Showing posts with label GS-7977 now Sofosbuvir and simeprevir (TMC435). Show all posts
Showing posts with label GS-7977 now Sofosbuvir and simeprevir (TMC435). Show all posts

Tuesday, May 27, 2014

Sofosbuvir in the Treatment of Hepatitis C-A Review of Its Clinical Potential

Therapeutic Advances in Gastroenterology

Sofosbuvir, a NS5B Polymerase Inhibitor in the Treatment of Hepatitis C

A Review of Its Clinical Potential

Abstract
Treatment of chronic hepatitis C (HCV) is currently undergoing a significant change. Traditional interferon-based therapy has been limited by both efficacy and tolerability, and many direct acting antiviral (DAA) drugs are emerging. Sofosbuvir (GS-7977) is a HCV NS5B nucleotide polymerase inhibitor that has now been evaluated extensively in phase II and III interferon-free clinical trials. The focus of this review is on the clinical potential of sofosbuvir in the treatment of HCV. Sofosbuvir has a pan-genotypic effect on HCV, although viral genotype-specific differences in sustained virological response (SVR) have emerged in phase III clinical trials. Sofosbuvir has been studied both as dual therapy with ribavirin and also as triple therapy with either NS5A inhibitors or a protease inhibitor. High rates of SVR have been reported with these interferon-free combinations, particularly with genotypes 1 and 2, and the safety profile has been very favourable in both cirrhotic and noncirrhotic patients, without issues of viral resistance. Interferon-free, once-daily treatment of HCV is now becoming a reality.

Introduction
Chronic hepatitis C virus (HCV) infection is a cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. For the past two decades, interferon-based therapy has been the cornerstone of HCV treatment, but success has been limited by poor tolerability and suboptimal sustained virological response (SVR) rates, even when combined with ribavirin. Boceprevir and telaprevir were the first direct-acting antiviral (DAA) drugs to be approved for the treatment of HCV in 2011, and resulted in improved SVR rates from approximately 40–44% to 68–75% in treatment-naïve patients with genotype 1 HCV [Jacobson et al. 2011; Poordad et al. 2011]. However, because of rapid emergence of viral resistance with protease inhibitor monotherapy, these agents are only effective when used as triple therapy in conjunction with peginterferon and ribavirin. Consequently the use of these NS3/4 protease inhibitors adds to the adverse event profile of peginterferon plus ribavirin, particularly in patients with cirrhosis where cytopaenias and other serious adverse events represent a significant safety concern [Fontaine et al. 2013].

There are three major classes of DAA drugs currently in phase III clinical trials: NS3/4A protease inhibitors, NS5A inhibitors and NS5B polymerase inhibitors, which can be subdivided into nucleoside inhibitors or nonnucleoside inhibitors. The NS5B polymerase is responsible for viral RNA replication, and the catalytic site of the NS5B protein is highly conserved across the different HCV genotypes, making nucleos(t)ide inhibitors that target this protein appealing as a treatment option. The nucleoside analogues interfere with the viral lifecycle by inducing a chain termination event and breaking transcription of the viral polyprotein [Sofia et al. 2010]. In general terms, they also have reasonably high potency and a high barrier to viral resistance. In contrast, the nonnucleoside inhibitors that target allosteric sites on NS5B tend to display lower potency and a low barrier to viral resistance.

Sofosbuvir, also known as GS-7977 (and previously known as PSI-7977), is a nucleotide inhibitor of NS5B and this review will consider its clinical potential as a promising drug for the treatment of HCV infection.

Pharmacology of Sofosbuvir
Sofosbuvir is a prodrug of 2'-deoxy-2'-fluoro- 2'-C-methyluridine monophosphate that is converted within hepatocytes to its active uridine triphosphate form, causing chain termination during replication of the viral genome [Murakami et al. 2010]. In vitro, the active triphosphate inhibits recombinant NS5B polymerases from HCV genotypes 1-4 with similar half maximum inhibitory concentration values for each genotype, indicating broad activity across HCV genotypes [Lam et al. 2012]. The chemistry of sofosbuvir has previously been reviewed [Herbst and Reddy, 2013] and will not be reviewed in detail in this paper.

Sofosbuvir is primarily eliminated from the body via the kidney as GS-331007 (formerly called PSI-6206), an inactive nucleoside metabolite. Single-dose pharmacokinetics of sofosbuvir were studied in subjects with normal renal function (estimated glomerular filtration rate [eGFR] > 80 ml/min), mild (eGFR 50–80 ml/min), moderate (eGFR 30–49 ml/min) and severe (eGFR < 30 ml/min) renal impairment. The area under the curve (AUC) of GS-331007 and, to a lesser extent, sofosbuvir increased with decreased renal status. There was a linear relationship between GS-331007 renal clearance and creatinine clearance. Subjects with mild, moderate and severe renal impairment had approximately 56%, 90% and 456% higher GS-331007 AUC, respectively, than subjects with normal renal function [Cornpropst et al. 2012]. Further studies are required to determine the safe use of sofosbuvir in patients with severe renal impairment.

In a study of hepatic impairment, HCV-infected subjects with moderate hepatic impairment were administered sofosbuvir 400 mg QD for 7 days; sofosbuvir was generally well tolerated and resulted in similar systemic exposure to GS-331007 as noncirrhotic subjects. Significant declines in HCV RNA were observed in all subjects over 7 days of dosing [Lawitz et al. 2012]. Therefore, dose modifications are not required in hepatic impairment.

There is no clinically significant interaction of sofosbuvir with food, or with coadministration of methadone, cyclosporine or tacrolimus [Denning et al. 2011; Mathias et al. 2012].

Clinical Trial Data
In the initial phase II studies, sofosbuvir was evaluated in combination with peginterferon and ribavirin (PEG/RBV). In a 28-day, dose-ranging trial in subjects infected with genotype 1 HCV, 64 patients were randomized to receive one of three once-daily doses of oral sofosbuvir (100, 200 or 400 mg) or placebo plus peginterferon and ribavirin for 28 days, after which all patients continued to receive peginterferon and ribavirin for a further 44 weeks [ClinicalTrials.gov identifier: NCT01054729].

Patients in the sofosbuvir/peginterferon/ribavirin groups showed mean reductions in HCV RNA >5 log10IU/ml for all doses versus 2.8 log10IU/ml for placebo/peginterferon/ribavirin after 28 days. Although response during the 28-day sofosbuvir/placebo phase of the study was nearly identical for all three sofosbuvir groups, differences emerged during the peginterferon and ribavirin phase of dosing, with SVR24 of 56% for the 100 mg group as compared with 83% and 80% for the 200 and 400 mg groups, respectively [Rodriguez-Torres et al. 2013]. The 200 and 400 mg doses were therefore selected for further evaluation in phase IIb trials.

PROTON
PROTON was a double-blind, randomized, placebo- controlled, dose-ranging phase II study that demonstrated that sofosbuvir was highly effective against genotypes 1, 2 and 3 HCV when used in combination with peginterferon and ribavirin as 12-week triple therapy, followed by additional peginterferon and ribavirin in the genotype 1 patients, with SVR12 results greater than 90% in all sofosbuvir-containing arms of the study [Lawitz et al. 2013c] (Table 1) - See Below.

ATOMIC
The ATOMIC study explored shorter treatment durations of sofosbuvir-based triple therapy, and randomized 316 treatment-naïve patients with genotype 1 HCV into three treatment arms that included sofosbuvir 400 mg plus peginterferon and ribavirin therapy of 12 or 24 weeks duration, and one arm who received sofosbuvir triple therapy for 12 weeks, and then subjects were randomized to receive a further 12 weeks of sofosbuvir alone or with ribavirin [Kowdley et al. 2013]. A total of 11 patients with genotype 4 and 5 patients with genotype 6 were also included in cohort B of the study (Table 1)-See Below, SVR rates remained greater than 90% in all arms of this study, with minimal differences in SVR seen in patients with factors traditionally associated with reduced response to interferon-based therapy such as high baseline viral load, patients with non-CC IL28B genotypes or bridging fibrosis on liver biopsy [Kowdley et al. 2013]. The findings also suggested that there was no additional benefit from extending sofosbuvir triple therapy beyond 12 weeks.

ELECTRON
Following on from PROTON and ATOMIC, the ELECTRON study evaluated sofosbuvir in interferon- sparing and interferon-free regimens for the treatment of HCV infection in noncirrhotic patients (Table 1)-See Below. In the initial cohort, 40 treatment- naïve patients with genotype 2 or 3 HCV were randomized to four groups, all containing sofosbuvir 400 mg/day and weight-based ribavirin. Three of the groups also received peginterferon for 4, 8 or 12 weeks. All 40 patients had a SVR at week 24, irrespective of whether or not they received peginterferon [Gane et al. 2013c]. Two additional cohorts of patients with genotype 2 or 3 infection received either sofosbuvir monotherapy for 12 weeks, resulting in 60% SVR24, or sofosbuvir-based triple therapy for 8 weeks, with 100% SVR24.

Two groups of patients with HCV genotype 1 infection also received sofosbuvir and ribavirin for 12 weeks without peginterferon, including 25 treatment-naïve patients and 10 prior null responders to peginterferon. Among patients with genotype 1 infection, 84% of previously untreated patients and 10% of prior null responders achieved SVR24 in this interferonfree regimen. Again, a high proportion of patients had a non-CC IL28B genotype, and 89% were infected with genotype 1a which has been associated with lower response rates to other DAA therapy such as telaprevir- or boceprevir-based triple therapy. This study was proof of concept that SVR can be obtained with sofosbuvir-based, interferon-free regimens in genotypes 1, 2 and 3 HCV infection, and also demonstrated an ongoing role of ribavirin in preventing relapse after treatment.

Later cohorts of ELECTRON explored sofosbuvir/ribavirin in treatment-experienced patients with genotypes 2 and 3 and also cohorts with shorter durations of treatment and lower doses of ribavirin [ClinicalTrials.gov identifier: NCT01260350], although these results have only been partially published in abstract form [Gane et al. 2012], and weight-based ribavirin dosing has been used for ongoing clinical development with sofosbuvir-dual therapy. Patients with genotype 1 HCV were also treated with triple therapy combinations of sofosbuvir/ribavirin and additional DAA drugs including the NS5A inhibitor ledipasvir (LDV; GS-5885) in a once-daily fixed dose combination, or the HCV NS5B nonnucleoside inhibitor GS9669. With both of these triple therapy combinations, excellent SVR rates have been reported in both treatment-naïve patients and also null responders who are traditionally resistant to other forms of DAA triple therapy with first-generation protease inhibitors [Gane et al. 2013a; Gane et al. 2013b] (Table 1)-See Below.

