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Hepatitis
C virus (HCV) treatments could reach $9 billion over the
next decade if more effective and safer therapies can be
designed, and protease inhibitors are one of the most
promising new classes of such drugs. Below, John
Thomson, who has worked on this project at Vertex
Pharmaceuticals since 1993, describes the development of
telaprevir (VX-950) – the most advanced HCV protease
inhibitor in trials today. It is also a drug that owes a
great deal to structure-based drug design.
“From
the beginning, Vertex thought this was going to have to
be a different type of molecule.
We already suspected the HCV protease was going
to have a flat active site; therefore, to inhibit it, we
would probably need a large, hydrophobic (or greasy)
molecule. That departs from the ideal qualities of most
oral drugs, and that challenge alone tied some
people’s minds into pretzels. But Vertex is not
weighed down by a lot of history and dogma, so we
pressed forward anyway to get the best possible
inhibitor. We also studied the problem from so many
angles that we understood it very well.
For
example, Vertex knew we would need to get a lot of this
drug into the liver. But pharmacokinetics (PK) experts
often focus mainly on getting drugs well supplied to
plasma. So
we had to be on our toes about the PK profile.
In
addition, there was no reliable decent animal disease
model, and no in vitro viral replication assay for most
of the time we were working on this. To make things
worse, some of the “breakthrough” assays ended up
being more than disappointing. The whole HCV research
community chased a lot of false alarms and phantoms. In
the end, Vertex overcame great technical challenges and
developed our own viral replication assays.
Over
the past few years, we also learned that HCV replication
occurs on membranous surfaces–in replication
complexes. That helps explain why these proteins are
very hydrophobic and such difficult rascals to handle,
and has a profound effect on many techniques and assays.
The
major breakthrough came when the Vertex team solved the
three-dimensional crystal structure of HCV protease. The
structure confirmed the flat active site and also showed
the NSA4 peptide embedded in the middle of the protease.
Another little protein expressed by the virus
acts as a core and the whole protease wraps around it.*
All of the information gleaned from the crystal
structure suddenly explained so much more about what we
had to do with it to design drugs against it. From
there, we could fire with all cylinders.
Now
that early clinical trials have shown the antiviral
effect of telaprevir,
we believe that’s partly because we paid close
attention to the PK issues. We also think there may be
something specific about this chemical class.
In addition, a fascinating series of biology
studies has revealed a pleasant surprise: The HCV
protease (telaprevir’s target) disassembles at least
two key defensive proteins in the cell, which in turn
control multiple protective mechanisms for natural
interferon production. Hence, protease inhibitors may
have additional “bonus” effects, in helping restore
natural interferon production. We also worked really
hard on the synthesis of this molecule to make sure it
was something we could really make at commercial scale.
With
this compound, we exceeded our own expectations.
The Company realized it was a good molecule from
preclinical data, and clinical data thus far has
confirmed this belief in early Phase Ib and Phase II
trials. For telaprevir to be a true
breakthrough, we will need to clear the virus in
a large majority of patients, which is what we are now
evaluating in ongoing clinical trials.”
John
Thomson is currently Vice President of Strategic
Research Alliances for Vertex.
*
“Crystal structure of the hepatitis C virus NS3
protease domain complexed with a synthetic NS4A cofactor
peptide.” Cell. 1996;87:343–355.
More
On the Web:
VX-950
champion: Vertex’s John Thomson, saw promise
despite challenges
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