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.