LONESTAR
The LONESTAR study continued to evaluate different lengths of therapy (8 or 12 weeks) with the fixed-dose combination of sofosbuvir and ledipasvir with or without ribavirin in patients with genotype 1 HCV (Table 1). Cohorts included both treatment-naïve GT1 patients, and also 40 patients who had previously failed therapy with an HCV-specific protease inhibitor-based regimen. Half of these patients had compensated cirrhosis. SVR4 rates of at least 95% in all cohorts have been reported in a recent Gilead press release [Gilead Sciences, 2013], and phase III trials are planned with the fixed-dose combination of sofosbuvir and ledipasvir.

Daclatasvir and Sofosbuvir
Two clinical trials have evaluated sofosbuvir in combination with the NS5A inhibitor daclatasvir. The first trial reported was of treatment-naïve patients with HCV genotypes 1, 2 and 3 who were randomized to daclatasvir plus sofosbuvir with or without ribavirin for a total treatment duration of 24 weeks although some arms had a 1-week sofosbuvir lead-in phase before the daclatasvir was added. SVR12 was achieved in 100% of genotype 1 patients and 86–100% of patients in the genotype 2/3 cohort [Sulkowski et al. 2012].

The combination of daclatasvir and sofosbuvir has also been evaluated in 41 HCV genotype 1 patients who had previously failed protease-inhibitor- based triple therapy with either telaprevir or boceprevir and were treated with 24 weeks of sofosbuvir plus daclatasvir, with or without ribavirin [Sulkowski et al. 2013]. Impressively, SVR12 rates of 95–100% were obtained, whether or not the combination included ribavirin, demonstrating that this combination of sofosbuvir with an NS5A inhibitor is an effective therapy even in people with NS3A protease inhibitor resistance.

COSMOS
The COSMOS study is evaluating a once-daily regimen of the NS3/4A protease inhibitor simeprevir (TMC435) plus sofosbuvir with or without ribavirin for 12 or 24 weeks in HCV genotype 1 patients (Table 1). Cohort 1 consists of patients with prior null response to peginterferon with mild to moderate fibrosis, and preliminary results from the 12-week cohort have been recently presented showing SVR4 rates of 96% and 93% for patients with and without ribavirin, respectively [Lawitz et al. 2013b]. Cohort 2 includes both peginterferon null responders and treatment-naïve patients with advanced fibrosis and a recent press release reports SVR4 results of 96–100% in the 12-week group [Medivir, 2013].

Phase III Trials of Sofosbuvir
Four phase III trials of sofosbuvir have been published to date, all evaluating sofosbuvir 400 mg plus ribavirin (weight-based dosing) for at least 12 weeks in patients with chronic HCV (Table 2)-See Below.

In the FISSION study, 499 treatment-naïve patients with genotype 2 or 3 HCV were randomized to sofosbuvir 400 mg plus ribavirin for 12 weeks or peginterferon plus ribavirin for 24 weeks in a noninferiority trial. In this trial, despite a marked difference in the RVR rates (99% versus 67%, respectively), the SVR12 rates were identical at 67% [Lawitz et al. 2013d] (Table 2)-See Below. Notably, in this study there was a marked difference in response rates between patients with genotype 2 (97% SVR 12) and genotype 3 (56% SVR12) HCV, and between cirrhotic (47% SVR12) and noncirrhotic (72% SVR12) patients.

The NEUTRINO study was a 12-week open label study of sofosbuvir plus ribavirin in treatment naive patients with HCV genotype 1, 4, 5 or 6 (of whom 98% had genotype 1 or 4). SVR12 rates of 90% were observed overall, with 81% response rates in genotype 1 with cirrhosis. These cirrhotic patients also had extremely low rates of treatment discontinuation of only 2%, suggesting that this combination is safe and extremely well tolerated even in cirrhotic patients [Lawitz et al. 2013d].
POSITRON evaluated sofosbuvir plus ribavirin compared with placebo in patients with genotype 2 and 3 HCV in whom interferon was not an option (previously intolerant of interferon, unwilling or unable to take interferon). Overall SVR12 rates in the sofosbuvir/ribavirin group were higher than in FISSION (78%), possibly because of the higher proportion of genotype 2 patients who again demonstrated significantly higher SVR12 rates (92%) than genotype 3 (68%). Degree of liver fibrosis did not appear to significantly influence outcomes in genotype 2 patients (94% SVR12 even in those with cirrhosis), but in genotype 3 patients, SVR12 rates were low at 21% in patients with cirrhosis [Jacobson et al. 2013].

FUSION
The FUSION study was a blinded, active-control study involving patients with genotype 2 or 3 HCV who had not had a response to prior treatment with an interferon-containing regimen. Patients were randomly assigned to either 12 weeks of sofosbuvir and ribavirin followed by 4 weeks of matching placebo, or 16 weeks of sofosbuvir and ribavirin. One third of participants were cirrhotic. Overall rates of SVR were significantly higher in the 16-week arm (73%) than in the 12-week arm (50%), and again the genotype 2 patients had higher SVR rates (86% and 94% for 12 and 16 weeks, respectively) than genotype 3 patients (30% and 62% respectively for 12 and 16 weeks) [Jacobson et al. 2013]. Cirrhosis was associated with a decreased rate of SVR, particularly in genotype 3 receiving 12 weeks of therapy rather than 16 weeks (SVR 19% versus 61%). In genotype 2 patients SVR rates ranged from 60% to 78% in cirrhotic patients, and up to 100% in noncirrhotic patients without cirrhosis who were treated for 16 weeks.

Potential for Sofosbuvir in Liver Transplantation
One obvious clinical need is for data regarding safety and efficacy of sofosbuvir in patients who have decompensated chronic liver disease, are peri-transplant or post-liver-transplant. The excellent safety data to date and the lack of significant drug interactions makes sofosbuvir an appealing choice to be studied in these groups. To date there is one case report published of a patient with severe recurrent cholestatic hepatitis C, 6 months post-transplant, who was effectively rescued and achieved SVR with treatment with sofosbuvir and daclatasvir in combination [Fontana et al. 2013]. This is promising, and results of future trials of sofosbuvir in these types of patient groups are awaited with interest.

Adverse Events
Treatment discontinuations because of adverse events have been uncommon in these sofosbuvirbased interferon-free treatment regimens. In phase III trials, treatment discontinuation rates of 1–2% were seen in the sofosbuvir plus ribavirin cohorts, as compared with 11% among patients receiving peginterferon–ribavirin for 24 weeks. Adverse events associated with ribavirin therapy (fatigue, insomnia and anaemia) were commonly reported, and headache was also frequently reported. Haematologic abnormalities were more common among patients who received interferon than among patients who did not in FISSION and ELECTRON [Gane et al. 2013c; Lawitz et al. 2013d].

Neutropenia and thrombocytopenia were not generally seen in groups who did not receive interferon. Depression is a common side effect of interferon therapy, and in the FISSION study, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir plus ribavirin. In a recent analysis of the impact of HCV treatment on quality of life, in the FISSION and POSITRON trials, sofosbuvir plus ribavirin was associated with better health-related quality of life than peginterferon plus ribavirin, and was similar to patients not receiving active treatment. Achieving SVR on sofosbuvir plus ribavirin was also associated with improvement in health-related quality of life [Younossi et al. 2013].

Concordance Data: SVR At Weeks 4, 12 and 24
Traditionally, with interferon-based therapy for HCV, the absence of detectable virus 24 weeks after completing treatment has been used to define SVR24. However, recent analyses have suggested that SVR12 and SVR24 are concordant across treatments that include peginterferon/ribavirin and also peginterferon/ribavirin triple therapy including telaprevir and boceprevir, with positive predictive values of 98% for SVR12 and 91% for SVR4 [Chen et al. 2013]. The concordance of SVR4, SVR12 and SVR24 has been assessed in the sofosbuvir phase II program including 590 patients. High levels of concordance were observed between SVR4 and later time points and positive predictive values and sensitivity of SVR4 for SVR12 and SVR24 were greater than 98.5% [Lawitz et al. 2013a]. Increasing reliance on these earlier time points of SVR4 and SVR12 to determine outcomes is almost certainly accelerating the pace of drug development.

Viral Resistance
Viral mutations in the HCV NS3 and NS5B regions have been associated with resistance to protease and nonnucleoside inhibitors, and can be present even in previously untreated patients with HCV infection. The S282T mutation has been identified as the common mutation selected in replicon studies with sofosbuvir, and this change can confer resistance to sofosbuvir [Lam et al. 2012]; however, this mutation is not generally present in untreated patients with HCV, and has very poor replicative fitness [Kuntzen et al. 2008]. In the initial large phase II and III studies involving sofosbuvir the S282T mutation was not detected on deep-sequencing assays in any patient receiving sofosbuvir and is in marked contrast with the rapid emergence of viral resistance that has been observed with other classes of DAA in patients who had breakthrough during treatment or relapse after completion of therapy [Gane et al. 2013c; Jacobson et al. 2013; Lawitz et al. 2013d]. Encouragingly, the emerging data suggest that sofosbuvir/NS5A inhibitor combination therapy is highly effective in NS3A protease-inhibitor experienced patients, even when they have protease inhibitor resistance [Sulkowski et al. 2013].

Conclusions and Future Directions
Although sofosbuvir is by no means one of the first DAA drugs to reach phase III clinical trials, the collective trial data for sofosbuvir do represent a significant paradigm shift in the management of HCV infection. With sofosbuvir-based regimens, successful interferon-free treatment of HCV is now achievable across multiple genotypes, but different patterns of genotypic response to treatment have emerged compared with those seen in traditional interferon-based therapy. It is now clear that in the current DAA era, genotypes 2 and 3 should be evaluated quite separately, as SVR rates in genotype 3 patients are significantly lower than those seen in genotype 2 [Jacobson et al. 2013; Lawitz et al. 2013d]. Genotype 2 is a readily treatable strain of HCV, with superb SVR rates with sofosbuvir/ribavirin dual therapy even in patients with established cirrhosis.

