Combination Therapy of RNA Interference and Small Molecules for Treating Hepatitis B Virus Infection

Important Compound Classes

Title

Combination Therapy for Treating Hepatitis B Virus Infection

Patent Publication Number

WO 2020/214974 A1

Publication Date

October 22, 2020

Priority Application

US 62/836,069; US 62/852,743; US PCT/US2019/046035; US 62/932,332

Priority Date

April 18, 2019; May 24, 2019; August 9, 2019; November 7, 2019

Inventors

Biermer, M.; Kalmeijer, R.; Lenz, O.; Beumont-Mauviel, M. G.; Snoeys, J.; Simmen, K. A.

Assignee Company

Janssen Pharmaceuticals, Inc., USA

Disease Area

Hepatitis B Virus Infection

Biological Target

RNA interference (RNAi) agents and small molecules of capsid assembly modulator (CAM)

Summary

Hepatitis B virus (HBV) is a strict, hepatotropic, double-stranded DNA containing virus. Although DNA is a genetic material, the replication cycle involves a reverse transcription step to copy a pregenomic RNA into DNA. HBV is classified as one member of the Hepadnaviruses and belongs to the family Hepadnaviridae. The primary infection of adult humans with HBV causes an acute hepatitis with symptoms of organ inflammation, fever, jaundice, and increased liver transaminases in blood. Those patients that are not able to overcome the virus infection suffer a chronic disease progression over many years with increased risk of developing cirrhotic liver or liver cancer. Perinatal transmission from HBV-infected mothers to newborns leads to chronic hepatitis.

Upon uptake by hepatocytes, the nucleocapsid is transferred to the nucleus, and DNA is released. There, the DNA strand synthesis is completed, and gaps are repaired to give the covalently closed circular (ccc) supercoiled DNA of 3.2 kb. The cccDNA serves as a template for transcription of five major viral mRNAs, which are 3.5, 3.5, 2.4, 2.1, and 0.7 kb long. All mRNAs are 5′-capped and polyadenylated at the 3′-end. There is sequence overlap at the 3′-end between all five mRNAs. One 3.5 kb mRNA serves as template for core protein and polymerase production. The other 3.5 kb mRNA encodes precore, the secretable e-antigen (HBeAg). The 2.4 and 2.1 kb mRNA carry the open reading frames (ORF) pre-S1, pre-S2, and S expression of viral large, medium, and small surface antigens. The 0.7 kb mRNA encodes the X protein. HBV-specific RNA interference (RNAi) agents have been shown to inhibit expression of HBV gene expression. Additionally, HBV inhibitors such as CAM can bind to hepatitis B core protein and interfere with the viral capsid assembly process, thereby preventing the polymerase-bound pgRNA encapsulation.

The present application describes a combination therapy of RNA interference (RNAi) agents and small molecules of capsid assembly modulator (CAM) and are useful for treatment of Hepatitis B virus infection. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = CR₇;

R_a, R_b, and R_c = H, halogen, −CHF₂, −CF₂-methyl, −CH₂F, −CF₃, −OCF₃, −CN, C₁–C₃ alkyl and C₃–C₄ cycloalkyl;

R_d = H or fluoro;

R₄ = H, C₁–C₃ alkyl or C₃–C₄ cycloalkyl;

R₅ = H;

R₆ = C₂–C₆ alkyl or C₁–C₄ alkyl-R₈ optionally substituted with one or more fluoro, C₁–C₄ alkyl-R₉ optionally substituted with one or more fluoro, and a 3–7 membered mono- or polycyclic saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such as 3–7 membered saturated ring or C₂–C₆ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of H, −OH, fluoro, oxo, R₉, R₁₀, and C₁–C₄ alkyl optionally substituted with R₁₀;

R₇ = H, −CN, halogen, −CHF₂, −CF₂-methyl, −CH₂F, −CF₃, C₁–C₃ alkyl optionally substituted with methoxy, C₂–C₃ alkenyl or C₃–C₄ cycloalkyl;

R₈ = 3–7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S, and N, such as 3–7 membered saturated ring optionally substituted with one or more C₁–C₄ alkyl optionally substituted with R₁₀;

R₉ = C₁–C₄ alkyloxy, −SO₂-methyl, −C(=O)-OR₁₁ or −C(=O)–N(R₁₁)₂;

R₁₀ = −CN, −OH, fluoro, −CHF₂, −CH₂F, or −CF₃; and

R₁₁ = H or C₁–C₃ alkyl.

Key Structures

Biological Assay

A clinical study of the combination therapy was performed. A multisite, Phase I/2a human clinical trial assessing the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of a combination comprising an RNAi component and a small molecule capsid assembly modulator in normal adult volunteers was conducted. The study was designed to evaluate the safety and pharmacological effects of the combination therapy in patients with chronic hepatitis B (CHB). The combination comprised Compound A and an RNAi component comprising of a first RNAi agent comprising SEQ ID NO: 2 and SEQ ID NO: 11 and an effective amount of a second RNAi agent comprising SEQ ID NO: 16 and SEQ ID NO: 8 in a ratio of 2:1. The study subject population included adult males and females, aged 18–55, with or without CHB.

Biological Data

A cohort exploring combination therapy of RNAi component, compound A, and NA (nucleos(t)ide) analogue (i.e., cohort 12) was reported. The combination therapy was well-tolerated, and all CHB patients achieved robust reductions in HBsAg, HBV DNA, and HBV RNA. Reductions in HBeAg and HBcrAg were generally less pronounced during the dosing period. All patients achieved ≥1.0 log₁₀ IU/mL (90%) reduction (nadir range from −1.01 to −2.26 log₁₀ IU/mL) in HBsAg. HBsAg reductions were similar in HBeAg positive and HBeAg negative patients.

Claims

Total claims: 38. Combination for use claims: 38.

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The author declares no competing financial interest.