Showing posts with label geno6. Show all posts
Showing posts with label geno6. Show all posts

Monday, May 14, 2018

Elbasvir and grazoprevir with or without ribavirin, treatment–naive participants HCV genotype 2, 4, 5 or 6

Patients with non-genotype 1 HCV infection differ with regard to response to DAAs. This study evaluated the efficacy and safety of EBR/GZR, with or without RBV, in HCV genotype 2, 4, 5, or 6 infection.

A. Brown C. Hézode E. Zuckerman G. R. Foster A. Zekry S. K. Roberts F. Lahser C. Durkan C. Badshah B. Zhang M. Robertson J. Wahl E. Barr B. Haber on behalf of the C‐SCAPE Study Investigators

J Viral Hepat. 2018;25(5):457-464. 

Introduction
People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group of individuals who differ with regard to their profile of response to all–oral, direct–acting antiviral regimens.[1,2] The recent approval of sofosbuvir/velpatasvir for people infected with HCV genotypes 1–6 now provides a single treatment option across genotypes. However, prior to the introduction of sofosbuvir/velpatasvir, treatment recommendations for genotype 2, 3, 5 and 6 were based on small studies with limited numbers of participants, or on subgroup analyses where small numbers of participants were enrolled alongside participants with genotype 1 or 4 infection.

The fixed–dose combination of elbasvir (EBR, MK–8742), an NS5A inhibitor, and grazoprevir (GZR, MK–5172), an NS3/4A protease inhibitor, is approved in the US, Europe and Canada as a treatment for HCV genotype 1 and 4 infection.[12] In those with HCV genotype 1 or 4 infection, EBR/GZR has shown efficacy in the subpopulations of treatment–naive people,[13] HIV/HCV co–infected people,[14] people who have previously failed treatment[15,16] and people with chronic kidney disease.[17] In vitro, EBR and GZR have shown pangenotypic potency in HCV replicons;[18,19] however, less has been reported about the clinical efficacy and safety of EBR/GZR in people with HCV nongenotype 1/4 infection. The phase 2 C–SCAPE study evaluated the efficacy and safety of EBR/GZR, with or without ribavirin (RBV), in treatment–naive participants with HCV genotype 2, 4, 5 or 6 infection...

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Wednesday, May 9, 2018

HCV genotype 4, 5 and 6 Cure Rates In Clinical Trials

In Case You Missed It

Journal of Viral Hepatitis
First published: 8 May 2018

HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct‐acting antiviral regimens
S. D. Boyd P. Harrington T. E. Komatsu L. K. Naeger K. Chan‐Tack J. Murray D. Birnkrant K. Struble

First published: 25 March 2018 https://doi.org/10.1111/jvh.12896

Full-Text Article
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Summary
Multiple direct‐acting antiviral (DAA)‐based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post‐treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Discussion
The recent FDA approvals of various IFN‐free DAA regimens provide highly effective treatment options for HCV GT 4, 5 or 6 infection. Individual registrational trials generally demonstrated high SVR12 rates in these populations, with virologic failure occurring in a small proportion of patients. To conduct a more comprehensive analysis of HCV GT 4, 5 and 6 patient populations in HCV DAA clinical trials, including treatment outcomes and viral subtypes represented, we conducted independent analyses of 18 registrational trials submitted to FDA from 2014 to 2017 in new drug applications (NDAs) for elbasvir/grazoprevir, glecaprevir/pibrentasvir, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

The analysis population comprises a substantially larger data set compared to individual clinical development programs for GT 4, 5 and 6 and allows for several observations. First, the combined clinical trial data in this analysis confirm that approved regimens for GT 4, 5 and 6 are all highly efficacious, with SVR12 rates similar to GT1. Overall, only a few participants did not achieve SVR12 with one of the FDA‐approved DAA regimens. No trends emerged associating virologic failure with baseline viral load, cirrhosis or prior treatment experience. Although limited sample sizes prevented statistical cross‐regimen comparisons, no clear differences in treatment efficacy emerged between any regimen with a reasonable sample size, and the few occurrences of virologic failure were distributed across different regimens.

