Toll-like Receptor Antagonist IMO-2125 Stimulates Production of Natural Interferons with Activity against Hepatitis C Virus

		SUMMARY: The investigational toll-like receptor 9 (TLR9) antagonist IMO-2125 induced production of high levels of endogenous (natural) interferon alpha and other interferons that exhibited potent activity against hepatitis C virus (HCV), according to 2 presentations at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) last month in Boston. Idera Pharmaceuticals recently announced the start of a Phase 1 clinical trial of IMO-2125 plus ribavirin in treatment-naive chronic hepatitis C patients.

Current standard treatment for hepatitis C involves administration of recombinant (genetically engineered) pegylated interferon alpha plus ribavirin. The directly targeted oral anti-HCV agents now in development work by interfering with various steps of the viral lifecycle.

IMO-2125 and related agents work a third way, by stimulating production of the body's own interferons, which play a key role in immune response against the virus.

At AASLD, Idera researchers presented data from 2 laboratory studies of IMO-2125. As with recombinant conventional and pegylated interferon, IMO-2125 is injected subcutaneously.

In the first study, they found that IMO-2125 induced high levels of endogenous interferon alpha, interferon beta, interferon lambda, and other cytokines (chemical messengers) in human peripheral blood mononuclear cells and dendritic cells; the cytokines demonstrated potent antiviral activity in HCV replicons. Adding antibodies against interferon alpha reduced this antiviral activity, but not completely, suggesting that other substances induced by IMO-2125 also play a role.

The second study, looking at gene expression profiles, offered more details about IMO-2125's mechanism of immune activation. The results showed that IMO-2125 mediated immune responses through TLR9 and associated interferon signaling pathways involving MyD88 and interferon regulatory factor 7 (IRF7). Several type 1 interferon-response genes, interferon-inducible proteins, antiviral proteins, TLR9 signaling molecules, and transcription factors were also up-regulated.

In early October, Idera announced the start of a Phase 1 clinical trial evaluating once-weekly IMO-2125 for 4 weeks in combination with oral ribavirin in treatment-naive chronic hepatitis C patients. Since ribavirin helps prevent relapse in people treated with recombinant interferon alpha, the same might be true for naturally produced interferon.

Another ongoing trial is looking at IMO-2125 as monotherapy in treatment-experienced hepatitis C patients who did not achieve a sustained response with standard-of-care pegylated interferon plus ribavirin.

12/11/09

References

L Bhagat D Yu, AF Trombino, and others. IMO-2125, a TLR9 agonist, induces Th1-type cytokines and interferons with potent anti-HCV activity in human peripheral blood mononuclear cells and plasmacytoid dendritic cells. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1593.

W Jian, L Bhagat, D Yu, and others. Gene expression profiles induced by IMO-2125, an agonist of Toll-like receptor 9, in human peripheral blood mononuclear cells. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1597.

Other sources

Idera Pharmaceuticals. Idera Pharmaceuticals Initiates Phase 1 Clinical Trial of IMO-2125, a TLR9 Agonist, in Combination with Ribavirin for Chronic Hepatitis C Virus Infection. Press release. October 7 2009.

Idera Pharmaceuticals. Idera Pharmaceuticals Presents Preclinical Data on IMO-2125, its Lead Drug Candidate for Chronic Hepatitis C Virus Infection, at Liver Meeting 2009. Press release. November 3, 2009.