Gilead Announces SVR12 Rates SOF/VEL/VOX(GS-9857) Treatment-Naïve/Treatment-Experienced HCV Geno 1-6

Update Of Interest - Nov 4

Reported by Jules Levin
IDWeek Oct 26-30
New Orleans 2016 Nov 4
Sofosbuvir/Velpatasvir Plus Voxilaprevir for 6, 8, or 12 Weeks in Genotype 1-6 HCV-infected Patients: An Integrated Analysis of Safety and Efficacy from Two Phase 2 Studies  ​

Press Release
Oct 20
Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naïve and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients

Date(s): 20-Oct-2016 10:07 AM

- If Approved, SOF/VEL/VOX Would Be the First Once-Daily Single Tablet Regimen Available for Salvage for Patients Who Have Failed Prior HCV Therapy with Oral Direct-Acting Antiviral Agent Regimens -

- U.S. NDA Planned for Q4 2016 -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 20, 2016-- Gilead Sciences, Inc. (NASDAQ: GILD) today announced topline results from four international Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluating an investigational, once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.

In the POLARIS-1 and POLARIS-4 studies, 445 patients with genotype 1-6 HCV infection who were previously treated with direct-acting antiviral agents (DAAs) received 12 weeks of SOF/VEL/VOX. The POLARIS-1 study enrolled patients who failed prior treatment with an NS5A inhibitor. The POLARIS-4 study enrolled patients who failed prior treatment with a DAA that was not an NS5A inhibitor, most with either an NS5B inhibitor alone (73 percent) or an NS5B inhibitor and an NS3/4A protease inhibitor (25 percent).

In the POLARIS-2 and POLARIS-3 studies, 611 patients who were not previously treated with a DAA received 8 weeks of SOF/VEL/VOX. The POLARIS-2 study enrolled patients with genotype 1-6 HCV infection with or without compensated cirrhosis. The POLARIS-3 study enrolled patients with genotype 3 HCV infection, all of whom had compensated cirrhosis.

The primary endpoint for all studies was SVR12. The intent-to-treat SVR12 rates observed in the POLARIS studies are summarized in the following table. Complete results from all four studies will be presented at The Liver Meeting^® 2016 in Boston.

Study		Population		Genotype		Treatment		Duration		SVR12 Rates
POLARIS-1		NS5A inhibitor-experienced   41 percent (172/415) had cirrhosis		1, 2, 3, 4, 5, 6		SOF/VEL/VOX		12 Weeks		96% (253/263)
						Placebo		12 Weeks		0% (0/152)
POLARIS-4		DAA-experienced (No NS5A inhibitor)   46 percent (153/333) had cirrhosis		1, 2, 3, 4		SOF/VEL/VOX		12 Weeks		97% (177/182)
						SOF/VEL		12 Weeks		90% (136/151)
POLARIS-2		DAA-naïve   18 percent (174/941) had cirrhosis		1, 2, 3, 4, 5, 6		SOF/VEL/VOX		8 Weeks		95% (476/501)
						SOF/VEL		12 Weeks		98% (432/440)
POLARIS-3		DAA-naïve   All had cirrhosis		3		SOF/VEL/VOX		8 Weeks		96% (106/110)
						SOF/VEL		12 Weeks		96% (105/109)

Patients treated with SOF/VEL/VOX for 12 or eight weeks had similar overall incidence of adverse events compared to placebo-treated or SOF/VEL-treated patients. The most common adverse events among patients who received SOF/VEL/VOX were headache, fatigue, diarrhea and nausea. Among the 1,056 patients who received SOF/VEL/VOX in the four studies, one patient (less than one percent) receiving SOF/VEL/VOX for 12 weeks discontinued due to an adverse event.

"Despite recent advances that have provided high cure rates and simplified treatment for most HCV patients, those who have failed previous treatment with direct acting antivirals continue to represent an unmet medical need. The POLARIS study results demonstrate that combining three potent antivirals with different mechanisms of action and high barriers to resistance can provide high cure rates for patients who have failed other highly effective oral DAA regimens," said Norbert Bischofberger, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. "Based on these Phase 3 results, we plan to submit regulatory applications for SOF/VEL/VOX for the treatment of chronic HCV in the United States in the fourth quarter of 2016 and shortly thereafter in Europe."

