A new three-drug regimen of sofosbuvir, velpatasvir and voxilaprevir,
taken without ribavirin for 8 weeks, produced sustained virological response in
96% of previously untreated people with all hepatitis C virus (HCV)
genotypes, while a 12-week course cured 99% of treatment-experienced people,
researchers reported at the recent IDWeek meeting in New Orleans. Response
rates dropped off, however, when treatment was shortened to 6 weeks.
The advent of direct-acting antiviral agents (DAAs) used in interferon-free
regimens has revolutionised treatment for chronic hepatitis C, but there is
still room for shorter, simpler therapy and better options for
difficult-to-treat patients. Pangenotypic regimens active against all HCV
genotypes could potentially be used worldwide without the need for genotypic
testing.
Gilead Sciences is testing a new three-drug regimen combining agents
from three different classes: the previously approved HCV polymerase inhibitor
sofosbuvir, the NS5A inhibitor velpatasvir and the investigational HCV protease
inhibitor voxilaprevir (formerly GS-9857).
Gilead already sells two highly effective two-drug co-formulations,
sofosbuvir/ledipasvir (Harvoni) and
sofosbuvir/velpatasvir (Epclusa), the
latter of which is pangenotypic. It does not yet have an HCV
protease inhibitor approved by the US Food and Drug Administration (FDA), although other companies do (Janssen's simeprevir [Olysio], AbbVie's paritaprevir [in Viekirax co-formulation], Merck's
grazoprevir [in Zepatier
co-formulation], and Bristol-Myers Squibb's asunaprevir [Sunvepra]). In early studies voxilaprevir appeared to have an
improved resistance profile compared to other protease inhibitors.
At IDWeek Ronald Nahass of ID Care, Inc. presented findings from a post-hoc
integrated analysis of the safety and efficacy of sofosbuvir/velpatasvir plus voxilaprevir in a pair of phase 2 clinical
trials.
The integrated analysis
included a total of 325 participants. Around two-thirds were men, most were
white and the average age was approximately 56 years. Study GS-US-367-1168 enrolled people
with HCV genotype 1, while GS-US-367-1169 enrolled people with genotypes 2-6.
Taken together, about 60%
of participants had genotype 1, 10% had genotype 2, 23% had hard-to-treat
genotype 3, 5% had genotype 4, none had genotype 5 and 3 people had genotype 6.
Nearly half had liver cirrhosis. About 40% were treatment-experienced,
including 27% who had previously used NS5A inhibitors, 52% who had used other
DAAs and 21% who had used pegylated interferon plus ribavirin.
Regimens were assigned on
the basis of genotype, prior treatment history and presence of cirrhosis:
- 67 easier-to-treat participants – treatment-naive genotype 1-6 patients
without cirrhosis – received sofosbuvir/velpatasvir plus voxilaprevir for 6
weeks.
- 99 treatment-naive genotype 1 participants with or without cirrhosis
received sofosbuvir/velpatasvir plus voxilaprevir for 8 weeks.
- 31 treatment-naive genotype 1 participants with cirrhosis received
sofosbuvir/velpatasvir plus voxilaprevir with ribavirin for 8 weeks.
- 128 treatment-experienced genotype 1-6 participants with or without
cirrhosis received sofosbuvir/velpatasvir plus voxilaprevir for 12 weeks.
The primary endpoint was
sustained virological response, or continued undetectable HCV RNA at 12 weeks
after completing treatment (SVR12). Results from the treatment-experienced
group were previously presented at this year's EASL International Liver Congress.
The 6-week
regimen was least effective, with an overall SVR12 rate of 79%. However, all 21
genotype 3 participants (100%) were cured, compared to 71% of people with genotype
1 and 64% with genotypes 2, 4 or 6.
The 8-week
regimen without ribavirin produced an overall SVR12 rate of 96%, with similar
rates across all genotypes (92-97%). The 8-week regimen with ribavirin cured
81% of people with genotype 1 – the only ones treated with this combination.
The 12-week
regimen produced an overall cure rate of 99%, again similar across all
genotypes (97-100%).
Looking at
various factors that predict response to DAA treatment, the 8- and 12-week
regimens without ribavirin cured 94% and 98% of people with cirrhosis,
respectively, and 100% of people without cirrhosis. SVR12 rates were high for
hard-to-treat genotype 3 patients with or without cirrhosis (94% and 100%,
respectively), even using the short 6-week regimen.
Nearly half (47%)
of previously untreated participants had pre-existing resistance-associated
variants, and their overall cure rate was the same as that of people without
baseline RAVs (96%). Treatment-experienced people had high SVR12 rates with
or without a prior history of NS5A use (100% and 99%, respectively).
Treatment with sofosbuvir/velpatasvir plus voxilaprevir
was generally safe and well tolerated, with only one serious adverse event and four
discontinuations due to adverse events. The most common adverse events were
headache, fatigue, nausea and diarrhoea, generally mild or moderate.
Side-effects and laboratory abnormalities were more common in the group that
received ribavirin, including six cases of anaemia (versus none in the
ribavirin-free arms).
"Treatment
with sofosbuvir/velpatasvir plus
voxilaprevir administered once daily for 8 weeks was generally safe,
well tolerated and highly effective in treatment-naive HCV genotype 1-6
patients with and without cirrhosis," the researchers concluded. "6
week treatment duration was associated with higher relapse rate for genotypes
1, 2, 4 and 6. Sofosbuvir/velpatasvir
plus voxilaprevir for 12 weeks resulted in 99% SVR12 rate in
treatment-experienced patients with HCV genotypes 1-6."
Sofosbuvir/velpatasvir
plus voxilaprevir have been combined in a once-daily single-tablet regimen and
evaluated in the phase 3 POLARIS trials. Gilead recently reported in a press release that the co-formulation taken for 8 or
12 weeks produced SVR12 rates of 95 to 97% for DAA-naive and DAA-experienced
people with HCV genotypes 1-6, with or without cirrhosis. The company
indicated that it plans to request FDA approval
of the new co-formulation by the end of the year.