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Source: Gastroenterology
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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with HCV Genotype 2, 3, 4, or 6 Infections in an Open-label, Phase 2 Trial
Edward Gane, Kris V. Kowdley, David Pound, Catherine A.M. Stedman, Mitchell Davis, Kyle Etzkorn, Stuart C. Gordon, David Bernstein, Gregory Everson, Maribel Rodriguez-Torres, Naoky Tsai, Omer Khalid, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Myron Tong, Raymond T. Chung, Kimberly Beavers, John E. Poulos, Paul Y. Kwo, Mindie H. Nguyen
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.038
Publication stage: In Press Accepted Manuscript
Published online: July 30, 2016
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Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections who have failed by a prior course of antiviral therapy, and the feasibility of further shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients.
With the recent approval of DAAs, safe and effective combination regimens are now available for the majority of patients chronically infected with HCV. SVR rates exceeding 90% can be achieved in most patient populations regardless of genotype, treatment experience, or presence of cirrhosis. Although the proportion of patients who do not achieve SVR with currently approved DAA regimens is small, the absolute number of DAA failures will steadily increase in parallel with the rate of treatment uptake. DAA failures represent an unmet medical need without, at this time, any approved retreatment options. In this open-label, phase 2 study, the combination of sofosbuvir velpatasvir plus GS-9857 for 12 weeks was safe and highly effective for the treatment of patients with genotypes 2, 3, 4, or 6 HCV infection with or without compensated cirrhosis who were treatment-experienced, including those who had failed previous DAA regimens. The high SVR12 rate among treatment-experienced patients with genotype 3 HCV infection and cirrhosis is noteworthy, given the lower SVR12 rates generally experienced by patients this patient population.
Currently approved regimens for non-genotype 1 HCV have durations of 12 to 24 weeks, depending on choice of regimen and patient’s baseline characteristics, such as HCV genotype, treatment history and presence or absence of cirrhosis. The feasibility of further shortening the duration of treatment has been a goal of research, especially for non-ribavirin containing regimens. Several trials have evaluated various combinations of DAAs for four weeks, but with uniformly disappointing 0utcomes—SVR12 rates of 20% to 40%
In this trial, 6 weeks of sofosbuvir-velpatasvir plus GS-9857 achieved suboptimal results (<90% SVR12 rate) in a historically easy-to-treat population of treatment-naïve patients without cirrhosis. Eight weeks of sofosbuvir-velpatasvir plus GS-9857 was safe and effective for treatment-naïve patients with cirrhosis, including those with HCV genotype 3. Thus, the 8-week regimen may serve as a shorter-duration option for treatment-naïve patients with or without cirrhosis and is currently being evaluated in Phase 3 clinical trials.
Additionally, the high SVR12 rates across genotypes suggests the pangenotypic treatment potential of sofosbuvir-velpatasvir plus GS-9857. While genotype 1 patients were not treated in this study, a parallel open-label, phase 2 study of patients infected with HCV genotype 1 was also conducted,where patients received treatment for 6 to 12 weeks.
This study was limited by its small sample size and open-label design. Although the first Phase 2 clinical trial to evaluate retreatment of non-genotype 1 HCV infected patients previously treated with DAA-regimens that included NS5A inhibitors, only six patients in this subgroup were enrolled. Also, no patients with genotype 5 HCV and only 3 patients with genotype 6 HCV were enrolled, reflecting the low prevalence of these infections in North America and New Zealand.
In conclusion, sofosbuvir-velpatasvir plus GS-9857 is a safe and effective treatment in patients with HCV genotypes 2, 3, 4, and 6, with and without compensated cirrhosis. High SVR rates were achieved in treatment-experienced patients, including those with DAA-experience, after12 weeks of sofosbuvir-velpatasvir plus GS-9857 and in treatment-naïve patients with compensated cirrhosis after 8 weeks of this regimen. These three potent pangenotypic DAAs have been coformulated into afixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination in patients for eight weeks treatment-naïve patients of all genotypes and for twelve weeks in patients of all genotypes who had received previous treatment with a DAA.
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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with Genotype 1 Hepatitis C Virus Infection in an Open-label, Phase 2 Trial
Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr., K. Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.039
Publication stage: In Press Accepted Manuscript
Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with Genotype 1 Hepatitis C Virus Infection in an Open-label, Phase 2 Trial
Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr., K. Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.039
Publication stage: In Press Accepted Manuscript
Published online: July 30, 2016
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DISCUSSION ONLY
The development of oral DAAs represents a major advance in the treatment of HCV in patients of all genotypes. Currently available DAA combination regimens offer SVR rates well over 90% overall and in most patient subpopulations. Nevertheless, some patients do not achieve SVR with existing regimens. Patients who have failed prior treatment with first generation NS3/4A protease inhibitors (e.g., telaprevir, boceprevir, or simeprevir) may be retreated with ledipasvir sofosbuvir, but patients who have been unsuccessfully treated with a regimen that includes an NS5A inhibitor have no approved retreatment options. In a previous trial, patients with genotype 1 HCV who did not achieve SVR after 8 or 12 weeks of ledipasvir-sofosbuvir-based regimens and were subsequently retreated with 24 weeks of ledipasvir-sofosbuvir had an SVR12 rate of only 71%. In this population, the presence of baseline NS5A RASs was associated with a higher rate of virologic failure (Lawitz et al: J Hepatol 62:S192 Abstract, 2015).