About the POLARIS Studies
The POLARIS-1 study was a double-blind, placebo-controlled study in 415 genotype 1-6 NS5A inhibitor-experienced patients. The most common prior NS5A inhibitors were ledipasvir (55 percent) and daclatasvir (23 percent).

The open-label POLARIS-4 study evaluated the use of SOF/VEL/VOX or SOF/VEL for 12 weeks in 333 genotype 1-4 HCV-infected patients with prior DAA experience that did not include an NS5A inhibitor. Most patients (85 percent) had prior DAA experience with sofosbuvir.

The open-label POLARIS-2 study evaluated the use of SOF/VEL/VOX for eight weeks or SOF/VEL for 12 weeks in 941 genotype 1-6 DAA-naïve HCV-infected patients, including 18 percent with cirrhosis and 23 percent who had previously failed treatment with an interferon-based regimen.

The open-label POLARIS-3 study randomized patients with genotype 3 HCV infection and cirrhosis to receive SOF/VEL/VOX daily for eight weeks or SOF/VEL for 12 weeks. Of the 219 patients treated, 31 percent had previously failed treatment with an interferon-based regimen.

The POLARIS-1, POLARIS-3 and POLARIS-4 studies met their respective pre-specified primary endpoints for the patients receiving SOF/VEL/VOX. The POLARIS-2 study did not meet its primary endpoint; with a pre-specified 5 percent margin, the SVR12 rate for patients receiving treatment with SOF/VEL/VOX for eight weeks was not statistically non-inferior to the SVR12 rate for patients receiving SOF/VEL for 12 weeks.

About SOF/VEL/VOX
The SOF/VEL/VOX fixed-dose combination is an investigational product and its safety and efficacy have not been established. It has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of chronic genotype 1 HCV patients who have previously failed an NS5A inhibitor-containing regimen.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that future trials involving the SOF/VEL/VOX fixed-dose combination may have unfavorable results. In addition, Gilead may be unable to file for U.S. regulatory approval of the SOF/VEL/VOX fixed-dose combination in the United States and Europe in the currently anticipated timelines. In addition, the FDA and other regulatory agencies may not approve the SOF/VEL/VOX fixed-dose combination, and any marketing approvals, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2016, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Of Interest

Gilead unveils promising hep C, fatty liver data; setbacks elsewhere​

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection

Journal of Viral Hepatitis

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection
A Randomized, Double-blind, Dose-ranging Phase 1 Study

M. Rodriguez-Torres; S. Glass; J. Hill; B. Freilich; D. Hassman; A. M. Di Bisceglie; J. G. Taylor; B. J. Kirby; H. Dvory-Sobol; J. C. Yang; D. An; L. M. Stamm; D. M. Brainard; S. Kim; D. Krefetz; W. Smith; T. Marbury; E. Lawitz Disclosures J Viral Hepat. 2016;23(8):614-622.

Abstract and Introduction

Methods

Results 

Discussion

Discussion Only

In this randomized, phase 1b study, the safety, antiviral efficacy and PK of GS-9857 at doses ranging from 50 to 300 mg were assessed in patients with chronic genotype 1–4 HCV infection. GS-9857 was generally well tolerated by patients with chronic HCV infection when administered once daily for 3 days. All AEs were of mild or moderate severity, with diarrhoea and headache occurring most commonly during this study. Although increased incidence of rash, pruritus, nausea and anaemia have been commonly reported with the use of certain protease inhibitor-based regimens,^[7–10] no such events were observed during this study. Grade 3 or Grade 4 laboratory abnormalities occurred in 16.9% of patients receiving GS-9857 and were not associated with GS-9857 dose or AEs. Notably, assessments of ALT, AST and alkaline phosphatase levels did not reveal any Grade 3 or Grade 4 abnormalities, indicating that GS-9857 administration was not associated with significant changes in liver function. Physical examination and ECG evaluation did not reveal clinically significant findings.

Treatment with GS-9857 at doses of 100 mg or 300 mg resulted in >3 log₁₀ IU/mL median maximal reduction in viral load from baseline across all genotypes, including genotype 3, indicating that GS-9857 exhibited potent antiviral activity in HCV-infected patients. This observation is consistent with in vitro data showing that GS-9857 has pan-genotypic activity against genotype 1 to 6 replicons, with the half-maximal effective concentration ranging from 1.5 to 6.6 nm.^[5] With the exception of patients with genotype 3a infection who received GS-9857 doses of <100 mg, a rapid and consistent reduction in HCV RNA was achieved and maintained through day 10. For patients with genotype 3a infection who received GS-9857 50 mg, HCV RNA reductions occurred more slowly.

