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HIV and Hepatitis.com Coverage of the
45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010)

April 14 - 18, 2010, Vienna, Austria
Cyclophilin Inhibitor SYC-635 May Reduce Fibrosis in Addition to Inhibiting Hepatitis C Virus Replication

SUMMARY: The novel cyclophillin inhibitor SCY-635 appears to have an anti-fibrogenic effect in addition to its previously demonstrated antiviral activity against hepatitis C virus (HCV), according to an analysis presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) this month in Vienna. Two other studies presented at the conference indicated that SCY-635 has a high barrier to resistance and may not cause the same type of bilirubin elevation as other agents in its class.

By Liz Highleyman

Cyclophilins are a family of enzymes that assist in the folding and transport of proteins synthesized within a cell. SCY-635, being developed by Scynexis, is a derivative of cyclosporine A that was designed to separate cyclophilin-binding activity (responsible for activity against HCV) from calcineurin-binding activity (which has undesired immunosuppressive properties).

Fibrosis

According to a poster presented by B. Scorneaux and colleagues from Scynexis, SCY-635 demonstrated anti-fibrogenic properties in rat and human liver cells in laboratory studies.
Recent research indicates that cyclosporine and non-immunosuppressive analogs can suppress the proliferation of hepatic stellate cells (support cells in the liver that produce scar tissue material responsible for fibrosis) and reduce their production of collagen. The investigators therefore examine the effects of SCY-635 on liver fibrosis and apoptosis (programmed cell death or "cell suicide"). They analyzed cell growth, collagen synthesis, transforming growth factor-beta (TGF-beta) signaling, and levels of chemical messengers involved in fibrosis, including tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase 1 (MMP-1).

At concentrations suitable for clinical use, SCY-635 reduced stellate cell collagen production by more than 70%. There was a parallel decrease in TIMP-1 secretion and an increase in MMP-1 production. Furthermore, SCY-635 inhibited proliferation of stellate cells without triggering apoptosis.

These data, the investigators concluded, "suggest that SCY-635 may not only reduce the replication of HCV but also reduce the fibrosis associated with chronic hepatitis C virus infection." These findings will be explored further in Phase 2 studies of SCY-635 expected to start soon.

Drug Resistance

In an oral presentation at the conference, Scynexis Chief Scientific Officer Sam Hopkins described findings from a study looking at resistance to SCY-635, which can interfere with long-term response to antiviral agents.

The study showed that HCV must evolve multiple mutations in order establish resistance to SCY-635, in contrast to a single or a few mutations to become resistant to some of the other directly targeted antiviral agents currently in development.

No treatment-associated mutations in the HCV NS5A protein (a non-structural protein that appears to play a role in viral replication) were detected in any samples collected on day 15 (the last day of dosing) or day 22. Two participants developed treatment-associated mutations in NS5B (the HCV polymerase), but neither showed evidence of virological breakthrough during treatment.

"Over the year, we have established that single-agent treatment with SCY-635 yields a clinically meaningful reduction in viral load while exhibiting a very favorable safety profile," Hopkins said in a press release issued by Scynexis. "We have shown that SCY-635 exhibits additive to synergistic antiviral activity when combined with both approved and leading investigational agents, and now we have demonstrated that SCY-635 appears to present the hepatitis C virus with a much a higher barrier to resistance than current therapies in development."

The company suggested that these findings position SCY-635 as a strong candidate for inclusion in future "cocktails" or combinations of directly-targeted anti-HCV drugs.

Bilirubin Levels

Finally, S. Wring and colleagues from Scynexis presented a poster indicating that SCY-635 is not associated with elevated bilirubin over 15 days of treatment, unlike some other cyclophilin inhibitors.

Potentially toxic total bilirubin elevations in hepatitis C patients associated with exposure to some cyclophilin inhibitor analogs have been reported in the medical literature, but have not been observed to date in clinical studies of SCY-635, Scynexis Chief Executive Officer Yves Ribeill explained in a company press release.

Based on the latest study results, he said, "we believe that SCY-635 is a very weak inhibitor of the major drug transporter, MRP2, a conjugated bilirubin transporter, and, as a result, treatment with SCY-635 does not appear to interfere with the normal processing and transport of bilirubin in the liver or bloodstream."

"The results of our bilirubin transport studies demonstrate a potentially important differentiation among candidates within the cyclophilin class of drugs and further position SCY-635 as the leading cyclophilin inhibitor in development for the treatment of HCV," he added.

4/30/10

References

B. Scorneaux, G Thomas, S Hopkins, and RR Harris. The effects of SCY-635 a non-immunosuppressive cyclosporin analog on stellate cell proliferation, collagen synthesis, TIMP-1 and collagenase production. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

S Hopkins, S Mosier, R Harris, and others. Resistance selection following 15 days of monotherapy with SCY-635 a non-immunosuppressive cyclophilin inhibitor with potent anti-HCV activity. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

S Wring, K Wille, C Rewerts, and others. In vitro models for assessing the relative risk of hyperbilirubinemia associated with cyclophilin inhibitor therapy. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

Other sources

Scynexis, Inc. Scynexis Presents In Vitro Toxicity Study Suggesting that SCY-635 is Unique in the Cyclophilin Inhibitor Class. Press release. April 16, 2010.

Scynexis' SCY-635 Demonstrates Impressive Barrier to Resistance in HCV Treatment. Press release. April 15, 2010.


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



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