In contrast, the presence of advanced liver fibrosis has a significant detrimental effect on SVR rates in genotype 3 patients when a 12-week regimen is used. The FUSION data strongly suggest that for this group of patients, at least 16 weeks of therapy is needed for the dual sofosbuvir/ribavirin regimen, and the results of ongoing trials evaluating a 24-week duration of treatment are awaited with interest. The other strategy that could be considered is addition of another DAA to the regimen, but until these data are available to clarify the optimal interferon-free treatment of genotype 3 HCV patients with advanced fibrosis or previous treatment failure, there may be an initial role for continuing to use peginterferon together with sofosbuvir in this group of patients.

For genotype 1 HCV, the NEUTRINO data have shown the highest yet reported SVR rates for patients with genotype 1 HCV and cirrhosis when treated with sofosbuvir/ribavirin dual therapy, and this is particularly notable for the lack of significant adverse events, in contrast with the ongoing emerging data about safety of protease inhibitor/peginterferon-based triple therapy. However this dual therapy is not sufficient for the genotype 1 null responder group. Emerging phase II data in genotype 1 patients of triple therapy regimens of sofosbuvir plus ribavirin combined with an NS5A inhibitor, either daclatasvir or ledipasvir, demonstrate SVR rates close to 100%, in both treatment-naïve and null-responder patients, with potential to further shorten the duration of therapy to 8 weeks with this triple therapy approach, utilizing the fixed-dose once daily regimen of sofosbuvir/ledipasvir. Data on the effectiveness of this combination in cirrhotic genotype 1 null responders is awaited. A new era of successful interferon-free DAA therapy for HCV is emerging, with potential to broaden treatment of HCV to include patient groups who have either avoided or not been suitable for previous interferon- based therapy, and it is likely that sofosbuvir will form the backbone of this treatment approach.

 References
 
Table 1.  Phase II studies of sofosbuvir.
StudyDesignGenotypeRVREOT (%)SVR4SVR12
PROTON [ClinicalTrials.gov identifier: NCT01188772] [Lawitz et al. 2013c]
SOF 200 mg/PEG/RBV 12 wk + 12–36 wk PEG/RBV (RGT) (n = 48)1989490
SOF 400 mg/PEG/RBV 12 wk + 12–36 wk PEG/RBV (RGT) (n = 47)19810091
Placebo/PEG/RBV 12 wk + 36 wk PEG/RBV (n = 26)1196258
SOF 400 mg/PEG/RBV 12 wk (n = 25)2 & 39610092
ATOMIC [ClinicalTrials.gov identifier: NCT01329978] [Kowdley et al. 2013]
SOF 400 mg/RBV/PEG 12 wk (n = 52)194989490
SOF 400 mg/RBV/PEG 24 wk (n = 125)1, 4 & 698999493
SOF 400 mg/RBV/PEG 12 wk + SOF 400 mg/RBV 12 wk or SOF 400 mg 12 wk (n = 155)197999391
ELECTRON [ClinicalTrials.gov identifier: NCT01260350]
Part 1 (randomized) [Gane et al. 2013c]1. SOF 400 mg/RBV 12 wk (n = 10)

2. SOF 400 mg/RBV 12 wk +PEG (wk 1–4) (n = 9)

3. SOF 400 mg/RBV 12 wk +PEG (wk 1–8) (n = 10)

4. SOF 400 mg/RBV/PEG 12 wk (n = 11)
2 & 3

2 & 3

2 & 3

2 & 3100
100

100

100
100

100

100

100
100

100

100

100
100

100

100

100
Part 2 [Gane et al. 2013c]5. SOF 400 mg 12 wk (n = 10)2 & 31001006060
[Gane et al. 2013c]6. SOF400 mg/RBV/PEG 8 wk (n = 10)2 & 3100100100100
[Gane et al. 2013c]7. SOF 400 mg/RBV 12 wk (n = 10 null responders)11001001010
Part 3 [Gane et al. 2013c]8. SOF 400 mg/RBV 12 wk (n = 25; naïve)11001008884
[Gane et al. 2012]9. SOF 400 mg/RBV 12 wk (n = 25; treatment experienced)2 & 31001008068
Part 410. SOF 400 mg/RBV 8 wk (n = 25)

11. SOF 400 mg/RBV800 mg 12 wk (n = 10)
2 & 3, naïve

2 & 3, naïve
64
[Gane et al. 2013a, 2013b]12. SOF/ledipasvir 90 mg/RBV 12 wk (n = 9)1; null89100100100
[Gane et al. 2013a, 2013b]13. SOF/ledipasvir 90 mg/RBV (n = 25)1; naïve100100100100
Part 5 [Gane et al. 2013a, 2013b]14. SOF/GS9669 500 mg/RBV 12 wk (n = 10)1; null100100100100
[Gane et al. 2013a, 2013b]15. SOF/GS9669 500 mg/RBV (n = 25)1; naïve921009292
COSMOS [Lawitz et al. 2013b]
1. Simeprevir 150 mg/SOF 400 mg ± RBV
12 wk: SMV/SOF/RBV (n = 27)1, noncirrhotic null responders851009696% SVR 8
SMV/SOF (n = 14)571009393% SVR 8
24 wk: SMV/SOF/RBV (n = 24)8283
SMV/SOF (n = 15)6790
[Medivir, 2013]2. 12 wk: SMV/SOF/RBV (n = 27)1, naïve & null responders with advanced fibrosis96
SMV/SOF/(n = 14)100
24 wk: SMV/SOF/RBV SMV/SOF
LONESTAR [Gilead Sciences, 2013]
SOF/ledipasvir FDC 8 wk (n = 20)1, naïve95% SVR8
SOF/ledipasvir FDC + RBV 8 wk (n = 21)1, naïve100% SVR8
SOF/ledipasvir FDC 12 wk (n = 19)1, naïve100
SOF/ledipasvir FDC 12 wk (n = 19)1, protease inhibitor experienced95
SOF/ledipasvir FDC + RBV 12 wk (n = 21)1, protease inhibitor experienced95
Daclatasvir plus sofosbuvir
[Sulkowski et al. 2012]SOF 400 mg/daclatasvir 60 mg ± RBV:
SOF for 7 days then DCV/SOF 23 wk (n = 15) or1; noncirrhotic, naïve100100100100
DCV/SOF 24 wk (n = 14) or100100100100
DCV/SOF/RBV 24 wk (n = 15)100100100100
SOF for 7 days then DCV/SOF 23 wk (n = 16) or2 or 3; noncirrhotic, naïve100948888
DCV/SOF 24 wk (n = 14) or100100100100
DCV/SOF/RBV 24 wk (n = 14)1001008686
[Sulkowski et al. 2013]Daclatasvir 60 mg/SOF 400 mg 24 wk (n = 21) or1; previous failed TVT or100100100100
Daclatasvir 60 mg/SOF 400 mg/RBV 24 wk (n = 20)BOC; noncirrhotic9510010095
PEG, peginterferon; RBV, ribavirin; SOF, sofosbuvir; FDC, fixed-dose combination; EOT, end of therapy; RVR, rapid virological response (viral load undetectable by week 4 on treatment); SVR, sustained virological response; TVT, telaprevir-based triple therapy; BOC, boceprevir-based triple therapy; wk, week.

Blank spaces in the table represent incomplete or unpublished data.


 
Table 2.  Phase III studies of sofosbuvir.
StudyDesignGenotypeRVREOT (%)SVR4SVR12
FISSION [ClinicalTrials. gov identifier: NCT01497366] [Lawitz et al. 2013d]SOF 400 mg/RBV 12 wk (n = 253) or PEG/RBV (n = 243)2 & 3; naïve99

67
98

89
74

74
67 (G2 97; G3 56)

67
NEUTRINO [ClinicalTrials.gov identifier: NCT01641640] [Lawitz et al. 2013d]SOF 400 mg/RBV/PEG 12 wk (n = 327)1, 4, 5, 6; naïve (98% G1 or 4)99999290 (G1a 92; G1b 82; G4 96)
POSITRON [ClinicalTrials.gov identifier: NCT01542788] [Jacobson et al. 2013]SOF 400 mg/RBV (n = 207) or placebo (n = 71) 12 wk2 & 3; naïve (IFN not an option)991008378 (G2 93; G3 61)
FUSION [ClinicalTrials. gov identifier: NCT01604850] [Jacobson et al. 2013]SOF 400 mg/RBV2 & 3; previous treatment failure
12 wk (n = 103) or971005650 (G2 86; G3 30)
16 wk (n = 98)981007773 (G2 94; G3 62)
PEG, pegylated interferon alpha; RBV, ribavirin; SMV, simeprevir (TMC435); SOF, sofosbuvir (GS7977); DCV, daclatasvir; RGT, response guided therapy, EOT, end of therapy; SVR, sustained virological response.

Wednesday, May 7, 2014

Janssen Submits Supplemental NDA to U.S. FDA for OLYSIO™ (Simeprevir) and Sovaldi (Sofosbuvir) Combo


Janssen Submits Supplemental New Drug Application to U.S. FDA for OLYSIO™ (Simeprevir) for Once-Daily Use in Combination with Sofosbuvir for 12 Weeks for the Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C

-- Filing Includes Data from Treatment-Naive Patients with Advanced Fibrosis and Null Responders with All Stages of Liver Fibrosis

--



OLYSIO™ is currently approved for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. OLYSIO™ efficacy has been established in combination with peginterferon alfa and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis.

"Hepatitis C places a significant burden on the lives of those infected and if left untreated may cause significant damage to the liver, including cirrhosis and complications such as liver failure," said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. "This filing brings us closer to potentially offering these patients a once-daily all-oral treatment combination that includes the direct-acting antiviral agents simeprevir and sofosbuvir."

The regulatory submission for OLYSIO™ and sofosbuvir is supported by data from the Phase 2 COSMOS study which included treatment-naive patients with advanced fibrosis (METAVIR F3 to F4 scores) and null-responder patients with all stages of liver fibrosis (METAVIR F0 to F4 scores).

In April 2014, Janssen announced initiation of the Phase 3 OPTIMIST trials examining the safety and efficacy of simeprevir and sofosbuvir without interferon or ribavirin for the treatment of chronic genotype 1 HCV infection. In the first trial, known as OPTIMIST-1, the combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naive or treatment experienced. In the second trial, known as OPTIMIST-2, the combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naive or treatment experienced. For more information please visit www.clinicaltrials.gov.