A second observation is that the SVR12 rates for the most prevalent GT4 and GT6 subtypes either exceeded or corresponded with the SVR12 rates overall for these GTs. While the SVR12 rate for non‐4a, non‐4d GT4 subtypes was numerically lower, virologic failures in this group occurred only among participants with one of two uncommon subtypes, 4b and 4r. Extensive HCV genetic variability exists at multiple key NS5A resistance‐associated amino acid positions, both across and within different HCV subtypes.40 Recent studies have shown that reduced susceptibility to ledipasvir for some GT 4b and 4r isolates is associated with the presence of NS5A resistance‐associated substitutions, which may explain occurrences of ledipasvir/sofosbuvir virologic failure among patients with these subtypes.21, 41 Nevertheless, more data are needed with various NS5A inhibitor‐containing regimens before we can draw firm conclusions about the impact of NS5A genetic variability on treatment outcomes for patients with GT 4b, 4r and other less common subtypes. Importantly, the combined SVR12 rate for non‐4a, non‐4d GT4 subtypes across clinical trials still exceeded 90%. Because SVR12 rates were 100% for the most common GT6 subtypes, and only one participant with GT6 infection did not achieve SVR12, we cannot speculate on whether any of the less common GT6 subtypes may have a different response rate.

A third observation is our analysis confirms that the most common subtypes for GT4 and GT6 represented in clinical trials are consistent with previously published reports of subtype distribution in the United States, Europe and regions where these GTs are highly prevalent.40, 42, 43 For example, subtype 4a was not only the most common GT4 subtype in clinical trials that largely recruited participants located in the United States and Europe but is also the most common subtype in geographic areas with a high prevalence of GT4, such as Egypt.40, 42 Possibly, GT4 participants migrated from geographic areas where this genotype is highly prevalent, but specific demographic data such as geographic location of initial infection or country of origin usually were not available. Similarly, the two most common GT6 subtypes 6a and 6e observed in clinical trials are similar to previous reports.40

One limitation of our clinical trial analyses is the number of participants with uncommon subtypes was either low or not represented. This limitation makes it difficult to understand if treatment efficacy truly varies for certain infrequent subtypes and if baseline factors such as baseline viral load, presence of cirrhosis, HCV treatment history, or presence of baseline resistance‐associated substitutions affect response rates among different subtypes. However, we find the results reassuring because the SVR12 rates were close to 100% for the most common subtypes, and the overall SVR12 rates were high in the combined populations. Another limitation is that certain parts of the world (eg Sub‐Saharan Africa) are not well represented in clinical trials, and GT 4, 5 or 6 subtypes or other viral genetic characteristics may differ in these underrepresented regions.

This compilation of data from participants with HCV GT 4, 5 or 6 provides the largest pool of clinical trial data for FDA‐approved DAA regimens for these less common GTs. Combined clinical trial data enhance descriptive subgroup analysis such as frequency of viral subtypes and confirms high SVR12 or low virologic failure rates across FDA‐approved regimens. The geographic distribution of viral subtypes in our clinical trial database is consistent with the existing information on the general prevalence of these subtypes.

Overall, the data presented provide comprehensive information about efficacy including SVR and virologic failure rates. These analyses may be useful for clinicians treating patients with HCV GT 4, 5 or 6.

Wednesday, April 4, 2018

Elbasvir/grazoprevir in Asia‐Pacific/Russian participants with chronic hepatitis C genotype 1, 4, or 6 infection

Elbasvir/grazoprevir in Asia‐Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection
Jacob George Eduard Burnevich I‐Shyan Sheen Jeong Heo Kinh Van Nguyen Tawesak Tanwandee Pin‐Nan Cheng Do Young Kim Won Young Tak Svetlana Kizhlo Konstantin Zhdanov Vasily Isakov Liwen Liang Pauline Lindore Joy Ginanni Bach‐Yen Nguyen Janice Wahl Eliav Barr Michael Robertson Paul Ingravallo Rohit Talwani on behalf of the C‐CORAL Study Investigators

First published: 4 April 2018 https://doi.org/10.1002/hep4.1177

The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia‐Pacific countries and Russia. In this phase 3, randomized, placebo‐controlled, double‐blind study, treatment‐naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate‐treatment group [ITG]) or placebo (deferred‐treatment group [DTG]) once daily for 12 weeks (Protocol PN‐5172‐067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty‐seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow‐up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, −0.3%; 95% confidence interval, −12.3, 11.9).

