NTCP Entry Inhibitor Combination Therapy for HBV HDV
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Solution Overview
Problem
Current treatments for hepatitis B and D infections, particularly chronic hepatitis B, are inadequate in achieving long-term remission or cure, with limited efficacy in reducing HBsAg levels and high resistance development to nucleoside/nucleotide analogues, and significant side effects from interferon therapy, while hepatitis D co-infection poses a severe and rapid progression of liver disease with limited therapeutic options.
Innovation Solution
A combination therapy comprising an HBV/HDV pre-S1 entry inhibitor, such as Myrcludex B, with a nucleotide/nucleoside analogue or immunomodulator like interferon, targeting the Na+-taurocholate cotransporting polypeptide (NTCP) to inhibit viral entry and reduce HBsAg and HDV RNA levels, aiming for sustained viral suppression and potential cure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If interferon therapy is used to treat HBV/HDV infection, then some degree of virological and biochemical response is achieved, but significant side effects occur and efficacy is limited to only a small proportion of patients
Solution Approach 1:
The patent combines interferon with an HBV/HDV entry inhibitor (such as pre-S1 peptide or small molecule compounds that block NTCP receptor) to create a combination therapy. This merging of two different mechanisms of action aims to achieve synergistic effects, improving virological response while allowing for reduced interferon dosing to minimize side effects.
Solution Approach 2:
The treatment approach segments the antiviral mechanism into two distinct parts: (1) interferon that modulates immune response and has broad antiviral effects, and (2) entry inhibitors that specifically block viral attachment and entry into hepatocytes. This segmentation allows each component to address different aspects of the infection with potentially reduced individual dosing requirements.
2Reliability
If nucleotide/nucleoside analogues are used to treat HBV infection, then viral replication is suppressed, but resistance development occurs and they do not work against HDV
Solution Approach 1:
The entry inhibitor component is designed to target the NTCP receptor, which is the cellular receptor for both HBV and HDV entry. This provides universal activity against both viruses, overcoming the limitation of nucleotide/nucleoside analogues that are ineffective against HDV. The combination therapy thus gains multi-functionality by addressing both HBV and HDV infections simultaneously.
Solution Approach 2:
The entry inhibitor acts as an intermediary that blocks the interaction between viral envelope proteins and the NTCP receptor on hepatocyte surfaces. This mediator approach prevents viral entry before replication can occur, providing a different mechanism of action that does not select for the same resistance mutations as nucleotide/nucleoside analogues targeting viral polymerase.
3Reliability
If current HBV therapies are used to achieve sustained HBsAg loss, then complete and definitive remission is the ideal endpoint, but this goal can be achieved only in minority of patients
Solution Approach 1:
The entry inhibitor works at the very beginning of the viral life cycle by blocking viral attachment and entry into hepatocytes. This preliminary action prevents new infections of hepatocytes, which is crucial for achieving sustained HBsAg loss and functional cure. By stopping viral entry early, the combination therapy creates conditions more favorable for complete remission.
Solution Approach 2:
The combination therapy changes the therapeutic parameter from solely suppressing viral replication (nucleotide/nucleoside analogues) or modulating immunity (interferon alone) to also blocking viral entry. This parameter change in the mechanism of action opens new pathways to achieve HBsAg loss and complete remission in a higher proportion of patients who have not responded to monotherapies.
Data Source
Figure 1
AI summary
The invention provides a composition comprising an inhibitor of Na+-taurocholate cotransporting polypeptide (NTCP) and a active ingredient selected from the group consisting of a nucleoside analogue such as lamivudine, telbivudine, or entecavir, a nucleotide analogue such as tenofovir, adefovir and an immunomodulator such as interferon alpha. The NTCP inhibitor inhibits HBV/HDV entry into a cell and is preferably derived from an HBV pre-Sl peptide. Also provided are methods of treating HBV and HDV infection, hepatitis B and D, or chronic hepatitis B and D.