About Hepatitis CHepatitis C is a blood-borne infectious disease of the liver that affects approximately 3.2 million people in the United States and is a leading cause of chronic liver disease. Approximately 150 million people are infected with hepatitis C worldwide and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver, including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About OLYSIO™ (simeprevir)OLYSIO™ is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S., and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.

Important Safety InformationWhat Is OLYSIO™?
OLYSIO™ (simeprevir) is a prescription medicine used with other antiviral medicines, peginterferon alfa and ribavirin, to treat genotype 1 chronic (lasting a long time) hepatitis C in adults with stable liver problems.

OLYSIO™ must not be taken alone. The efficacy of OLYSIO™ in combination with peginterferon and ribavirin is greatly decreased in patients who have genotype 1a Q80K. Please talk to your doctor about testing for genotype 1a Q80K and using a different therapy when genotype 1a Q80K is present.
It is not known if OLYSIO™ is safe and effective in children under 18 years of age.


What is the most important information I should know and who should not take OLYSIO™ (simeprevir)?

OLYSIO™, in combination with peginterferon alfa and ribavirin may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking OLYSIO™ with peginterferon alfa and ribavirin and for 6 months after treatment is over.
Females and males must use two effective forms of birth control during treatment and for 6 months after treatment with OLYSIO™, peginterferon alfa, and ribavirin combination therapy. Talk to your healthcare provider about forms of birth control that may be used during this time.

Females must have a pregnancy test before starting treatment with OLYSIO™, peginterferon alfa, and ribavirin combination therapy, every month while being treated, and every month for 6 months after your treatment with OLYSIO™, peginterferon alfa, and ribavirin combination therapy is over.
If you or your female sexual partner becomes pregnant while taking OLYSIO™, peginterferon alfa, and ribavirin combination therapy or within 6 months after you stop taking these medicines, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant.

OLYSIO™ in combination with peginterferon alfa and ribavirin may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during treatment with OLYSIO™, peginterferon alfa, and ribavirin combination therapy.

Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with OLYSIO™.

Limit sunlight exposure during treatment with OLYSIO™.
Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with OLYSIO™.

Call your healthcare provider right away if you get any of the following symptoms:
burning, redness, swelling or blisters on your skin
mouth sores or ulcers
red or inflamed eyes, like "pink eye" (conjunctivitis)
Do not take OLYSIO™ alone. OLYSIO™ should be used together with peginterferon alfa and ribavirin to treat chronic hepatitis C infection.


What should I tell my healthcare provider before taking OLYSIO™?
Before taking OLYSIO™, tell your healthcare provider if you:
have liver problems other than hepatitis C virus infection
have taken the medicines telaprevir (Incivek®) or boceprevir (Victrelis®)
had a liver transplant
are receiving phototherapy
have any other medical condition
are of East Asian descent
are breastfeeding. It is not known if OLYSIO™ passes into your breast milk. You and your healthcare provider should decide if you will take OLYSIO™ or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

OLYSIO™ and other medicines may affect each other. This can cause you to have too much or not enough OLYSIO™ or other medicines in your body, which may affect the way OLYSIO™ or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

Especially tell your healthcare provider if you take any of the following medicines:
amiodarone (Cordarone®, Pacerone®), amlodipine (Norvasc®), atazanavir (Reyataz®), atorvastatin (Lipitor®, Caduet®), carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®), cisapride (Propulsid®, Propulsid Quicksolv®), clarithromycin (Biaxin®, Prevpac®), cobicistat-containing medicine: (Stribild®), cyclosporine (Gengraf®, Neoral®, Sandimmune®), darunavir (Prezista®), delavirdine mesylate (Rescriptor®), dexamethasone (when administered by injection or when taken by mouth), digoxin (Lanoxin®), diltiazem (Cardizem®, Dilacor XR®, Tiazac®), disopyramide (Norpace®), efavirenz (Sustiva®, Atripla®), erythromycin (E.E.S.®, Eryc®, Ery-Tab®, Erythrocin®, Erythrocin Stearate®), etravirine (Intelence®), felodipine (Plendil®), flecainide (Tambocor®), fluconazole (when taken by mouth or when administered by injection) (Diflucan®), fosamprenavir (Lexiva®), indinavir (Crixivan®), itraconazole (when taken by mouth) (Sporanox®, Onmel®), ketoconazole (when taken by mouth) (Nizoral®), lopinavir (Kaletra®), lovastatin (Advicor®, Altoprev®, Mevacor®), mexiletine (Mexitil®), midazolam (when taken by mouth), milk thistle (Silybum marianum) or products containing milk thistle, nelfinavir (Viracept®), nevirapine (Viramune®, Viramune XR®), nicardipine (Cardene®), nifedipine (Adalat CC®, Afeditab CR®, Procardia®), nisoldipine (Sular®), oxcarbazepine (Trileptal®), phenobarbital (Luminal®), phenytoin (Dilantin®, Phenytek®), pitavastatin (Livalo®), posaconazole (when taken by mouth) (Noxafil®), pravastatin (Pravachol®), propafenone (Rythmol SR®), quinidine (Nuedexta®, Duraquin®, Quinaglute®), rifabutin (Mycobutin®), rifampin (Rifadin®, Rifamate®, Rifater®), rifapentine (Priftin®), ritonavir (Norvir®), rosuvastatin (Crestor®), saquinavir mesylate (Invirase®), sildenafil (Revatio®, Viagra®), simvastatin (Zocor®, Vytorin®, Simcor®), sirolimus (Rapamune®), St. John's wort (Hypericum perforatum) or products containing St. John's wort, tacrolimus (Prograf®), tadalafil (Adcirca®, Cialis®), telithromycin (Ketek®), tipranavir (Aptivus®), triazolam (when taken by mouth) (Halcion®), verapamil (Calan®, Covera-HS®, Isoptin®, Tarka®), voriconazole (when taken by mouth or when administered by injection) (Vfend®), warfarin (Coumadin®)
This is not a complete list of medicines that could interact with OLYSIO™. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

What are the most common side effects of OLYSIO™?

The most common side effects of OLYSIO™ when used in combination with peginterferon alfa and ribavirin include skin rash, itching, nausea.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of OLYSIO™. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please see full Prescribing Information, including Patient Information for more details.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in new product development, including obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; general industry conditions including trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2013, including in Exhibit 99 thereto, and our subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.)

Wednesday, April 30, 2014

Watch Donald Jensen MD on Chicago Tonight on the high price of new hepatitis C treatments

Treating Hepatitis C Chicago Tonight 
April 28, 2014 10:30 am

An estimated 3.2 million Americans live with hepatitis C. Traditional treatments didn’t always cure the viral infection and often came with severe side effects. Late last year, the Food and Drug Administration approved two new drugs, Sovaldi and Olysio, for the treatment of hepatitis C. But the drugs come with a hefty price tag, starting at $66,000 for Olysio and $84,000 for Sovaldi. Brandis Friedman has more on the treatments and their costs.
Continue to article....

Saturday, April 12, 2014

EASL - Final data phase II COSMOS study with Simeprevir in combination with Sofosbuvir

Final data from the phase II COSMOS study with Simeprevir in combination with Sofosbuvir presented at EASL
Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that positive new simeprevir data were presented at The International Liver Congress™ 2014 of the European Association for the Study of the Liver (EASL) in London.

The data presented included;
Final phase II data from the interferon-free COSMOS study
Phase III efficacy data in patients with genotype 4 hepatitis C
Subgroup analyses of patients from phase III studies QUEST-1, QUEST-2 and PROMISE

Final phase II data from the interferon-free COSMOS study

Cohort 2
Final results from cohort 2 of the phase II COSMOS study demonstrated that 93 percent of prior null responder and treatment-naïve patients with genotype 1 HCV and advanced liver fibrosis (METAVIR scores F3 and F4) who were treated with simeprevir and sofosbuvir for 12 weeks achieved sustained virologic response 12 weeks after the end of treatment (SVR12). The addition of ribavirin did not improve SVR rates and consistent responses for both treatment arms were seen across HCV genotype subgroups after 12 weeks.

Click To Enlarge


*Excluding non-virologic failures.

The most common adverse events reported during the study were fatigue, headache, nausea, anemia, pruritus, dizziness, rash and photosensitivity. One patient discontinued treatment due to adverse events.

Cohort 1
Previously presented data from cohort 1 at AASLD in November 2013, demonstrated that 96 percent and 93 percent of prior null responder patients with METAVIR F0-F2 scores treated with simeprevir and sofosbuvir without or with ribavirin, respectively, for 12 weeks achieved SVR12.

Click To Enlarge



*Excluding non-virologic failures.

In genotype 1a patients with the Q80K polymorphism at baseline, 83 percent and 89 percent achieved SVR12 after 12 weeks of treatment without and with ribavirin, respectively. The most common adverse events reported during the study were fatigue, headache, nausea and insomnia. Two patients discontinued treatment due to adverse events.

Phase III efficacy data in patients with genotype 4 hepatitis C

Results from the Phase III RESTORE trial of simeprevir in combination with pegylated interferon and ribavirin in HCV genotype 4 treatment-naïve and treatment-experienced patients demonstrated that overall 65 percent of patients achieved SVR12, including 83 percent of treatment-naïve patients, 86 percent of prior relapsers, 60 percent of prior partial responders, and 40 percent of prior null responders. Among patients with more severe liver fibrosis characterized by a METAVIR score of F3 or F4, 67 percent and 47 percent achieved SVR12, respectively. Among patients with genotype 4a and 4d HCV, 69 percent and 52 percent achieved SVR12, respectively. The most frequent adverse events included influenza-like illness, asthenia (weakness) and fatigue.

Genotype 4 HCV is considered particularly difficult to cure and currently only limited treatment options are available.

Subgroup analyses of patients from phase III studies of Simeprevir

Analyses of pooled efficacy data from the QUEST-1 and QUEST-2 studies found 87 percent of European patients treated with simeprevir in combination with pegylated interferon and ribavirin achieved SVR12, compared to 80 in the overall study population. In an analysis from the PROMISE study, 88 percent of European patients treated with simeprevir in combination with pegylated interferon and ribavirin achieved SVR12 compared to 79 percent in the overall study population.

