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Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naïve patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial
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a randomized, 28-day, dose-ranging trial
Article in Press
Journal of Hepatology
Nov 26 2012
Authors: Maribel Rodriguez-Torres1, Eric Lawitz2, Kris V. Kowdley3, David R. Nelson4,
Edwin DeJesus5, John G. McHutchison6, Melanie T. Cornpropst7*, Michael Mader6*, Efsevia Albanis6*, Deyuan Jiang6, Christy M. Hebner6, William T. Symonds6*, Michelle M. Berrey8*, Jay Lalezari9
Affiliations: 1Fundacion de Investigacion de Diego, Santurce, PR, USA; 2Alamo Medical
Research, San Antonio, TX, USA; 3Digestive Disease Institute, Virginia Mason Medical
Center, Seattle, WA, USA; 4University of Florida, Gainesville, FL, USA; 5Orlando
Immunology Center, Orlando, FL, USA; 6Gilead Sciences, Foster City, CA, USA; 7BioCryst, Durham, NC, USA; 8Independent Consultant; 9Quest Clinical Research, San Francisco, CA, USA
*Employed by Pharmasset, Inc., Princeton, NJ, USA at the time the study was conducted
Abstract
Background and aims
Sofosbuvir (formerly GS-7977) is a pyrimidine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase. We assessed the safety, tolerability, antiviral activity, and pharmacokinetics of sofosbuvir plus pegylated-interferon (peg-IFN)/ribavirin (RBV) in a 28-day, dose-ranging trial in treatment-naïve patients infected with genotype 1 HCV.
Methods
In this double-blind study, 64 patients were randomized (1:1:1:1) to receive one of three once-daily doses of oral sofosbuvir (100, 200, or 400mg) or placebo plus peg-IFN/RBV for 28days, after which all patients continued to receive peg-IFN/RBV alone for a further 44weeks.
Results
Patients in the sofosbuvir/peg-IFN/RBV groups experienced mean reductions in HCV RNA >5log10IU/mL (-5.3 for 100mg, -5.1 for 200mg and -5.3 for 400mg) vs -2.8log10IU/mL for placebo/peg-IFN/RBV after 28 days. Rapid virologic response (RVR) rates were markedly higher after sofosbuvir treatment (88-94%) than placebo (21%), as were rates of sustained virologic response (SVR) at post-treatment Week24 (56%, 83%, and 80% for sofosbuvir 100, 200, and 400mg, respectively, vs 43% for placebo). The number of patients experiencing virologic breakthrough and post-treatment relapse were higher in the sofosbuvir 100 mg group than sofosbuvir 200 and 400 mg groups. Sofosbuvir was well tolerated; the most frequent adverse events were fatigue and nausea.
Conclusions
These results support further studies with sofosbuvir at 200mg and 400mg to determine the optimal dose and treatment duration of sofosbuvir in HCV genotype 1. (Clinicaltrials.gov: NCT01054729)
RESULTS
Study Population Disposition and Demographics
The demographic characteristics of the study population were similar across treatment groups (Table 1); patients in the placebo/peg-IFN/RBV treatment group had higher mean weight and body mass index than those in the sofosbuvir/peg-IFN/RBV treatment groups. There were no notable differences between the treatment groups for any disease characteristic (Table 1). Of the 64 randomized patients, 63 received at least one dose of study medication and were included in the safety analysis: sofosbuvir 100 mg (16 subjects), sofosbuvir 200 mg (18 subjects), sofosbuvir 400 mg (15 subjects), and placebo (14 subjects). Sixty-two completed the sofosbuvir/peg-IFN/RBV treatment period. One patient in the sofosbuvir 200 mg arm withdrew consent before receiving the first dose of study medication, and another patient in the same arm was lost to follow-up. Forty-six patients completed the 44-week peg-IFN/RBV treatment period (Table 2).