This study characterized substitutions at positions 36, 41, 43, 54, 55, 80, 122, 155, 156, 168 and 170, which have been reported to be associated with resistance to NS3/4A protease inhibitors.^[11–17] Prior to the start of GS-9857 treatment, 22.4% of patients who were sequenced harboured NS3 RAVs. Treatment with GS-9857 resulted in similar mean maximal viral load reductions in patients with and without NS3 RAVs, indicating that the antiviral efficacy of GS-9857 was maintained in the presence of mutations commonly associated with resistance to treatment. The majority of patients (73.6%) who were sequenced after 3 days of GS-9857 treatment did not have emergent NS3 RAVs, and there were no emergent NS3 RAVs in patients with genotype 2 or 4 infection. A156V or A156T were the most prevalent substitutions to emerge in patients with genotype 1a or 1b infection. In vitro data indicate that GS-9857 has potent activity against the most common genotype 1 RAVs except A156T;^[5] this substitution is associated with high levels of resistance (>100-fold) but low viral fitness (1.5% compared to wild-type genotype 1a replicon).^[12] The overall low frequency of emergent NS3 RAVs suggests that GS-9857 has a relatively high barrier to resistance as compared with other first-generation protease inhibitors, which may be a substantial benefit in the context of retreatment of patients who have failed a prior treatment with a DAA-based regimen.

Administration of GS-9857 at doses ranging from 50 to 300 mg under fasting conditions resulted in dose-proportional increases in exposure. The median half-life across cohorts ranged from approximately 29–42 h, supporting once-daily dosing. Consistent with its long median half-life, significant accumulation of GS-9857 exposure was observed. GS-9857 plasma PK was similar among patients with genotype 1a, 1b, 2, 3 or 4 HCV infection.

Patients with cirrhosis or chronic liver disease were excluded from this preliminary investigational study. As such, the lack of significant safety concerns observed may be the result of selection for a study population less prone to AEs. Further evaluations of GS-9857 in patients with more advanced disease or additional complications will be necessary to confirm the findings of this study.
In summary, administration of multiple doses of GS-9857 was well tolerated and resulted in a robust decline of HCV RNA levels in patients with genotype 1–4 HCV infection. Notably, the potent antiviral activity of GS-9857 was preserved in the presence of commonly observed NS3 mutations associated with resistance to protease inhibitors. GS-9857 demonstrated linear PK when administered at doses ranging from 50 to 300 mg under fasting conditions. The median half-life of GS-9857 ranged from 29 to 42 h, conducive to once-daily dosing. Lastly, GS-9857 has demonstrated additive antiviral activity when evaluated in vitro in combination with sofosbuvir or velpatasvir.^[5] Together, these data support the further development of once-daily GS-9857 in combination with other DAAs for the treatment of patients with chronic HCV infection.

Full Article -  GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection

This phase 1b study of the investigational drug GS-9857 showed positive results on its efficacy and tolerability in chronic HCV infection, supporting its further evaluation.

August 05, 2016

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 Genotype 1, 2,3,4 or 6 / Phase 2 Trial

Articles In Press

Source: Gastroenterology

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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.

DISCUSSION ONLY
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

The best regimen to retreat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed 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 patients with hepatitis C virus (HCV) genotype 1 infection.

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

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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New Combination Therapy May Be Effective Against Chronic HCV Infection

New Combination Therapy May Be Effective Against Chronic HCV Infection
By Will Boggs MD
June 14, 2016

NEW YORK (Reuters Health) - The new NS3/4A protease inhibitor GS-9857, in combination with sofosbuvir and velpatasvir (SOF/VEL), produces sustained viral response in most patients with hepatitis C virus (HCV) genotype 1 or 3 infections, according to a phase 2 trial from Gilead Sciences.

Various combinations of direct-acting antiviral agents (DAAs) provide sustained virologic responses in most patients infected with HCV, but there are ongoing efforts to optimize and shorten regimens.