The efficacy of simeprevir in combination with pegylated interferon and ribavirin was also observed among European patients with baseline characteristics typically considered more difficult to cure. In QUEST-1 and QUEST-2, 71 percent of patients with METAVIR F4 scores, 86 percent of patients with the IL28B CT genotype, 69 percent of patients with the IL28B TT genotype and 64 percent of genotype 1a patients with the Q80K polymorphism at baseline achieved SVR12 in the simeprevir arm, compared to 25 percent, 44 percent, 31 percent and 50 percent of patients in the active placebo arm, respectively. In PROMISE, 85 percent of patients with METAVIR F4 scores, 88 percent of patients with the IL28B CT genotype, 77 percent of patients with the IL28B TT genotype and 75 percent of genotype 1a patients with the Q80K polymorphism at baseline achieved SVR12 in the simeprevir arm, compared to 30 percent, 41 percent, 18 percent and 57 percent of patients treated in the active placebo arm, respectively.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 17.15 CET on 12 April 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S. and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

EASL - Simeprevir- and sofosbuvir-based regimens in HCV genotype 4-infected patients

New data showing efficacy of simeprevir- and sofosbuvir-based regimens in HCV genotype 4-infected patients

Simeprevir with peginterferon and ribavirin is effective and well tolerated in treatment-naïve and treatment-experienced patients infected with HCV genotype 4

London, UK, Saturday 12 April 2014: Results from RESTORE[1], a phase III, multicentre, single-arm, open-label study presented today at the International Liver CongressTM 2014 showed that simeprevir 150 mg once-daily for 12 weeks in combination with peginterferon and ribavirin (followed by 12 or 36 weeks of peginterferon and ribavirin) was effective and well tolerated in hepatitis C virus (HCV) genotype 4-infected patients, consistent with previous observations in HCV genotype 1-infected patients.

Overall, 65.4% of patients achieved SVR12 (82.9% of treatment-naïve, 86.4% of prior-relapser, 60.0% of prior partial-responder and 40.0% of prior null-responder patients). The rapid virological response (RVR) rates in the IL28B CT and TT patient sub-groups were 65.5% and 62.2%, respectively, while 65.6% and 59.5% achieved SVR12, respectively. Among those patients with more severe liver fibrosis (METAVIR score F4), 62.1% and 46.7% achieved RVR and SVR12, respectively.

Response-guided therapy criteria used to identify patients eligible for a total treatment duration of 24 weeks were met by 88.6% and 90.9% of treatment-naïve and prior-relapser patients, respectively. Among them, 93.5% and 95.0%, respectively, achieved SVR12. No patients meeting response-guided therapy criteria experienced on-treatment failure, while three patients experienced viral relapse (treatment-naive, n=2; relapsers, n=1).

“HCV genotype 4 is a strain of virus which currently only has limited treatment options,” said EASL’s Secretary General Professor Markus Peck-Radosavljevic. “We therefore welcome these positive results for the simeprevir-based regimen.”

Although HCV genotype 4 is mainly found in the Middle East, Egypt and Central Africa, it has recently spread in several Western countries, particularly in Europe, with rates of 10% to 24%.[2]

Overall simeprevir was well tolerated; most adverse events (AEs) were grade 1 or 2. Serious AEs were infrequent (five patients [4.7%]; no deaths) and considered unrelated to simeprevir. Most frequent AEs (>30% of patients) included influenza-like illness, asthenia and fatigue.

In this phase III study conducted in France and Belgium, 107 patients with chronic HCV genotype 4 received simeprevir once daily with peginterferon and ribavirin for 12 weeks. Treatment-naïve and prior-relapser patients received response-guided therapy with peginterferon and ribavirin continued for up to 24 or 48 weeks. Prior partial responders and prior null responders continued to receive peginterferon and ribavirin for 48 weeks.

Out of a total patient population of 107 patients, 35 were treatment-naïve, 22 relapsers, 10 partial responders, and 40 null responders. The demographics of the patient population were as follows: 78.5% male; median age, 49 years; 28.0% Black; 28.8% METAVIR F4; 92.5% IL28B non-CC host genotype; and 42.5/23.6/33.9% HCV GT4a/4d/4other genotype.

Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, with antiviral activity against HCV genotypes 1, 2, 4, 5 and 6, and approved in Japan, Canada, the United States and Russia for the treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis. Taken as one capsule, once-daily, simeprevir works by blocking the protease enzyme that enables HCV to replicate in host cells.

Patients of Egyptian ancestry infected with Genotype 4 HCV achieve high virological response rates with sofosbuvir plus ribavirin

In a second study[3] involving treatment-naive and treatment-experienced patients of Egyptian ancestry with chronic genotype 4 HCV infection, sofosbuvir plus ribavirin was shown to provide a simple, effective, and well-tolerated, interferon-free regimen.

After 12 weeks of treatment with sofosbuvir plus ribavirin, SVR12 rates were 79% (11/14) in treatment-naïve patients and 59% (10/17) in treatment-experienced patients. Extending treatment duration to 24 weeks resulted in higher SVR12 rates in both treatment-naïve and -experienced patients: 100% (14/14) and 87% (13/15) respectively.

Relapse accounted for all virological failures except in one treatment-naïve subject receiving 12 weeks treatment who had a partial response.

Most AEs were mild or moderate in severity and consistent with the known side effects of ribavirin.

Presenting these results, Professor Peck-Radosavljevic said “the current treatment for GT4 is sofosbuvir + pegylated interferon + ribavirin for 12 weeks which resulted in a 96% (27/28) SVR12 rate in the Phase 3 NEUTRINO trial.

“What makes the results from this new study with sofosbuvir so important is that it included those patients who were interferon-ineligible, -intolerant, and failures, where a significant unmet medical need exists”, Professor Peck-Radosavljevic added.

In this study, patients, born in Egypt and of Egyptian ancestry, with chronic HCV GT4 infection were randomised 1:1, stratified by prior treatment status and cirrhosis status, to receive 12 or 24 weeks sofosbuvir (400 mg/day) + ribavirin (1000-1200 mg/day). Approximately 20% could have compensated cirrhosis.

Of the 60 patients enrolled, 28 were treatment-naïve and 32 treatment-experienced. 68% were male, 23% cirrhotic, and 17% had the IL28B CC host genotype.

Sofosbuvir is a nucleotide polymerase inhibitor with a high barrier to resistance that is taken as an oral, once-daily formulation. With activity against HCV genotypes 1-6, in-vitro activity of sofosbuvir against genotype 4a HCV has been shown to be similar to its activity against other HCV genotypes. With more than 3000 patients treated to date, sofosbuvir appears to be safe and well tolerated.

Disclaimer: the data referenced in this release is based on the submitted abstract. Final SVR results by baseline characteristics, including GT4 subtype, and resistance data will be presented at the International Liver Congress™ 2014.
Source - EASL

Wednesday, April 2, 2014

Phase 3 Trials evaluating Simeprevir and Sofosbuvir have been initiated

Press Release 2 April 2014
Two phase III trials evaluating once-daily Simeprevir and Sofosbuvir in hepatitis C infected patients have been initiated

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that two phase III trials are recruiting patients to examine the efficacy and safety of the NS3/4A protease inhibitor simeprevir in combination with the nucleotide inhibitor sofosbuvir for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection in treatment-naïve and treatment-experienced patients with and without cirrhosis.

“Positive safety and efficacy results have previously been demonstrated in genotype 1 HCV infected patients with the interferon- and ribavirin free combination of simeprevir and sofosbuvir in the phase II COSMOS study. The OPTIMIST trials aim to further consolidate these data and to explore a shorter treatment duration of eight weeks to potentially further simplify this promising treatment option,” says Charlotte Edenius, EVP Development, Medivir AB

Study design
OPTIMIST-1
The first trial, called OPTIMIST-1 or TMC435HPC3017, is a phase III, open-label, randomized study investigating the efficacy and safety of simeprevir 150 mg in combination with sofosbuvir 400 mg.
The combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naïve or treatment experienced. This study will enroll approximately 300 patients in the U.S. and Canada.

OPTIMIST-2
The second trial, called OPTIMIST-2 or TMC435HPC3018, is a phase III, open-label, single-arm study investigating the efficacy and safety of simeprevir 150 mg in combination with sofosbuvir 400 mg.

The combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naïve or treatment experienced. This study will enroll approximately 100 patients in the U.S. and Canada.

Ribavirin will not be administered in the OPTIMIST trials. The primary efficacy endpoint in each study is the proportion of patients achieving sustained virologic response 12 weeks after the end of treatment (SVR12).

For additional information, including inclusion and exclusion criteria for these trials, please visit www.clinicaltrials.gov

COSMOS study
The combination of simeprevir and sofosbuvir was previously evaluated in the phase II COSMOS trial.

The final cohort 1 study results (SVR12) in patients without fibrosis or cirrhosis (METAVIR score of F0-2) and the interim cohort 2 study results (SVR4) in patients with fibrosis or cirrhosis (METAVIR score of F3-4) from the COSMOS study were presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting 2013 in Washington, D.C.

Final cohort 2 results (SVR12) have been accepted for presentation at the European Association for the Study of the Liver (EASL) International Liver Congress 2014 on April 12.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.00 CET on 2 April 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB will retain marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. The treatment was approved for the treatment of genotype 1 hepatitis C in September 2013 in Japan and in November 2013 in Canada and the U.S. and in March 2014 in Russia. The Committee for Medicinal Products for Human Use (CHMP) recently recommended Marketing Authorisation in the European Union for the use of Simeprevir in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients. An approval is expected during Q2-2014.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

Monday, March 24, 2014

EASL-Simeprevir plus sofosbuvir with/without ribavirin data to be presented

New Simeprevir data will be presented at The International Liver Congress 2014 of the European Association for the Study of the Liver, (EASL)

Presentations Include late-breaking final results from the phase II COSMOS study

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that new data from the clinical development program for simeprevir in the treatment of genotype 1 or genotype 4 chronic hepatitis C virus (HCV) in adult patients with compensated liver disease will be presented at The International Liver Congress of the European Association for the study of the Liver (EASL). The International Liver Congress 2014 will take place from April 9-13 in London, United Kingdom.

Eight oral and poster presentations spanning over the phase II and phase III development program for simeprevir in treatment combinations with and without ribavirin and interferon are planned. New analyses of data from the phase III QUEST-1, QUEST-2 and PROMISE clinical trials of simeprevir in combination with pegylated interferon and ribavirin, as well as final data from the phase II COSMOS study will be presented during the Congress.

