Investigational drugs in development for Hepatitis D

ABSTRACT

Introduction: Treatment of chronic hepatitis D still relies on Interferon. To improve efficacy, new therapeutic strategies are in development which aim to deprive the Hepatitis D Virus (HDV) of functions of the Hepatitis B Virus and of the host required for its life-cycle.

Areas covered: The therapeutic options are; 1) The inhibition of the farnesylation of the large HD-protein permissive of virion assembly with Lonafarnib, 2) The blocking of HBsAg entry into cells with Myrcludex B via the inhibition of the Sodium Taurocholate Cotransporting Receptor, to prevent the spreading of HDV to uninfected hepatocytes, 3) The reduction of subviral HBsAg particles by REP 2139, leading to diminished virion morphogenesis .

Expert opinion: Lonafarnib and Myrcludex reduced serum HVD-RNA; neither diminished serum HBsAg. NAP REP-2139 diminished both HDV-RNA and HBsAg in serum; a full report is awaited. In combination with Peg-Interferon, these new drugs may provide additional efficacy.

KEYWORDS:

• Hepatitis D Virus
• chronic hepatitis D
• hepatitis delta
• lonafarnib
• myrcludex
• REP-2139
• therapy

Article highlights

• Due to its unique virologic features, the Hepatitis D Virus (HDV) cannot be targeted by conventional antivirals. Therapeutic strategies under investigation aim to deprive the virus of functions provided to its life cycle by the Hepatitis B Virus (HBV) or by the infected host.

• Lonafarnib, an inhibitor of farnesyl- transferase, prevents the farnesylation of the large HD-antigen, necessary to drive virion assembly through the coating of the HD-ribonucleoprotein with the HBsAg. The drug diminishes the titer of HDV-RNA in serum but its effect is not lasting and it does not diminish the titer of the HBsAg.

• Myrcludex B, a synthetic myristolated lipopeptide of the pre-S1 domain of the HBsAg, was tested for its capacity to block HDV entry into hepatocyes and control infection by preventing spreading of HDV to yet non-infected hepatocytes. During therapy it inhibited HDV replication without diminishing the titer of HBsAg; HDV viremia rebounded after therapy.

• REP-2139, a nucleic acid polymer active against the HDV by a putative inhibition of the synthesis of subviral HBsAg particles, was shown in preliminary reports to consistently reduce the titer of HDV-RNA and HBsAg in serum.

• Lonafarnib, Myrcludex B and REP 2139 are only partially efficacious in monotherapy but may provide an additive antiviral effect in combination with standard Peg-Interferon therapy; long-term combination treatments and prolonged follow-ups are in order to evaluate their ultimate efficacy in chronic hepatitis D.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.