Dr. Edward J. Gane from Auckland City Hospital in New Zealand and colleagues evaluated the efficacy and safety of short-duration regimens (four, six, or eight weeks) of SOF/VEL plus GS-9857 in a broad range of patients with genotype 1 (n=120) and 3 (n=41) HCV infections, including 63 treatment-naïve patients and 98 previously-treated patients.

Sustained viral response at 12 weeks (SVR12) was achieved by 27% of treatment-naïve patients with genotype 1 infection without cirrhosis after four weeks of treatment and by 93% after six, the team reports in Gastroenterology, online May 27.

SVR12 was 87% among treatment-naïve patients with cirrhosis after six weeks of treatment, while it was 67% among DAA-experienced patients with and without cirrhosis. In patients who had received other previous treatment and did or did not have cirrhosis, SVR12 with eight weeks of therapy ranged from 89% to 100%.

Among patients with genotype 3 infection, SVR12 was achieved by 83% of treatment-naïve patients with cirrhosis after six weeks of treatment and by 100% of previously treated patients with or without cirrhosis after eight weeks of treatment.

Of the 30 patients who did not achieve SVR12, 28 had virologic relapse after completing treatment, one withdrew consent four weeks after the treatment ended (at which time the patient had undetectable HCV RNA), and one never attained HCV RNA below 15 IU/mL on treatment.

Relapse rates were 73% among patients who received only four weeks of treatment, 19% among those who received six weeks of treatment, and 4% among those who received eight weeks of treatment.

SVR12 rates were also high among patients who had resistance-associated substitutions at baseline (84%-86%, depending on the threshold), and no treatment-emergent resistance-associated substitutions were detected in 26 of 28 patients who relapsed.

Common adverse events included headache, nausea, fatigue, and diarrhea, most of which were mild in severity. No patient discontinued treatment due to an adverse event.

"These results suggest that 8 weeks is the threshold of treatment duration with combination DAAs for the easier-to-treat patient population, not 4 or 6 weeks as suggested by recent viral kinetic models," the researchers note. "Future attempts to shorten duration of DAA regimens to less than 8 weeks will probably require the addition of a host-targeting agent such as RG-101, an miR-122 antagonist, which has been shown to do so in the interim results of an ongoing phase 2 study."

"SOF/VEL/GS-9857 is now coformulated as a single tablet which is being evaluated in the larger Phase III program, which includes different patient populations, including DAA-experienced patients," they add. "This group of DAA-experienced patients is growing and currently represents an unmet medical need."

Dr. Assy Nimer from Ziv Medical Center in Haifa, Israel, who has studied various aspects of HCV infection and its treatment, told Reuters Health by email, "The most interesting or surprising results is the low rate of SVR at week 4 in naïve HCV genotype 1 patients without cirrhosis, indicating that the combination of three potent DAA is not effective for 4 weeks but is highly effective for 8 weeks of treatment."

"The best treatment duration of the new DAA combination would be between 8 and 12 weeks," he concluded, adding that "this type of new medications will likely be effective in minimizing resistance-associated variants (RAV), which persist for years."

Gilead Sciences supported the trial, employed several authors, and had various relationships with the rest, including Dr. Gane.

Dr. Gane did not respond to a request for comments.

http://www.journalofclinicalpathways.com/news/new-combination-therapy-may-be-effective-against-chronic-hcv-infection

SOURCE: http://bit.ly/1UaduVG
Gastroenterology 2016.

ILC2016 Sofosbuvir/velpatasvir and experimental compound GS-9857 shows promise in Hepatitis C infected patients whose previous treatment has failed

New triple drug combination shows promise in Hepatitis C infected patients whose previous treatment has failed
April 14, 2016
Press Releases

High sustained virologic response achieved with sofosbuvir/velpatasvir and GS-9857, even in patients unsuccessfuly treated with direct-acting antivirals

The study showed that 99% of patients with HCV genotype 1, 2, 3, 4 and 6 who had previously received treatment, achieved SVR 12 weeks after treatment using this triple combination.