The data to be presented at the International Liver Congress 2014 include:

Late-Breaking Presentations
Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior null-responder/treatment-naïve patients (COSMOS Study): primary endpoint (SVR12) results in patients with METAVIR F3-4 (Cohort 2)
- Lead Author: Eric Lawitz; The Texas Liver Institute, University of Texas Health Science Center, San Antonio, USA

Once-daily simeprevir (TMC435) with peginterferon/ribavirin in treatment-naïve or treatment-experienced chronic HCV genotype-4 infected patients: SVR12 results of a Phase 3 trial (RESTORE Study)
- Lead Author: Christopher Moreno; ULB Hôpital Erasme, Brussels, Belgium

Oral Presentations
Once-daily simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 prior null responders with METAVIR F0-2: COSMOS Study Cohort 1 subgroup analysis
- Lead Author: Mark Sulkowski; Johns Hopkins University School of Medicine, Baltimore, USA

Simeprevir with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in European patients who relapsed after previous interferon-based therapy: the PROMISE trial
- Lead Author: Xavier Forns; Liver Unit, Hospital Clinic, Barcelona, Spain

Poster Presentations
Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve European patients in the QUEST-1 and QUEST-2 Phase 3 trials
- Lead Author: Graham R. Foster; Queen Mary’s, University of London, London, UK

Simeprevir reduces time with peginterferon/ribavirin-induced symptoms and quality-of-life impairments: 72-week results from three Phase 3 studies
- Lead Author: Jane Scott; Janssen

Virology analyses of simeprevir in Phase 2b and 3 studies
- Lead Author: Oliver Lenz; Janssen

Deep sequencing analyses of minority baseline polymorphisms and persistence of emerging mutations in HCV genotype 1-infected patients treated with simeprevir
- Lead Author: Bart Fevery; Janssen

Full session details and data presentation listings for The International Liver Congress 2014 can be found at

http://www.ilc-congress.eu.

Friday, March 21, 2014

Hepatitis C-Two-Drug Combo Sovaldi Plus Olysio: Free for Needy Travis County Residents

TEXAS: Getting Free Hepatitis C Drugs a Boon for Needy Travis County Residents
By Mary Ann Roser

The companies that make expensive but highly effective hepatitis C drugs are offering the new treatments for free or nearly free to eligible patients who need help.

The usual 12-week course of treatment costs $84,000 for Sovaldi and $66,000 for Olysio, a total of $150,000. Patient advocates, private insurers and organizations that provide drugs through publicly funded programs, such as Medicaid and the Veterans Health Administration, have raised concerns about those costs.

But officials with the two companies, Sovaldi maker Gilead Sciences and Olysio maker Janssen Therapeutics, said they have assistance programs for people with insurance - and without - who need the drugs, which can be taken together or with other drugs. Sovaldi said it provides the drug for free to eligible patients who lack health insurance and have annual incomes below $100,000 for a family of up to three or earnings that are at or below 500 percent of the federal poverty level.

Among the organizations helping patients tap into the companies' patient assistance programs is Travis County's taxpayer-supported CommUnityCare, which operates a network of 23 health centers.

A new clinic for hepatitis C patients that relies on the drug assistance programs opened March 3 at the system's North Central Health Center at 1210 W. Braker Lane. That clinic is using the two-drug combination treatment and expects to initially help "hundreds" of uninsured patients obtain the drugs, said Sarah Cook, Central Health's Medicaid waiver director. The clinic saw 38 patients in its first seven days.

"It's an incredible game-changer," Cook said.

For this year, Central Health, which oversees CommUnityCare, is contributing $370,000 to pay for clinic staff led by Dr. Imtiaz Alam, medical director of the Austin Hepatitis Center, Cook said. Alam is at the clinic on Mondays and Tuesdays and works with nurses and other providers who take care of patients throughout the week. Eventually, hepatitis C clinic services are expected to also be offered at the Southeast Health & Wellness Center, which CommUnityCare expects to open at 2901 Montopolis Drive in October.

Before the hepatitis C clinic opened at North Central, some patients had to wait a year to see a CommUnityCare doctor, says a document Cook provided. About 6,500 CommUnityCare patients are affected by hepatitis C, Alam said.

More than 3 million Americans have chronic hepatitis C infection, which can cause cirrhosis and liver cancer. It is generally transmitted through blood and can be deadly. Many people don't know they're infected, prompting the U.S. Centers for Disease Control and Prevention to recommend screening for anyone born between 1945 and 1965.

Alam said he is asking the state of Texas Medicaid to put Sovaldi and Olysio on its formulary. "I believe these new medications are well worth their cost and their utilization will have a positive impact in reduction of future health care costs with fewer long-term liver disease complications," he wrote in an email. Dr. William Lee, a professor of internal medicine who is doing clinical trials on new hepatitis C drugs at the University of Texas Southwestern Medical Center in Dallas, expects a single-dose pill to come out later this year. He does not yet know how much it will cost but hopes that the marketplace eventually brings down the costs of new hepatitis drugs.

He believes the drugs he is testing have potential to be as effective or more effective than Sovaldi and Olysio. "I think what's coming around the corner is competition," Lee said.

Hepatitis C "takes a big chunk out of your life and out of your wallet," said Annalyn Earley, 62, of Austin. She is one of Alam's patients and is covered by an insurance program in Texas for people with costly pre-existing illnesses. Earley, who is transitioning to Obamacare, said she was infected by a blood transfusion after a car accident at age 25.

She takes a single dose of Sovaldi and of Olysio daily and says the change from her old drug regimen, known for its debilitating side effects, is "like day and night."

"I feel wonderful," Earley said. "I feel like I lost everything to this disease and now I'm going to get my life back."
 
http://www.aegis.org/DisplayContent/?sectionID=381011
http://www.mystatesman.com

Wednesday, March 5, 2014

Hepatitis C virus: Here comes all-oral treatment

Stay Updated
2018-HCV Genotypes/Treatment
Offered on this page is research updates with a focus on treating HCV according to genotype using FDA approved oral medicines. Information is extracted from news articles, peer-reviewed journals, as well as liver meetings/conferences, research manuscripts and interactive learning activities.

2017-
Novel emerging treatments for hepatitis C infection: a fast-moving pipeline

March 2014
Hepatitis C virus: Here comes all-oral treatment

MOHANNAD DUGUM, MD Department of Internal Medicine, Medicine Institute, Cleveland Clinic
ROBERT O’SHEA, MD

10.3949/ccjm.81a.13155 Cleveland Clinic Journal of Medicine
March 2014 vol. 81 3 159-172
Abstract
» Full Text
Full Text (PDF) 

Author Affiliations
Department of Gastroenterology and Hepatology, and Transplantation Center, Digestive Disease Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
ADDRESS: Robert O’Shea, MD, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue/A30, Cleveland, OH 44195; e-mail: oshear@ccf.org


Abstract
Treatment for chronic hepatitis C virus (HCV) infection is evolving rapidly. The approval in 2013 of two new direct-acting antivirals—sofosbuvir (a polymerase inhibitor) and simeprevir (a second-generation protease inhibitor)—opens the door for an all-oral regimen, potentially avoiding interferon and its harsh side effects. Other direct-acting antivirals are under development.

Key points
In clinical trials of treatment for chronic HCV infection, regimens that included a direct-acting antiviral agent were more effective than ones that did not.

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3, and in combination with ribavirin and interferon in patients infected with HCV genotype 1 or 4. It is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation.

Simeprevir is approved in an oral dose of 150 mg once daily in combination with ribavirin and interferon for patients with HCV genotype 1.

The new drugs are expensive, a potential barrier for many patients. As more direct-acting antiviral agents become available, their cost will likely decrease.

Combinations of direct-acting antiviral agents of different classes may prove even more effective and could eliminate the need for interferon entirely.

In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir, the newest direct-acting antiviral agents for treating chronic hepatitis C virus (HCV) infection. Multiple clinical trials have demonstrated dramatically improved treatment outcomes with these agents, opening the door to all-oral regimens or interferon-free regimens as the future standard of care for HCV.

In this article, we discuss the results of the trials that established the efficacy and safety of sofosbuvir and simeprevir and led to their FDA approval. We also summarize the importance of these agents and evaluate other direct-acting antivirals currently in the pipeline for HCV treatment.

HCV IS A RISING PROBLEM
Chronic HCV infection is a major clinical and public health problem, with the estimated number of people infected exceeding 170 million worldwide, including 3.2 million in the United States.1 It is a leading cause of cirrhosis, and its complications include hepatocellular carcinoma and liver failure. Cirrhosis due to HCV remains the leading indication for liver transplantation in the United States, accounting for nearly 40% of liver transplants in adults.2

The clinical impact of HCV will only continue to escalate, and in parallel, so will the cost to society. Models suggest that HCV-related deaths will double between 2010 and 2019, and considering only direct medical costs, the projected financial burden of treating HCV-related disease during this interval is estimated at between $6.5 and $13.6 billion.3

AN RNA VIRUS WITH SIX GENOTYPES
HCV, first identified in 1989, is an enveloped, single-stranded RNA flavivirus of the Hepacivirus genus measuring 50 to 60 nm in diameter.4 There are six viral genotypes, with genotype 1 being the most common in the United States and traditionally the most difficult to treat.
Once inside the host cell, the virus releases its RNA strand, which is translated into a single polyprotein of about 3,000 amino acids. This large molecule is then cleaved by proteases into several domains: three structural proteins (C, E1, and E2), a small protein called p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (FIGURE 1).5 These nonstructural proteins enable the virus to replicate. 

FIGURE 1
GOAL OF TREATING HCV: A SUSTAINED VIROLOGIC RESPONSE
The aim of HCV treatment is to achieve a sustained virologic response, defined as having no detectable viral RNA after completion of antiviral therapy. This is associated with substantially better clinical outcomes, lower rates of liver-related morbidity and all-cause mortality, and stabilization of or even improvement in liver histology.6,7 This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent.
TABLE 1 summarizes the patterns of virologic response in treating HCV infection. 


