Combinations and methods comprising a capsid assembly inhibitor
Inventors
Hartman, George • Flores, Osvaldo • Klumpp, Klaus • LAM, Man Iu • Berke, Jan Martin
Assignees
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Publication Number
US-11129834-B2
Publication Date
2021-09-28
Expiration Date
Abstract
The present disclosure is directed to capsid assembly inhibitor compositions and methods for use in the treatment of hepatitis B virus infection.
Core Innovation
The disclosure relates to HBV core protein allosteric modulators (CpAMs) as antiviral agents that cause assembly of capsids that are essentially empty with respect to their viral contents. The treatment approach is directed to disrupting HBV capsid assembly rather than only inhibiting reverse transcription, and includes CpAM exemplars such as compound 2 and compound 3, as well as pharmaceutically acceptable salts, hydrates, solvates, and crystalline forms.
A central aspect of the invention is a combination product for HBV treatment that includes a therapeutically effective amount of the CpAM together with a therapeutically effective amount of a reverse transcriptase inhibitor. In the provided claims, the reverse transcriptase inhibitor is lamivudine, and the disclosure also identifies reverse transcriptase inhibitors such as entecavir and tenofovir.
The combination-therapy regimens include administration of CpAMs together with reverse transcriptase inhibitors, including concurrent administration and same or separate formulations. The CpAM classes include phenylpropenamide-based compounds and mechanisms described as aberrant or incomplete capsid assembly and empty capsid-forming behavior.
Claims Coverage
The provided claim set contains 2 independent combination-product claims. Each independent claim defines the same combination framework, CpAM plus a reverse transcriptase inhibitor, while differing in which CpAM is used. The inventive features are the CpAM selection, the essential-empty capsid characteristic, and the pairing with lamivudine.
Combination product of compound 2 with lamivudine
A combination product comprising a therapeutically effective amount of a core protein allosteric modulator (CpAM) that causes assembly of capsids that are essentially empty with respect to their viral contents, wherein the CpAM is compound 2, or a pharmaceutically acceptable salt, hydrate, solvate, or crystalline form, and wherein the reverse transcriptase inhibitor is lamivudine.
Combination product of compound 3 with lamivudine
A combination product comprising a therapeutically effective amount of a core protein allosteric modulator (CpAM) that causes assembly of capsids that are essentially empty with respect to their viral contents, wherein the CpAM is compound 3, or a pharmaceutically acceptable salt, hydrate, solvate, or crystalline form, and wherein the reverse transcriptase inhibitor is lamivudine.
Across the independent claims, coverage centers on a combination product pairing lamivudine with a CpAM that causes assembly of essentially empty HBV capsids. The claims differentiate the CpAM by specifying compound 2 in one embodiment and compound 3 in the other, while permitting pharmaceutically acceptable salt, hydrate, solvate, and crystalline forms.
Stated Advantages
The combination approach supports antiviral activity and tolerability.
Viability results in primary human hepatocytes show no meaningful additional toxicity when combined with nucleoside analogs.
Combination interaction analyses indicate additive or synergistic effects for CpAMs with reverse transcriptase inhibitors.
Documented Applications
HBV treatment using combination-therapy regimens administering a CpAM with reverse transcriptase inhibitors.
Combination antiviral testing and interaction evaluation for CpAMs with reverse transcriptase inhibitors, including activity against lamivudine/entecavir/tenofovir-resistant HBV polymerase variants.
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