Thursday, December 9, 2010

IMO-2125 induces strong Th1-type (T helper type 1 cells) immune responses in null-responder Hepatitis C patients

Activation of the Innate Immune System: A Novel Immune Modulator for the Treatment of Hepatitis C
December 01, 2010

Hepatitis C (HCV) is caused by a single-stranded RNA virus; about 170 million people worldwide are chronically infected with the virus. Chronic infection can lead to liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. HCV is the leading cause for liver transplantation. Importantly, not all acutely-infected patients become chronically infected. It is estimated that 20 to 30% of HCV-infected patients may clear the virus on their own, demonstrating that chronic infection may be due to an inability of the host immune system clear the virus.1

Current standard of care for HCV infections is a 48-week regimen of interferon-α (IFN-α) or PEGylated IFN-α (the long-acting form of IFN-α) injections in combination with ribavirin, an oral generic antiviral. Only around 50% of patients infected with the HCV virus strain genotype 1—the most common form in the U.S. and Europe—respond to IFN-α based therapy. Response in HCV means a sustained virologic response (SVR) in which HCV RNA is undetectable in blood for six months after cessation of treatment. Phase 3 clinical trials have shown that adding a direct-acting antiviral, such as the protease inhibitors telaprevir or boceprevir, to standard of care may generate SVR rates of 70 to 75% among treatment-naïve genotype 1 subgroups, including patients treated for only 24 weeks.2,3

A major cause for discontinuing HCV treatment is patient intolerance to IFN-α therapy. The frequency and diversity of the side effects attributed to IFN-α are relatively significant and include flu-like symptoms, hematological side effects, and depression. Although adding a new agent to the current standard of care may improve efficacy, it doesn’t address the tolerability issue associated with the IFN-α. New options, including more tolerable and effective immune modulatory agents for non-responders (all patients who initiate therapy but do not reach an SVR) and null-responders (patients who failed to achieve a 2 log10 reduction in viral load with standard of care treatment of at least 12 weeks duration) are needed. The immune modulatory component will most likely continue to be part of standard of care even with the changing treatment landscape as direct antiviral agents are potentially introduced to the market. To date, nearly everyone cured of HCV infection has been treated with IFN-α.

IMO-2125 is a synthetic agonist of the Toll-like receptor 9 (TLR9).4 TLR9 recognizes DNA patterns, which are not shared with the host but are specific to viral or bacterial pathogens, as foreign and activates an innate immune response. Preclinical studies have shown that IMO-2125 induced IFN-α and other cytokines in a dose-dependent manner in human immune cell cultures in vitro and in non-human primates in vivo. Furthermore, IMO-2125 demonstrated marked antiviral activity in a test, which measures the potency of antiviral compounds against HCV replication.5

Stimulation of PBMCs with IMO-2125 induces higher levels of multiple cytokines including IFN-a, compared to stimulation with exogenous human INF-a. (Source: Idera Pharmaceuticals)

An ongoing Phase 1 study has revealed that IMO-2125 induces strong Th1-type (T helper type 1 cells) immune responses in null-responder HCV patients with dose-dependent increases in serum IFN-α, IP-10, 2’,5’-OAS, expression of CD69 activation marker on CD4+ and CD8+ T cells, and in the frequency of NK cells. Importantly, the induced serum IFN-α concentrations are inversely correlated with dose-dependent decreases in HCV viral load.6 IMO-2125 is well-tolerated and has not shown any serious adverse events for the doses investigated.

Enhancing the natural immune response of treatment-naïve patients may have a significant therapeutic effect for this patient population as well. A Phase 1 trial in treatment-naïve HCV patients for IMO-2125 in combination with ribavirin is ongoing.

IMO-2125 is being developed as a more effective and tolerable alternative to PEGylated IFN-α for administration in combination with ribavirin and direct-acting antiviral agents.

1. Horner SM, Gale M. Intracellular innate immune cascades and interferon defenses that control hepatitis C virus. Journal of Interferon & Cytokine Research. 2009;29(9):489.
2. Sherman KE, et al. Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD);2010.
3. Poordad F, et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. 61st Annual Meeting of the American Association for the Study of Liver Diseases; 2010.
4. Agrawal S, Kandimalla ER. Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem Soc Trans; 2007.

5. Sullivan T, et al. Presentation at 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago, 2007.

6. Rodriguez-Torres M, et al. IMO-2125, a TLR9 Agonist,

Induces Immune Responses which Correlate with Reductions in Viral Load in Null Responder HCV Patients. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD);2010.

1 comment:

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