April 14, 2016, Barcelona, Spain: New data presented today at The International Liver Congress™ 2016 in Barcelona, Spain, demonstrates a high sustained virologic response (SVR) at 12 weeks from the all-oral combination of sofosbuvir/velpatasvir and experimental compound GS-9857 in patients with the Hepatitis C virus (HCV). This triple combination treatment was generally safe and effective, even in patients who had been unsuccessfully treated with direct acting antivirals (DAAs, medicines which have been used to treat and cure almost all patients with HCV). The study showed that 99% of patients with HCV genotype 1, 2, 3, 4 and 6 who had previously received treatment, achieved SVR 12 weeks after treatment using this triple combination.

Hepatitis C is a virus carried via the blood, which infects and damages the liver.1 HCV infects liver cells, resulting in inflammation and fibrosis.1 In chronic HCV cases, such symptoms may continue to increase and result in liver cirrhosis, scarring of the liver.1 Despite the high overall SVR rate achieved with currently approved DAA therapies, approximately 5% of patients treated with DAAs will not be cured.2 According to the study authors, for this small proportion of patients who are not cured, retreatment options are significantly limited.

“Our study demonstrates that for HCV patients whose prior treatment has failed with the use of DAAs, this triple combination provides a high rate of sustained virologic response across HCV genotypes,” said Dr Eric Lawitz, Clinical Professor of Medicine at the University of Texas Health Science Center, San Antonio and lead author of the study. “Furthermore, the study indicates that the treatment combination is generally safe and well tolerated by patients, providing a promising alternative for HCV sufferers who have limited re-treatment options.”

Two global, open-label Phase 2 studies were conducted among chronic HCV-infected patients that had failed prior HCV treatment. Genotype 1 HCV-infected patients enrolled in the study had previously been treated with an NS5A-inhibitor or multiple classes of DAAs, and genotype 2-6 HCV-infected patients had previously been treated with pegylated-interferon (Peg-IFN) plus ribavarin and/or any DAA. All patients received the triple combination of sofosbuvir/velpatasvir plus GS-9857 for 12 weeks. Frequently reported adverse events (AEs) were headache, fatigue, diarrhea and nausea; most were mild or moderate in severity.

“Having offered promising results, this three drug combination is being further evaluated in Phase 3 trials as a single tablet regimen in DAA-experienced patients,” said Professor Laurent Castera, EASL Secretary General.

Study demonstrates the potential for a new triple combination treatment for hepatitis C patients whose prior treatment with direct-acting antivirals failed
April 14, 2016
Press Releases

The combination of sofosbuvir, velpatasvir, and GS-9857 demonstrates safety and efficacy in patients with genotype 1 hepatitis C

April 14, 2016, Barcelona, Spain: A new combination treatment for hepatitis C has potential for patients who were not cured by current treatment options. The study, presented at The International Liver CongressTM in Barcelona, Spain, demonstrated that the combination of sofosbuvir, velpatasvir and the investigational drug GS-9857 with or without ribavirin resulted in high rates of sustained virologic response 12 weeks after treatment (SVR12) in genotype 1 HCV patients who had previously received and failed treatment with direct-acting antivirals (DAAs). Overall, 98% of patients in the study achieved SVR12 with this three-drug combination in a single tablet with or without ribavirin.

Between 130 and 150 million people globally have chronic Hepatitis C virus (HCV) infection.1 It is estimated that 15 million people in the World Health Organization’s EU Region are living with Hepatitis C, representing 2% of adults.2 Worldwide, genotype 1 HCV is the most common, accounting for approximately half of all hepatitis C infections.3

“Our study set out to evaluate the safety and efficacy of this investigational combination for hard-to-treat patients with genotype 1 hepatitis C,” said Dr Eric Lawitz, Clinical Professor of Medicine at the Texas Liver Institute, University of Texas Health Science Centre, San Antonio and lead author of the study. “With the triple combination of three potent drugs, sofosbuvir, velpatasvir and GS-9857, we demonstrated that high SVR12 results were achieved with or without ribavirin.”

Patients previously treated with DAAs were randomised to receive the combination treatment with or without ribavirin for 12 weeks. The primary endpoint of the study was SVR12. SVR12 was achieved in 100% of patients who took sofosbuvir, velpatasvir and GS-9857 without ribavirin and in 96% of patients who additionally took ribavirin.

