment of HBV-related liver cancer, but claims that the active agent is polyphyllin I. US2019365838 discloses medical use of Panax extracts comprising a number of ginsenosides, but HBV infection treatment is not suggested. Disclosure of the Invention The invention is defined by the claims. The present invention relates to ginsenosides and mixtures thereof for use in treatment or prophylaxis of chronic HBV infections. The ginsenosides are selected from Rg6, Rh4 and Rb3. The structural formulas of the said ginsenosides are as follows: Within the framework of the present invention, the three ginsenosides Rg6, Rh4 and Rb3 were found unexpectedly to mediate efficient knockdown of hepatitis B surface (HBs) protein (S-HBs, M-HBs, and L-HBs) mRNA expression levels in the well-established in vitro recombinant hepatoma HBV cell model (HepG2.2.15) [Sells, M.A.; Chen, M.L.; Acs, G. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc. Natl. Acad. Sci. USA 1987, 84, 1005-1009, Wu, K.L; Zhang, X; Zhang, J; Yang, Y; Mu, Y.X; Liu, M; Lu, L; et al. Inhibition of Hepatitis B virus gene expression by single and dual small interfering RNA treatment. Virus Res. 2005, 112, 100-7]. In this context, Rg6, Rh4, and Rb3 mediate dose-dependent knockdowns of HBs protein mRNA expression levels with negative follow-on consequences for the levels of HBV DNA and HBs protein antigen (HBsAg) secretion. This "RNA interference surrogate" mechanism is a direct mechanism for the attenuation of HBV replication. At the same time, the ginsenosides show negligible cytotoxicity towards hepatic cells. Furthermore, the present invention relates to a combination of at least one ginsenoside selected from Rg6, Rh4 and Rb3 and at least one nucleoside/nucleotide analogue. Such combinations have a positive influence in the treatment or prophylaxis of chronic HBV infection. Preferably, ginsenosides mediate efficient knockdown of HBs protein mRNA expression levels by the "RNA interference surrogate" mechanism. Combinations involve doses of ginsenoside(s) at least 10x, 100x or 1000x (by molar ratio) higher than the doses of nucleoside/nucleotide analogue(s). A particularly preferred combination is a combination of Rh4 and lamivudine (LMV). This combination exhibits synergism in the treatment or prophylaxis of chronic HBV infection. Hence, Rh4/lamivudine combinations are expected to reduce the required dose of lamivudine below the regulator approved dose in patients of 300 mg/per oral/daily. The nucleoside/nucleotide analogue lamivudine is herein abbreviated as LMV. The combination of at least one ginsenoside and at least one nucleoside/nucleotide analogue may be administered simultaneously or sequentially, according to the consideration of the clinician. Nucleoside/nucleotide analogues are compounds containing a nucleic base analogue and a sugar (nucleoside analogues) or a nucleic base analogue, sugar and one to three phosphates (nucleotide analogues). Nucleoside/nucleotide analogues are selected from lamivudine, telbivudine, entecavir, adefovir, adefovi