Two other
presentations reported results from studies of sofosbuvir plus GS-5816 taken with
or without ribavirin for 8 weeks. A shorter treatment duration is more
tolerable and less expensive, but may increase the likelihood of relapse.
Tram Tran from Cedars-Sinai Medical Center in Los Angeles presented
findings from a phase 2 trial (GS-US-342-0102) evaluating sofosbuvir plus GS-5816 for
previously untreated patients with HCV genotypes 1 through 6 who did not have cirrhosis.
In Part A of the study, presented
at the EASL International Liver Congress in April, 55 patients with
genotype 1, 54 people with genotype 3, and 45 people with genotypes 2, 4, 5 or
6 were treated with sofosbuvir plus either 25mg or 100mg GS-5816, all without
ribavirin for 12 weeks. As previously reported, SVR12 rates ranged from 91% to
100% using the 25mg GS-5816 dose and from 86% to 100% using the 100mg dose.
Based on these promising results, Part B evaluated a shorter treatment
duration of 8 weeks in 120 genotype 1 patients (most with subtype 1a) and 103
genotype 2 patients. More than half were men, most were white, the mean age was
51 years and about one-third had unfavourable IL28B variants.
Again, they were randomly assigned to received sofosbuvir plus either
25mg or 100mg GS-5816, but this time they were also randomised to take this
regimen with or without ribavirin, all for 8 weeks.
Among genotype 1 patients, SVR12 rates were 87% for those taking 25mg GS-5816 without ribavirin, 83%
for those taking 25mg with ribavirin, 90% for those taking 100mg GS-5816
without ribavirin and 81% for those taking 100mg with ribavirin. Among the
genotype 2 patients, SVR12 rates were 77% for those taking 25mg GS-5816 without ribavirin and 88% in the
other three arms. In both groups, all virological failures were due to
post-treatment relapse.
One-quarter
of genotype 1 patients and half of genotype 2 patients had NS5A
resistance-associated viral variants present prior to treatment. Genotype 1
patients had similar cure rates regardless of the presence or absence of
resistance variants (86% vs 88%, respectively), but among people with genotype
2, those with baseline resistance variants had a lower response rate (81% vs
94%). One-third of patients with virological failure had resistance variants
detected post-treatment.
The
researchers concluded that "SVR rates were lower and relapse rates were
higher in genotype 1 and genotype 2 patients treated for 8 weeks compared to
those treated for 12 weeks."
Finally, Edward Gane from Auckland Clinical Studies in New Zealand
presented findings from the ELECTRON-2 trial, comparing the same 8-week
regimens for treatment-naive genotype 3 patients without cirrhosis.
In this study, which included 104 participants, about two-thirds were
men, most were white, the mean age was approximately 48 years and 25% to 56%
had favourable IL28B variants. Almost all had HCV subtype 3a, with a few having
3k and several having an unknown subtype.
SVR12 rates were 100% for those taking 25mg GS-5816 without ribavirin, 88% for those
taking 25mg with ribavirin (with two relapses and one discontinuation due to an
adverse event), 96% for those taking 100mg GS-5816 without ribavirin (with one
withdrawal of consent) and 100% for those taking 100mg with ribavirin.
Genetic
sequencing showed that 26% of participants had NS5A resistance variants at
baseline. One relapser had a Y93H mutation at baseline, but the other had no
baseline or treatment-emergent resistance variants. Conversely, 10 of the 11
patients with the Y93H variant at baseline nonetheless achieved SVR12.
In all three studies, sofosbuvir plus GS-5816 was generally safe and
well-tolerated with few serious adverse events or early discontinuations due to
adverse events. The most frequently reported side-effects were headache,
fatigue, nausea, diarrhoea, insomnia and itching or rash. Anaemia was observed more
often in the ribavirin-containing arms, but was rarely severe.
These findings indicate that some patients are likely to be cured with
only 8 weeks of treatment, but shortening therapy should be done cautiously. Among genotype 1 and 2 patients
in Tran's study, neither the higher GS-5816 dose nor addition of ribavirin
raised response rates into the now-expected 90% to 100% range using this short
treatment duration. But in Gane's study of genotype 3 patients, no one using
the higher GS-5816 dose, with or without ribavirin, experienced virological
failure.
Based on these results, the 100mg dose of GS-5816 has been selected and
combined with sofosbuvir in a co-formulation that will be tested for 12 weeks
without ribavirin in phase 3 trials. SVR12 rates have ranged from 86% to 100% for
patients across all genotypes treated with this regimen in phase 2 studies.
ASTRAL-2 and ASTRAL-3 (now recruiting)
will compare the sofosbuvir/GS-5816 coformulation without ribavirin for 12 weeks versus the
currently approved regimen of sofosbuvir/ribavirin for 12 weeks for genotype 2
or 24 weeks for genotype 3.