A total of 49 patients were randomised and treated in the American study. The majority were male (65%), and had HCV genotype 1a (88%). Overall, 41% of patients had previously received an NS5A inhibitor, and 47% of patients had previously received at least two classes of DAA. The triple combination of sofosbuvir, velpatasvir and GS-9857, with or without ribavirin was generally safe and well tolerated. There was one serious adverse event and two patients discontinued treatment with ribavirin due to adverse events. Most frequent adverse events were fatigue and anaemia, which were only observed in patients that received ribavirin.

“This new combination of treatments could add to our arsenal of therapies for patients with Hepatitis C, a disease which could eventually be eradicated. In the hard-to-treat patient population who had previously failed on existing treatment regimens, the combination with GS-9857 could provide these people with another hope,” said Professor Tom Hemming Karlsen, EASL Vice-Secretary.

Gilead Data for Investigational, All-Oral, Pan-Genotypic Three-Drug Regimen of Sofosbuvir, GS-5816 and GS-9857 for Chronic Hepatitis C

Gilead Announces Data for Investigational, All-Oral, Pan-Genotypic Three-Drug Regimen of Sofosbuvir, GS-5816 and GS-9857 for Chronic Hepatitis C

-- Data Support Ongoing Trials Evaluating Shortened Course of Therapy --

VIENNA, Austria--(BUSINESS WIRE)--Apr. 23, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced pre-clinical data and results from Phase 1 and Phase 2 studies supporting the development of an investigational all-oral, pan-genotypic regimen of Sovaldi® (sofosbuvir 400 mg/SOF), the investigational NS5A inhibitor GS-5816 and GS-9857, an investigational NS3/4A protease inhibitor. These data will be presented at the 50th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress™ 2015) in Vienna, Austria.

In pre-clinical studies, GS-9857 demonstrated similarly potent antiviral activity against HCV replicons of all tested genotypes (1-6), as well as an improved resistance profile compared to other HCV protease inhibitors (ePoster #P0899). In a healthy volunteer study, GS-9857 demonstrated a favorable pharmacokinetic profile (ePoster #P0861). Data from a three-day monotherapy study also demonstrated that GS-9857 was well-tolerated and achieved median HCV RNA reductions of more than 3 log10 IU/mL for HCV patients with genotypes 1, 2, 3 and 4 at the 100 mg dose (ePoster #P0901).

Presented as a late-breaker ePoster (ePoster #LP03), a Phase 2 study of triple-combination therapy with a fixed-dose combination of SOF/GS-5816 plus GS-9857 among genotype 1 patients demonstrated sustained virologic response (SVR12) rates following six weeks of treatment of 93 percent (n=14/15) among treatment-naïve, non-cirrhotic patients, 87 percent (n=13/15) among treatment-naïve, cirrhotic patients, and 67 percent (n=20/30) among those who had failed therapy with two or more direct-acting antiviral agents (DAAs). The four-week regimen resulted in a sub-optimal SVR12 rate of 27 percent (n=4/15).

“These data support the ongoing development of GS-9857 and the potential for an all-oral, triple combination therapy containing Sovaldi, GS-5816 and GS-9857 to attempt to further reduce treatment duration for hepatitis C patients,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “We are encouraged by the six-week SVR12 rates and other data presented at EASL demonstrating this regimen’s pan-genotypic potential, and have recently initiated additional Phase 2 studies to further evaluate the appropriate treatment duration of this regimen for all patients, regardless of genotype, including those who have failed prior therapy with directly acting antivirals and those with cirrhosis.”

SOF/GS-5816 plus GS-9857 was generally well tolerated. There were no Grade 3 or 4 adverse events nor serious adverse events. The most frequent adverse events were nausea (25 percent), headache (24 percent) and fatigue (16 percent). Transient, asymptomatic, elevated lipase (Grade 3 or 4) occurred in four patients (5 percent).

GS-5816 and GS-9857 are investigational products and their safety and efficacy have not been established. Additional information about these studies can be found at www.clinicaltrials.gov.

About Gilead

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that Gilead may observe unfavorable results from additional clinical trials involving GS-9857, including in combination with Sovaldi and GS-5816. In addition, Gilead may make a strategic decision to discontinue development of GS-9857, including in combination with Sovaldi and GS-5816 if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. As a result, GS-9857 may never be successfully commercialized. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full Prescribing Information for Sovaldi is available at www.gilead.com.

Sovaldi is a registered trademark of Gilead Sciences, Inc., or its related companies.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.


Source: Gilead Sciences, Inc.

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