Interferon plus ribavirin: The standard of care for many years
HCV treatment has evolved over the past 20 years. Before 2011, the standard of care was a combination of interferon alfa-polyethylene glycol (peg-interferon), given as a weekly injection, and oral ribavirin. Neither drug has specific antiviral activity, and when they are used together they result in a sustained virologic response in fewer than 50% of patients with HCV genotype 1 and, at best, in 70% to 80% of patients with other genotypes.8

Nearly all patients receiving interferon experience side effects, which can be serious. Fatigue and flu-like symptoms are common, and the drug can also cause psychiatric symptoms (including depression or psychosis), weight loss, seizures, peripheral neuropathy, and bone marrow suppression. Ribavirin causes hemolysis and skin complications and is teratogenic.9

An important bit of information to know when using interferon is the patient’s IL28B genotype. This refers to a single-nucleotide polymorphism (C or T) on chromosome 19q13 (rs12979860) upstream of the IL28B gene encoding for interferon lambda-3. It is strongly associated with responsiveness to interferon: patients with the IL28B CC genotype have a much better chance of a sustained virologic response with interferon than do patients with CT or TT.

Boceprevir and telaprevir: First-generation protease inhibitors
In May 2011, the FDA approved the NS3/4A protease inhibitors boceprevir and telaprevir for treating HCV genotype 1, marking the beginning of the era of direct-acting antiviral agents.10 When these drugs are used in combination with peg-interferon alfa and ribavirin, up to 75% of patients with HCV genotype 1 who have had no previous treatment achieve a sustained virologic response.
But despite greatly improving the response rate, these first-generation protease inhibitors have substantial limitations. Twenty-five percent of patients with HCV genotype 1 who have received no previous treatment and 71% of patients who did not respond to previous treatment will not achieve a sustained virologic response with these agents.11 Further, they are effective only against HCV genotype 1, being highly specific for the amino acid target sequence of the NS3 region. 

Also, they must be used in combination with interferon alfa and ribavirin because the virus needs to mutate only a little—a few amino-acid substitutions—to gain resistance to them.12 Therefore, patients are still exposed to interferon and ribavirin, with their toxicity. In addition, dysgeusia is seen with boceprevir, rash with telaprevir, and anemia with both.13,14

Finally, serious drug-drug interactions prompted the FDA to impose warnings for the use of these agents with other medications that interact with CYP3A4, the principal enzyme responsible for their metabolism. Thus, these significant adverse effects dampen the enthusiasm of patients contemplating a long course of treatment with these agents. 

The need to improve the rate of sustained virologic response, shorten the duration of treatment, avoid serious side effects, improve efficacy in treating patients infected with genotypes other than 1, and, importantly, eliminate the need for interferon alfa and its serious adverse effects have driven the development of new direct-acting antiviral agents, including the two newly FDA-approved drugs, sofosbuvir and simeprevir.

SOFOSBUVIR: A POLYMERASE INHIBITOR
Sofosbuvir is a uridine nucleotide analogue that selectively inhibits the HCV NS5B RNA-dependent RNA polymerase (FIGURE 1). It targets the highly conserved nucleotide-binding pocket of this enzyme and functions as a chain terminator.15 While the protease inhibitors are genotype-dependent, inhibition of the highly conserved viral polymerase has an impact that spans genotypes.

Early clinical trials of sofosbuvir
Sofosbuvir has been tested in combination with interferon alfa and ribavirin, as well as in interferon-free regimens (TABLE 2).1620
 
Rodriguez-Torres et al,15 in an early double-blind clinical trial, randomized 64 previously untreated patients with HCV genotype 1 to receive one of three doses of oral sofosbuvir (100, 200, or 400 mg) plus interferon and ribavirin or placebo plus interferon and ribavirin for 4 weeks, followed by 44 weeks of interferon and ribavirin alone. The rates of sustained virologic response were:
  • 56% with sofosbuvir 100 mg, peg-interferon, and ribavirin
  • 83% with sofosbuvir 200 mg, peg-interferon, and ribavirin
  • 80% with sofosbuvir 400 mg, peg-interferon, and ribavirin
  • 43% with peg-interferon and ribavirin alone.
The ATOMIC trial16 tested the efficacy and safety of sofosbuvir in combination with peg-interferon and ribavirin in patients with HCV genotype 1, 4, or 6, without cirrhosis, who had not received any previous treatment. Patients with HCV genotype 1 were randomized to three treatments:
  • Sofosbuvir 400 mg orally once daily plus peg-interferon and ribavirin for 12 weeks
  • The same regimen, but for 24 weeks
  • Sofosbuvir plus peg-interferon and ribavirin for 12 weeks, followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin.
The rates of sustained virologic response were very high and were not significantly different among the three groups: 89%, 89%, and 87%, respectively. Patients who were able to complete a full course of therapy achieved even higher rates of sustained virologic response, ranging from 96% to 98%. The likelihood of response was not adversely affected by the usual markers of a poorer prognosis, such as a high viral load (≥ 800,000 IU/mL) or a non-CC IL28B genotype. Although patients with cirrhosis (another predictor of no response) were excluded from this study, the presence of bridging fibrosis did not seem to affect the rate of sustained virologic response. The results in patients with genotypes other than 1 were very encouraging, but the small number of patients enrolled precluded drawing firm conclusions in this group. 

Important implications of the ATOMIC trial include the following:
There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks, since adverse events increased without any improvement in the rate of sustained virologic response. 

There is a very low likelihood of developing viral resistance or mutation when using sofosbuvir.
There is no role for response-guided therapy, a concept used with protease inhibitor-based regimens in which patients who have complete clearance of the virus within the first 4 weeks of treatment (a rapid virologic response) and remain clear through 12 weeks of treatment (an extended rapid viral response) can be treated for a shorter duration without decreasing the likelihood of a sustained virologic response. 

Lawitz et al17 conducted a randomized double-blind phase 2 trial to evaluate the effect of sofosbuvir dosing on response in noncirrhotic, previously untreated patients with HCV genotype 1, 2, or 3. Patients with HCV genotype 1 were randomized to one of three treatment groups in a 2:2:1 ratio: sofosbuvir 200 mg orally once daily, sofosbuvir 400 mg orally once daily, or placebo, all for 12 weeks in combination with peg-interferon (180 μg weekly) and ribavirin in a dosage based on weight. Depending on the viral response, patients continued peg-interferon and ribavirin for an additional 12 weeks if they achieved an extended rapid viral response, or 36 weeks if they did not achieve an extended rapid virologic response, and in all patients who received placebo. Patients with HCV genotype 2 or 3 were given sofosbuvir 400 mg once daily in combination with interferon and ribavirin for 12 weeks. 

As in the ATOMIC trial, all patients treated with sofosbuvir had a very rapid reduction in viral load: 98% of patients with genotype 1 developed a rapid virologic response, and therefore almost all were eligible for the shorter treatment course of 24 weeks.17 The latter finding again suggested that response-guided treatment is not relevant with sofosbuvir-based regimens. 

Very high rates of sustained virologic response were seen: 90% in patients with genotype 1 treated with sofosbuvir 200 mg, 91% in those with genotype 1 treated with 400 mg, and 92% in those with genotype 2 or 3. Although 6% of patients in the 200-mg group had virologic breakthrough after completing sofosbuvir treatment, no virologic breakthrough was observed in the 400-mg group, suggesting that the 400-mg dose might suppress the virus more effectively.17

The ELECTRON trial18 was a phase 2 study designed to evaluate the efficacy and safety of sofosbuvir and ribavirin in interferon-sparing and interferon-free regimens in patients with HCV genotype 1, 2, or 3 infection. Sofosbuvir was tested with peg-interferon and ribavirin, with ribavirin alone, and as monotherapy in previously untreated patients with genotype 2 or 3. A small number of patients with genotype 1 who were previously untreated and who were previously nonresponders were also treated with sofosbuvir and ribavirin. 

All patients had a rapid virologic response, and viral suppression was sustained through the end of treatment. All patients with genotype 2 or 3 treated with double therapy (sofosbuvir and ribavirin) or triple therapy (sofosbuvir, peg-interferon, and ribavirin) achieved a sustained virologic response, compared with only 60% of patients treated with sofosbuvir monotherapy. The monotherapy group had an equal number of relapsers among those with genotype 2 or 3. Of the genotype 1 patients treated with sofosbuvir and ribavirin, 84% of those previously untreated developed a sustained virologic response, whereas only 10% of the previous nonresponders did.

Phase 3 clinical trials of sofosbuvir

The NEUTRINO trial19 studied the efficacy and safety of sofosbuvir in previously untreated patients with HCV genotype 1, 4, 5, or 6. In this phase 3 open-label study, all patients received sofosbuvir plus peg-interferon and weight-based ribavirin therapy for 12 weeks. Of the patients enrolled, 89% had genotype 1, while 9% had genotype 4 and 2% had genotype 5 or 6. Overall, 17% of the patients had cirrhosis. 

The viral load rapidly decreased in all patients treated with sofosbuvir irrespective of the HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Ninety-nine percent of patients with genotype 1, 4, 5, or 6 achieved a rapid virologic response, and 90% achieved a sustained virologic response at 12 weeks after completion of treatment with sofosbuvir and ribavirin. Patients with cirrhosis had a slightly lower rate of sustained virologic response (80%, compared with 92% in patients without cirrhosis). Also, patients with non-CC IL28B genotypes had a lower rate of sustained virologic response (87% in non-CC allele vs 98% in patients with the favorable CC allele).

The FISSION trial19 recruited previously untreated patients with genotype 2 or 3 and randomized them to therapy with either sofosbuvir plus ribavirin in a weight-based dose for 12 weeks, or 24 weeks of interferon and ribavirin. In this study, 20% of patients in each treatment group had cirrhosis.
As in the NEUTRINO trial, the viral load rapidly decreased in all patients treated with sofosbuvir irrespective of HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Here, 100% of patients with genotype 2 or 3 who were treated with sofosbuvir and ribavirin achieved a rapid virologic response. Differences in outcome emerged based on genotype: 97% of those with genotype 2 and 56% of those with genotype 3 achieved a sustained virologic response. The overall rate was 67%, which was not different from patients treated with peg-interferon and ribavirin. In the subgroup of patients with cirrhosis, 47% of those treated with sofosbuvir and ribavirin achieved a sustained virologic response, vs 38% of those who received peg-interferon plus ribavirin.
In both the NEUTRINO and FISSION trials, few patients discontinued treatment, with higher rates of most adverse events occurring in patients treated with peg-interferon and ribavirin.