Conclusion: EBR/GZR for 12 weeks provides an effective and well‐tolerated regimen for chronic HCV GT1 infection in treatment‐naive people from Asia‐Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018)


Monday, January 1, 2018

HCV in Southeast Asia - Ledipasvir and Sofosbuvir for HCV Genotype 6

Kenneth Bender

The successful treatment of hepatitis C virus genotype 6 (HCV-GT6) with a non-interferon-based fixed dose oral regimen of ledipasvir and sofosbuvir (LDV/SOF) bodes well for treating HCV in Southeast Asia, where newer pangenotypic agents are not available to treat this region's most prevalent genotype.

Continue reading......

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

Tuesday, September 26, 2017

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret
Asselah T, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.09.027.
September 26, 2017
Most patients with hepatitis C genotype 2, 4, 5 or 6 who received Mavyret for 8 weeks achieved sustained virologic response with a high safety profile, according to results from three phase 3 studies. The rate of virologic failure was less than 1%.

Sunday, August 20, 2017

(grazoprevir-ruzasvir-uprifosbuvir) Shorter anti-HCV regimen effective in patients with or without cirrhosis

In Case You Missed It

Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
PDF provided by @HenryEChang via Twitter


Shorter anti-HCV regimen effective in patients with or without cirrhosis
Last Updated: 2017-08-18
By Will Boggs MD
NEW YORK (Reuters Health) - An eight-week regimen containing grazoprevir-ruzasvir-uprifosbuvir appears to be effective for treating hepatitis C virus (HCV) infection in patients with or without cirrhosis, according to findings from a pair of randomized phase 2 open-label trials.

Dr. Edward J. Gane from Auckland Clinical Studies, in Auckland, New Zealand, and colleagues - in part A of the C-CREST-1 and C-CREST-2 trials - randomly assigned 240 patients with HCV genotype 1, 2 or 3 and without cirrhosis to receive an eight-week course of a daily three-drug combination:

- grazoprevir 100 mg, plus

- either elbasvir 50 mg or ruzasvir 60 mg, plus

- either 300 mg or 450 mg of uprifosbuvir.

The studies were funded by Merck and Co.

Sustained virologic response rates 12 weeks after the end of therapy (SVR12) were 92% with both doses of the grazoprevir-ruzasvir-uprifosbuvir regimen and ranged from 85% to 88% (depending on uprifosbuvir dose) with grazoprevir-elbasvir-uprifosbuvir, according to one of the reports, both online August 9 in The Lancet Gastroenterology and Hepatology.

All four regimens were well-tolerated.

"These results support the selection of grazoprevir plus ruzasvir plus uprifosbuvir 450 mg as the regimen for further clinical investigation in broader populations," the researchers conclude.

Dr. Eric Lawitz from Texas Liver Institute at the University of Texas Health San Antonio and colleagues extended these findings in part B of C-CREST-1 and C-CREST-2. In this trial, 675 patients with HCV-1, -2, -3, -4 or -6, with or without cirrhosis, received eight, 12, or 16 weeks of grazoprevir-ruzasvir-uprifosbuvir 450 mg, with or without ribavirin.

SVR12 rates with eight weeks of therapy were 93% in individuals with genotype 1a, 98% with genotype 1b, 86% with genotype 2 (without cirrhosis; patients with HCV-2 and cirrhosis received a longer course), 95% with genotype 3 (treatment naive, without cirrhosis) and 100% with genotypes 4 and 6.

"We were surprised by the relatively lower efficacy of an 8-week duration of this regimen among those with genotype 2 infection," Dr. Lawitz told Reuters Health by email. "However, extending therapy to 12 weeks overcame this effect."

SVR12 rates were generally higher among participants with or without cirrhosis who received 12 or 16 weeks of therapy.

There were no documented virologic failures after week 12 of follow-up, although 10 participants who achieved SVR12 were lost to follow-up.

As in part A of the study, treatment with this fixed-dose combination with or without ribavirin was generally well tolerated.

"Results from the current studies support further investigation of grazoprevir, ruzasvir, and uprifosbuvir as a pan-genotypic regimen in individuals infected with HCV with and without cirrhosis, and suggest that this combination has the potential to provide a safe, single-duration regimen in most populations, including individuals with cirrhosis infected with genotype 3 who had previously received treatment with pegylated interferon and ribavirin," the researchers conclude.

