Adding GS-7977 to pegylated
interferon and ribavirin for 12 weeks led to a sustained response rate of 90%
for previously untreated chronic hepatitis C patients with difficult-to-treat
genotype 1, researchers reported at the 47th
International Liver Congress (EASL 2012) last week in Barcelona.
Last year's approval of the first
direct-acting antiviral agents has changed the face of hepatitis C treatment.
The first such drugs still must be taken with pegylated interferon and
ribavirin, but they increase cure rates and offer the potential for shorter
treatment.
GS-7977 (formerly PSI-7977) is a
uridine nucleotide HCV NS5B polymerase inhibitor that has demonstrated good
efficacy in early studies when combined with standard therapy or other direct-acting antivirals, though most people
relapsed when they used GS-7977 plus ribavirin alone.
Glossary
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
After favourable results from the PROTON trial showed
that most patients achieved a cure with 12 weeks of GS-7977 plus pegylated
interferon/ribavirin followed by another 12 weeks on pegylated interferon/ribavirin
alone, the phase IIb ATOMIC trial was designed to
test whether a similar outcomes could be obtained with GS-7977 and only 12
weeks of pegylated interferon/ribavirin.
Kris Kowdley from Virginia Mason Medical Center in
Seattle and investigators at several other US sites enrolled 332
treatment-naive hepatitis C patients without cirrhosis but with
difficult-to-treat HCV genotypes. All but 16 had HCV genotype 1, about 70% of
them with subtype 1a (the rest had genotype 4 or 6).
Two-thirds of participants were men, about 85% were
white and the average age was about 50 years. Approximately 25% had the
favourable IL28B CC gene pattern associated with good response to interferon.
Participants were randomly assigned to receive 400mg
once-daily GS-7977 plus once-weekly pegylated interferon and daily ribavirin
for 12 or 24 weeks, or else triple therapy for 12 weeks followed by either
GS-7977 alone or GS-7797/ribavirin for an additional 12 weeks (24 total weeks
on treatment).
Overall, viral suppression was rapid during the first
two weeks on treatment regardless of IL28B status. After four weeks on therapy,
rapid virological response rates (< LOD 15 IU/mL) were 94% in the 12-week
triple therapy arm, 98% in 24-week triple therapy arm and 97% for patients who
received 12-week triple therapy with 12 weeks of follow-on treatment.
At the end of treatment, the corresponding response
rates were 98%, 99% and 99%, respectively, with no patients experiencing viral
breakthrough while on therapy.
Four weeks after completing treatment, 94% of people
in the 12-week triple therapy arm and 92% in the other two groups achieved
sustained virological response (SVR4).
Looking just at participants in the first arm, who
received 12 weeks of triple therapy without further treatment, 90% achieved
12-week sustained virological response (SVR12), generally regarded as a cure.
Follow-up is continuing for the patients treated for 24 weeks.
Four people who relapsed after finishing treatment in
this arm had their virus sequenced to look for resistance, and none showed
evidence of the signature S282T mutation (deep sequencing results are pending).
GS-7977 triple therapy was generally well tolerated.
The most common side-effects were those associated with interferon including
fatigue and headache. Interestingly, fever and chills were more than twice as
common among people who received the short triple regimen. Skin rash and
anaemia were more common in the two groups treated for 24 weeks.
Although 10% of patients in the
12-week triple therapy arm experienced severe adverse events compared with 5%
and 4% in the other two arms, Kowdley explained that no
serious adverse events were attributed to GS-7977 and no two patients
experienced the same serious events.
"GS-7977 400mg once daily in combination with
[pegylated interferon/ribavirin] for 12 weeks is potent, safe and highly
effective for the treatment of HCV genotype 1", the researchers concluded,
adding that "12 weeks of GS-7977 in combination with [pegylated
interferon/ribavirin] appears to be as effective as 24 weeks of therapy".
During the question period following his presentation,
Kowdley noted that eight of the eleven genotype 4 patients in the study and all
five of the genotype 6 patients achieved SVR4.
Asked about his presentation's
provocative subtitle referencing "an end to response-guided therapy",
Kowdley suggested that a drug with a high barrier to resistance such as GS-7977
might allow a "paradigm shift" toward
standardised shorter treatment.