In another small trial, 14 of 16 patients (88%) who had previously failed a daclatasvir-containing regimen achieved SVR12 after retreatment with simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16 patients had NS5A RASs at baseline, and of these 13, 11 (85%) achieved SVR12. The 2 patients who did not achieve SVR12 had Q30K and L31M substitutions as the dominant viral populations at retreatment baseline.16
The development of oral DAAs represents a major advance in the treatment of HCV in patients of all genotypes. Currently available DAA combination regimens offer SVR rates well over 90% overall and in most patient subpopulations. Nevertheless, some patients do not achieve SVR with existing regimens. Patients who have failed prior treatment with first generation NS3/4A protease inhibitors (e.g., telaprevir, boceprevir, or simeprevir) may be retreated with ledipasvir sofosbuvir, but patients who have been unsuccessfully treated with a regimen that includes an NS5A inhibitor have no approved retreatment options. In a previous trial, patients with genotype 1 HCV who did not achieve SVR after 8 or 12 weeks of ledipasvir-sofosbuvir-based regimens and were subsequently retreated with 24 weeks of ledipasvir-sofosbuvir had an SVR12 rate of only 71%. In this population, the presence of baseline NS5A RASs was associated with a higher rate of virologic failure (Lawitz et al: J Hepatol 62:S192 Abstract, 2015).
In another small trial, 14 of 16 patients (88%) who had previously failed a daclatasvir-containing regimen achieved SVR12 after retreatment with simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16 patients had NS5A RASs at baseline, and of these 13, 11 (85%) achieved SVR12. The 2 patients who did not achieve SVR12 had Q30K and L31M substitutions as the dominant viral populations at retreatment baseline.16
In this open-label, phase 2 study, 12 weeks of treatment with sofosbuvir-velpatasvir plus GS9857 was safe and highly effective in patients with HCV genotype 1, with and without cirrhosis, who did not achieve SVR after prior treatment with DAA, including those who had previously received an NS5A inhibitor. In treatment-naive patients, the 8-week regimen was safe and effective, regardless of cirrhosis status. Among the treatment-naïve patients who relapsed, the presence of baseline RASs appeared to have no impact on treatment outcome. Treatment emergent RASs by deep sequencing with a 1% cutoff were rare (3/17, 18%) and no treatment emergent RASs among relapsers were detected with the 15% cutoff. This is consistent with the anticipated high barrier of resistance of the combination therapy based on in vitro data (Lawitz et al: Hepatology XXX Abstract 2015).
Treatment-naïve patients without cirrhosis treated for 8 weeks achieved a SVR12 rate of 100%,which is higher than results reported in other recent studies of combining 3 or 4 DAAs for treatment for the same population and treatment duration.20,21 Treatment-naïve patients with cirrhosis treated for 8 weeks had lower SVR12 rates of 81-94% than patients without cirrhosis. Larger studies will determine whether this short duration is adequate for this patient population. One unexpected result in our trial was the apparent lack of benefit of the addition of ribavirin to sofosbuvir-velpatasvir plus GS-9857 for treatment-naïve patients with cirrhosis. Although patients in this group receiving ribavirin had a numerically lower rate of SVR12 than treatment naïve patients with cirrhosis who received sofosbuvir-velpatasvir plus GS-9857 without ribavirin (81% vs 94%), the confidence intervals overlap and it is likely that this reflects the small sample sizes.
Factors limiting the interpretation of these results of this trial include its small size and uncontrolled, open-label design. Although the trial enrolled only patients with genotype 1 HCV, another trial of similar design has been conducted to assess this combination regimen in patients with non-genotype 1 HCV.
In conclusion, sofosbuvir-velpatasvir plus GS-9857 for 12 weeks provided a high rate of SVR12 (100%) and was well-tolerated in a group of patients currently without treatment options—those with and without compensated cirrhosis who have not achieved SVR after previous treatment with a NS5A inhibitor-containing regimen. The addition of GS-9857 to sofosbuvir-velpatasvir was also safe in the treatment-naïve population where it was effective in reducing the treatment duration to 8 weeks while preserving a high rate of SVR12. These three potent pangenotypic DAAs have been coformulated into a fixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination for eight weeks in treatment-naïve patients and for twelve weeks in DAA-experienced patients, including those who have previously received an NS5A inhibitor.
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