POSITRON,20 a phase 3 clinical trial, tested sofosbuvir in patients with HCV genotype 2 or 3 who were ineligible for peg-interferon, unwilling to take peg-interferon, or unable to tolerate peg-interferon (mainly because of clinically significant psychiatric disorders). Patients were randomized to two treatment groups for 12 weeks: sofosbuvir plus ribavirin, or placebo. About 50% of patients had HCV genotype 3, and 16% had cirrhosis.

The overall rate of sustained virologic response at 12 weeks after treatment was 78% in the sofosbuvir-and-ribavirin group (93% in genotype 2 patients and 61% in genotype 3 patients). Again, cirrhosis was associated with a lower rate of sustained virologic response (61% of patients with cirrhosis achieved a sustained virologic response vs 81% of patients without cirrhosis). None of the sofosbuvir-treated patients had virologic failure while on treatment.

FUSION,20 another phase 3 trial, evaluated sofosbuvir in patients infected with HCV genotype 2 or 3 for whom interferon-based treatment had failed. They were randomized to either 12 weeks or 16 weeks of sofosbuvir and weight-based ribavirin treatment. About 60% of patients had HCV genotype 3, and 34% had cirrhosis. 

The overall sustained virologic response rate was 50% in the patients treated for 12 weeks and 73% in those treated for 16 weeks: specifically, 86% of patients with genotype 2 achieved a sustained virologic response at 12 weeks and 94% at 16 weeks, whereas in those with genotype 3 the rates were 30% at 12 weeks and 62% at 16 weeks. 

Cirrhosis was again a predictor of lack of response to sofosbuvir. In the group treated for 12 weeks, 31% of those with cirrhosis achieved a sustained virologic response compared with 61% in those without cirrhosis. In the group treated for 16 weeks, 61% of those with cirrhosis achieved a sustained virologic response compared with 76% in those without cirrhosis. 

In both the POSITRON and FUSION trials, relapse accounted for all treatment failures, and no virologic resistance was detected in patients who did not have a sustained virologic response. The investigators concluded that 12 weeks of treatment with sofosbuvir and ribavirin can be effective for HCV genotype 2 infection, but extending the treatment to 16 weeks may be beneficial for genotype 3. This may be especially important in patients with cirrhosis or those who did not have a response to peg-interferon-based treatment. 

VALENCE,21 an ongoing phase 3 trial in Europe, is assessing the safety and efficacy of sofosbuvir 400 mg once daily and weight-based ribavirin in patients with HCV genotype 2 or 3. Eighty-five percent of the trial participants have received previous treatment, and 21% have cirrhosis. Patients were originally randomized in a 4:1 ratio to receive sofosbuvir plus ribavirin for 12 weeks or matching placebo, but as a result of emerging data suggesting that patients with genotype 3 would benefit from more than 12 weeks of treatment, the study was subsequently amended to extend treatment to 24 weeks for patients with genotype 3. 

Overall rates of sustained virologic response were 93% in patients with genotype 2 and 85% in patients with genotype 3. In previously treated patients with genotype 2 who were treated for 12 weeks, the rates of sustained virologic response were 91% in those without cirrhosis vs 88% in those with cirrhosis. In previously treated patients with genotype 3, the rates in those treated for 24 weeks were 87% in patients without cirrhosis vs 60% with cirrhosis. The safety profile was consistent with that of ribavirin.

Side effects of sofosbuvir
In clinical trials, side effects occurred most often when sofosbuvir was combined with interferon and ribavirin and were consistent with the known side effects of the latter two agents. The most frequently reported side effects included fatigue, insomnia, nausea, rash, anemia, headache, and arthralgia, with most of these adverse events rated by treating clinicians as being mild in severity.15,20
In the ATOMIC trial, the most common events leading to drug discontinuation were anemia and neutropenia, both associated with interferon and ribavirin. Patients receiving sofosbuvir monotherapy after 12 weeks of triple therapy showed rapid improvement in hemoglobin levels and neutrophil counts, indicating that hematologic abnormalities attributed solely to sofosbuvir are minimal. In the FISSION trial, the incidence of adverse events was consistently lower in those receiving sofosbuvir-ribavirin than in patients receiving interferon-ribavirin without sofosbuvir.19

In the POSITRON trial, discontinuation of sofosbuvir because of adverse events was uncommon, and there were no differences in the incidence of adverse events and laboratory abnormalities between patients with and without cirrhosis when they received sofosbuvir and ribavirin.20 

Sofosbuvir dosage and indications
Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3 and in combination with ribavirin and interferon alfa in patients infected with HCV genotype 1 or 4 (TABLE 3). It could be considered for HCV genotype 1 in combination with ribavirin alone for 24 weeks in patients who are ineligible for interferon. 


Sofosbuvir is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation, for up to 48 weeks or until they receive a transplant, to prevent posttransplant reinfection with HCV.

Sofosbuvir is expensive
A course of therapy is expected to cost about $84,000, which is significantly more than the cost of previous triple therapy (peg-interferon, ribavirin, and either boceprevir or telaprevir).22 This high cost will undoubtedly lead to less widespread use in developing countries, and potentially even in the United States. As newer direct-acting antiviral agents become available, the price will likely come down, enhancing access to these drugs.

SIMEPREVIR: A SECOND-GENERATION PROTEASE INHIBITOR
Telaprevir and boceprevir are NS3/A4 protease inhibitors that belong to the alfa-ketoamid derivative class. Simeprevir belongs to the macrocyclic class and has a different way of binding to the target enzyme.23 Like sofosbuvir, simeprevir was recently approved by the FDA for the treatment of HCV genotype 1. 

The therapeutic efficacy of simeprevir has been tested in several clinical trials (TABLE 4), including QUEST-124 and QUEST-225 (in previously untreated patients), PROMISE26 (in prior relapsers), and ASPIRE27 (in prior partial and null responders). Results from these trials showed high overall rates of sustained virologic response with triple therapy (ie, simeprevir combined with peg-interferon and ribavirin). It was generally well tolerated, and most adverse events reported during 12 weeks of treatment were of mild to moderate severity. 


In QUEST-1 and QUEST-2, both double-blind phase 3 clinical trials, previously untreated patients infected with HCV genotype 1 were randomized in a 2:1 ratio to receive either simeprevir 150 mg daily or placebo for 12 weeks; both groups also received peg-interferon and ribavirin. Patients then received peg-interferon and ribavirin alone for 12 or 36 weeks in the simeprevir group (based on response) and for 36 weeks in the placebo group.
The overall rate of sustained virologic response at 12 weeks was 80% in the simeprevir group (75% in those with genotype 1a and 85% in those with genotype 1b) vs 50% in the placebo group (receiving peg-interferon and ribavirin alone).24,25

PROMISE,26 another double-blind randomized phase 3 clinical trial, evaluated simeprevir in patients with HCV genotype 1 who relapsed after previous interferon-based therapy. It had a similar design to QUEST-1 and QUEST-2, and 15% of all patients had cirrhosis.
The overall sustained virologic response rate at 12 weeks after treatment was 79% in the simeprevir group (70% in patients with genotype 1a and 86% in those with genotype 1b) vs 37% in the placebo group. Rates were similar in patients with absent to moderate fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%). 

ASPIRE.27 Simeprevir efficacy in patients with HCV genotype 1 for whom previous therapy with peg-interferon and ribavirin had failed was tested in ASPIRE, a double-blind randomized phase 2 clinical trial. Patients were randomized to receive simeprevir (either 100 mg or 150 mg daily) for 12, 24, or 48 weeks in combination with 48 weeks of peg-interferon and ribavirin, or placebo plus peg-interferon and ribavirin for 48 weeks. 

The primary end point was the rate of sustained virologic response at 24 weeks. Overall, rates were 61% to 80% for the simeprevir treatment groups compared with 23% with placebo, regardless of prior response to peg-interferon and ribavirin. By subgroup, rates were:
  • 77% to 89% with simeprevir vs 37% with placebo in prior relapsers
  • 48% to 86% with simeprevir vs 9% with placebo in prior partial responders
  • 38% to 59% with placebo vs 19% for prior nonresponders.
The best rates of sustained viral response at 24 weeks were in the groups that received simeprevir 150 mg daily: 85% in prior relapsers, 75% in prior partial responders, and 51% in prior nonresponders.

Simeprevir vs other direct-acting antiviral drugs
Advantages of simeprevir over the earlier protease inhibitors include once-daily dosing, a lower rate of adverse events (the most common being fatigue, headache, rash, photosensitivity, and pruritus), a lower likelihood of discontinuation because of adverse events, and fewer drug-drug interactions (since it is a weak inhibitor of the CYP3A4 enzyme). 

Unlike sofosbuvir, simeprevir was FDA-approved only for HCV genotype 1 and in combination with interferon alfa and ribavirin. Compared with sofosbuvir, the treatment duration with simeprevir regimens is longer overall (interferon alfa and ribavirin are given for 12 weeks in sofosbuvir-based regimens vs 24 to 48 weeks with simeprevir). As with sofosbuvir, the estimated cost of simeprevir is high, about $66,000 for a 12-week course.

Simeprevir dosage and indications
Simeprevir was approved at an oral dose of 150 mg once daily in combination with ribavirin and interferon alfa in patients with HCV genotype 1 (TABLE 5). 


The approved regimens for simeprevir are fixed in total duration based on the patient’s treatment history. Specifically, all patients receive the drug in combination with peg-interferon and ribavirin for 12 weeks. Then, previously untreated patients and prior relapsers continue to receive peg-interferon and ribavirin alone for another 12 weeks, and those with a partial or null response continue with these drugs for another 36 weeks.
Patients infected with HCV genotype 1a should be screened for the NS3 Q80K polymorphism at baseline, as it has been associated with substantially reduced response to simeprevir.

Sofosbuvir and simeprevir in combination

The COSMOS trial.28 Given their differences in mechanism of action, sofosbuvir and simeprevir are being tested in combination. The COSMOS trial is an ongoing phase 2 randomized open-label study investigating the efficacy and safety of simeprevir and sofosbuvir in combination with and without ribavirin in patients with HCV genotype 1, including nonresponders and those with cirrhosis. Early results are promising, with very high rates of sustained virologic response with the sofosbuvir-simeprevir combination (93% to 100%) and indicate that the addition of ribavirin might not be needed to achieve sustained virologic response in this patient population.

THE FUTURE
The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention29 recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment. 

Future drugs promise further improvements (TABLE 6).3035 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials. 


Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents. 

Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).36 Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.

Challenges remaining
The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.37 For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. TABLE 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.



Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.38

As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.39 

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