A new experimental NS5A
inhibitor, GS-5816, was shown to be safe and effective when used in an
interferon- and ribavirin-free dual regimen with sofosbuvir (Sovaldi) for people with hepatitis C
genotypes 1 through 6, according to phase 2 trial results presented at the 49th
annual meeting of the European Association for the Study of the Liver (EASL) last week in London.
recently approved hepatitis C virus (HCV) nucleotide polymerase inhibitor
sofosbuvir has demonstrated good efficacy in combination with ribavirin against
HCV genotype 2. Sofosbuvir plus ledipasvir, Gilead's first-generation NS5A
replication complex inhibitor, cures most hepatitis C genotype 1 with a treatment duration as short as 8 weeks.
Sofosbuvir/ledipasvir without ribavirin is not as effective against HCV genotype 3, however, and some data indicate it is
susceptible to viral resistance.
As part of its ongoing
hepatitis C drug development programme, Gilead is also testing a
next-generation NS5A inhibitor, GS-5816, which demonstrated potent activity
against HCV genotypes 1 through 6 in early studies. The company is developing a
co-formulation of sofosbuvir and GS-5816, similar to the sofosbuvir and
ledipasvir co-formulation it has already submitted for regulatory approval in Europe
and the US.
Gregory Everson of the University of
Colorado at Denver presented findings from a phase 2 clinical trial looking at
the safety and efficacy of sofosbuvir plus GS-5816 taken without ribavirin for
12 weeks in treatment-naive people with genotype 1-6 chronic hepatitis C.
This study included 154 previously
untreated hepatitis C patients without liver cirrhosis. About 60% were men,
most were white and the mean age was approximately 50 years. Nearly 30% had HCV
subtype 1a, which is considered most difficult to treat. In addition, 7% had
HCV subtype 1b, 14% had genotype 2, 35% had genotype 3, 9% had genotype 4, a
single individual had genotype 5 and 6% had genotype 6. About one-third had the
favourable IL28B CC gene variant associated with interferon responsiveness.
Participants in this open-label study were
randomly assigned to receive 400mg once-daily sofosbuvir plus either 25mg or
100mg once-daily GS-5816 for 12 weeks. They were followed after finishing
therapy to determine sustained virological response, or continued undetectable
HCV viral load at 12 weeks post-treatment
(SVR12), which is considered a cure.
SVR12 rates for people with genotype 1 were
96% using the 25mg GS-5816 dose and 100% using the 100mg dose. For people with
genotype 2, the corresponding rates were 91% and 100%, respectively, while the
cure rates for genotype 3 were 93% in both dose arms.
Turning to the less common genotypes – where
the numbers were too small to draw meaningful conclusions – genotype 4 SVR12
rates were 100% and 86%, respectively, in the 25mg and 100mg dose groups. The
single genotype 5 patient and all genotype 6 patients in both dose arms were
cured. Across all genotypes, overall SVR12 rates were 95% using the 25mg dose
and 96% using the 100mg dose.
Looking at the patients who did not
achieve SVR12, three people relapsed after completing treatment: one person
with genotype 1 taking 25mg GS-5816, one person with genotype 3 taking 25mg and
one person with genotype 3 taking 100mg. In addition, one person with genotype
3 was a non-responder during treatment, one person with genotype 2 died during
follow-up and one person with genotype 3 was found to be re-infected.
Genetic sequencing revealed that about
one-quarter of people with genotype 1-3 had pre-existing resistance-associated NS5A
viral variants. Among them, virological failure was more likely using the lower
GS-5816 dose (5% vs 2%). However, most people with pre-existing variants were
Treatment with sofosbuvir and GS-5816 was
generally safe and well-tolerated. Four people had serious adverse events,
three of them in the 25mg dose arms. However, no one discontinued for this
reason. The most common side-effects reported by at least 10% of participants were
fatigue, headache, nausea and constipation. No one developed anaemia, a
side-effect often seen with ribavirin.
"Sofosbuvir + GS-5816 for 12 weeks
resulted in SVR12 rates >90% in all HCV genotypes (1-6)," the
researchers concluded. "The presence of pre-treatment NS5A variants was
not predictive of failure to achieve SVR12”.
that a combination of sofosbuvir and GS-5816 is now being tested in two
harder-to-treat groups, previously treated hepatitis C patients and people with