A new kind of compound to treat hepatitis C is showing promise in early clinical trials

April 21, 2010
Sarah Houlton
A new kind of compound to treat
hepatitis C is showing promise in early
clinical trials. The treatment, being developed
by Bristol-Myers Squibb
(BMS), was found to be very effective
at lowering viral load, both in a Phase I
trial published this week in Nature, and
in early results of a Phase IIa trial presented
at the European Association for
the Study of the Liver’s annual meeting
in Vienna last week.
Current HCV therapy is not ideal. The
standard treatment is with an interferon
and the antiviral agent ribavirin, but is
only effective in around half of all patients
and is plagued with side-effects.
Various new antiviral agents are under
development, including protease inhibitors
and polymerase inhibitors, and
BMS-790052 works against a new target,
the NS5A protein.
‘If we are to replace interferon with
small molecules, we would need at least
two if not three, so we set out to look for
new inhibitors,’ explains Nick Meanwell
of BMS’s research team. ‘We ran a
chemical genetics screen, and found a
single interesting inhibitor whose resistance
mapped to the NS5A protein. We
don’t know what this protein actually
does - it’s very enigmatic. We took that
lead compound, and after some very interesting
chemistry we finessed out the
pharmacophore, and that led to the final
molecule which is now in clinical trials.’
The hepatitis C virus has many different
genotypes. The initial screen was
run on type 1b, and BMS chemists got
to work to find an analogue that was active
more broadly. ‘We had to understand
how to inhibit type 1a, which was
quite a challenge, but we solved it,’ says
Meanwell. ‘Typically, there is an effect
on viral load by the 12 hour point, and
at the highest dose we are reducing viral
New Hep C Drug Shows Promise in Early Trial
load in plasma by almost 99.99 per cent.’
The compound also seems to be effective
against other genotypes. The next
step, says Meanwell, is a combination
study where it will be given alongside
the company’s protease inhibitor BMS-
650032, but without the standard interferon
and ribavirin, which was given to
patients in the reported trials. ‘It’s a small
study and very early days, but we hope
to release results towards the end of the
year,’ he says.
‘It looks a most interesting compound,’
says Geoff Dusheiko of the centre
for hepatology at University College
London, UK. ‘Other groups have
worked on NS5A inhibitors that have not
shown the same level of potency, which
is crucial. It looks like it has fairly broad
activity across HCV genotypes, which
would also be an important breakthrough.’
Chemistry World