Efficacy Results
On-treatment results
Patients receiving sofosbuvir co-administered with peg-IFN/RBV had substantially greater suppression of plasma HCV RNA than those receiving placebo/peg-IFN/RBV (Fig. 1). Mean change from baseline in HCV RNA at Day 28 was -5.3 log10 IU/mL for patients receiving sofosbuvir 100 mg, -5.1 log10 IU/mL for 200 mg, and -5.3 log10 IU/mL for 400 mg versus -2.8 log10 IU/mL for placebo/peg-IFN/RBV. Viral suppression was rapid; by Day 7 of treatment, patients receiving sofosbuvir experienced mean reductions of 3.49 log10 IU/mL in the 100-mg group, 4.03 log10 IU/mL in the 200-mg group, and 4.44 log10 IU/mL in the 400-mg group, vs 0.97 log10 IU/mL in the group receiving placebo plus peg-IFN and ribavirin.
Near maximal suppression of HCV RNA levels was observed on Day 22 for the sofosbuvir/peg-IFN/RBV 200 mg and 400 mg treatment groups and by Day 28 in the sofosbuvir 100 mg/peg-IFN/RBV treatment group.
Rapid virologic response rates were markedly higher in patients receiving sofosbuvir at all dose levels compared with placebo (Table 3). Three of the four patients who received sofosbuvir and did not achieve RVR had unfavourable prognostic factors (non-CC IL28B alleles and baseline HCV RNA >800,000 IU/mL). One patient in the sofosbuvir 200 mg group was lost to follow-up during the initial 28-day dosing period; this patient was classed as a treatment failure at all subsequent timepoints.
No viral breakthrough was observed in any patient receiving sofosbuvir during the 28-day dosing period. Eight patients experienced viral breakthrough during peg-IFN/RBV treatment (4 in the sofosbuvir 100 mg arm, 2 in the sofosbuvir 400 mg arm, and 2 in the placebo arm). All had baseline HCV RNA >800,000 IU/mL and most (7/8) had non-CC IL28B alleles.
Sustained virologic response
Patients in the sofosbuvir dose groups had higher rates of SVR than those treated with placebo/peg-IFN/RBV. SVR rates at post-treatment Week 24 were 56%, 83%, and 80% for sofosbuvir 100 mg, 200 mg, and 400 mg, respectively, versus 43% for peg-IFN/RBV (Table 3). One patient who completed treatment with sofosbuvir 400 mg/peg-IFN/RBV but discontinued peg-IFN/RBV on Day 29, achieved SVR12 and SVR24. This patient had genotype 1a HCV infection, the CC IL28B allele, and a baseline HCV RNA level of 1,740,000 IU/mL. Ten patients experienced viral relapse after the end of treatment, five who received sofosbuvir 100 mg, one each who received sofosbuvir 200 mg and 400 mg, and three who received placebo. All patients who received sofosbuvir and relapsed had baseline HCV RNA >800,000 IU/mL (range: 2,160,000-26,100,000 IU/mL) and most (6/7) had non- CC IL28B alleles.
Subgroup efficacy analysis showed that there was no effect of gender, race, ethnicity, HCV genotype, IL28B genotype, baseline HCV RNA levels or HOMA-IR score in the reduction of HCV RNA levels following 28 days of dosing with sofosbuvir/peg-IFN/RBV.
Resistance monitoring
The NS5B region of all 63 treated subjects was analyzed at baseline; the S282T mutation was not detected in any sample. Samples for the 12 patients who qualified for monitoring by the criteria specified in the methods section (non-responders or rebounders, those had virologic breakthrough, or HCV viral load plateaus between Day 1 and Day 28) were also analyzed. The S282T mutation was not detected in any of the samples at any of the timepoints tested. In addition, sequencing of the entire NS5B sequence from the virologic failures did not identify any mutation at positions 316, 414, 423, 482, 486, 495, 554, or 559, which have been previously reported to be associated with resistance to non-nucleoside inhibitors.
Safety Results
Fifty-four of the 63 study patients reported adverse events during the 28-day treatment period with sofosbuvir/peg-IFN/RBV, irrespective of dose. The most frequently reported adverse events during this period were fatigue, nausea, chills, headache, and arthralgia (Table 4). The frequency and intensity of adverse events was comparable between the sofosbuvir/peg-IFN/RBV treatment groups and the placebo/peg-IFN/RBV group. All adverse events were considered mild or moderate in intensity by the investigator; most (260/282; 92%) resolved. During the sofosbuvir plus peg-IFN/RBV treatment phase of the study, no serious adverse events and no adverse events that led to discontinuation of study medication were reported. However, during the peg-IFN/RBV treatment phase, five patients discontinued peg-IFN/RBV and five patients experienced a serious adverse event (one patient whose last dose was sofosbuvir 100 mg [peripheral ischemia]; three patients whose last dose was sofosbuvir 400 mg [acute pancreatitis; anemia; depression]; one patient whose last dose was placebo [abdominal pain]). All serious adverse events occurred at least 50 days after the end of sofosbuvir treatment and all resolved.
Changes in hematologic parameters, including hemoglobin (Fig. 2A), erythrocytes, lymphocytes, basophils, eosinophils, neutrophils, (Fig. 2B) and platelets were similar in sofosbuvir and placebo arms and were consistent with changes observed during treatment with peg-IFN and ribavirin alone. No significant changes were observed in vital signs and ECG evaluations.
Pharmacokinetic Results
Following single or multiple dosing, sofosbuvir was absorbed rapidly with a median [range] tmax of 1 hour [0.5-3.0]. Sofosbuvir elimination was rapid with median to in the range of 0.48-0.75 hours. GS-331007 exhibited a longer tmax (median [range]: 4 hours [1.5-8]) and half-life (median to range: 7.27-11.80) than sofosbuvir. No significant accumulation of sofosbuvir or GS-331007 was observed (accumulation ratio close to 1).
DISCUSSION
In this dose-ranging study, treatment-naïve genotype 1 patients receiving sofosbuvir 100-400 mg and peg-IFN/RBV for 28 days followed by 44 weeks of peg-IFN/RBV experienced more rapid viral suppression and substantially higher rates of on-treatment and post-treatment response than patients receiving 48 weeks of peg-IFN/RBV. By Day 21 of treatment, all three sofosbuvir groups experienced mean reductions of >5 log10 IU/mL in HCV RNA compared to 2.2 IU/mL in patients receiving peg-IFN/RBV. Rates of rapid virologic response for patients in the sofosbuvir arms ranged from 88% to 94% vs 21% in patients receiving peg-IFN/RBV alone.
Although response during the 28-day, sofosbuvir/placebo phase of the study was nearly identical for all three sofosbuvir groups, differences begin to emerge during the peg-IFN/RBV phase of dosing. Four patients in the 100-mg group experienced viral breakthrough soon after the end of sofosbuvir dosing. By contrast, no patients in the 200-mg group and two in the 400-mg group experienced breakthrough during peg-IFN/RBV dosing. In posttreatment follow-up, the inadequacy of the 100-mg dose of sofosbuvir became more evident. Five patients in the 100-mg group relapsed almost immediately after the end of treatment, whereas only one patient each in the 200- and 400-mg groups relapsed during follow-up. The rate of SVR24 for the 100-mg group was 56% as compared to 83% and 80% for the 200- and 400-mg groups, respectively. As a result, the 200- and 400-mg doses were selected for further evaluation in Phase IIb trials.
The adverse events seen during this trial were those commonly observed during treatment with peg-IFN and RBV [11, 12]. During the 28-day dosing period, sofosbuvir was generally safe and well-tolerated with all adverse events classified as mild or moderate in intensity. Changes in hematology parameters relating to anemia (reductions in the levels of hemoglobin and erythrocytes) and neutropenia were consistent with those observed for peg-IFN/RBV [11, 12].
The marked antiviral activity and SVR rates observed with 28 days of sofosbuvir in combination with PEG+RBV suggest that sofosbuvir may be a beneficial component of a treatment regimen for patients with HCV. Further studies are warranted to determine the optimal sofosbuvir treatment duration, efficacy of sofosbuvir in other genotypes of HCV infection (2 to 6), and whether sofosbuvir can play a role in interferon-sparing treatment regimens.
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