"We await data from phase 3 to know how this regimen might impact the current treatment landscape," Dr. Lawitz said. "We hope that this regimen will be able to give providers more options with regard to pan-genotypic regimens for the treatment of HCV."

Dr. Eleanor M. Wilson from the University of Maryland School of Medicine, Baltimore, who coauthored an accompanying comment in the journal, told Reuters Health by email, "The safety and efficacy data seem promising, but it's still investigational, so not sure about its impact on the field of hepatitis C treatment yet."

"With the recent approvals of Vosevi and Mavyret, in addition to the previously available options, I think the overall take-away is that it's fantastic that there are more hepatitis C treatment options for patients and providers," she said. "It's tremendous that previously so-called 'difficult-to-treat patients' including those with previous treatment experience, comorbid conditions like HIV or renal disease, and those with advanced fibrosis and cirrhosis now have a variety of safe and highly effective options to treat their hepatitis C."

"My area of expertise is in novel treatment approaches, including strategies to reduce the treatment duration in order to increase access and decrease treatment cost, as well as options for patients who haven't successfully cleared HCV with first-line therapy (due to problems of adherence or viral resistance), and from that standpoint, it's an exciting time to be a hepatitis C provider," Dr. Wilson said.

Dr. Mark Sulkowski, who directs the viral hepatitis center at Johns Hopkins University in Baltimore, told Reuters Health by email, "We currently have multiple outstanding HCV regimens for the treatment of all genotypes of hepatitis C, which typically include combinations of direct-acting antiviral inhibitors of HCV protein targets NS3 (protease), NS5A and NS5B (polymerase). While we have seen the regulatory approval of multiple inhibitors of the NS3 and NS5A proteins, to date, only one (nucleotide) inhibitor of the NS5B polymerase active site has been approved, sofosbuvir."

"The C-CREST-1 and -2 studies provide a phase 2 evaluation of another (nucleotide) analogue inhibitor of NS5B, uprifosbuvir," said Dr. Sulkowski, who was not involved in the research. "Based on the results of these studies, uprifosbuvir appears to be poised to move to phase 3 studies, and if successful in phase 3 trials, this agent could become a valuable addition to the available drugs to treat hepatitis C."

Dr. Gane did not respond to a request for comment.
Merck funded the trials and employed most of the authors.

SOURCE: Lancet Gastroenterol Hepatol 2017.
Abstract 
Abstract 
Abstract 

Friday, August 18, 2017

Hepatitis C - Newly Approved Mavyret Has High Response Rates

The Lancet
Download Full Text Article - PDF provided by Henry E. Chang‏ via Twitter:

Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial
Xavier Forns, Samuel S Lee, Joaquin Valdes, Sabela Lens, Reem Ghalib, Humberto Aguilar, Franco Felizarta, Tarek Hassanein, Holger Hinrichsen, Diego Rincon, Rosa Morillas, Stefan Zeuzem, Yves Horsmans, David R Nelson, Yao Yu, Preethi Krishnan, Chih-Wei Lin, Jens J Kort, Federico J Mensa

Summary Background
The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis......
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The Lancet
Download Full Text Article - PDF provided by Henry E. Chang‏ via Twitter:

Comment 
New anti-HCV drug combinations: who will benefit?
Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/S1473-3099(17)30486-3
In The Lancet Infectious Diseases1 Xavier Forns and colleagues present the results of a phase 3 trial assessing the efficacy and safety of 12 weeks of treatment with glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) in patients with chronic hepatitis C virus (HCV) genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Of 146 enrolled patients, 145 (99%, 95% CI 98–100) achieved a sustained virological response. The study did not include patients with decompensated cirrhosis; the same is true for studies of sofosbuvir, velpatasvir, and voxilaprevir.2....
Continue reading......

Newly Approved Hepatitis C Drug Has High Response Rates
By Amy Orciari Herman
Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Nearly all patients with chronic hepatitis C virus (HCV) infection treated with glecaprevir-pibrentasvir achieved sustained virologic response after 12 weeks of therapy, according to results of an industry-funded, phase 3 trial in the Lancet Infectious Diseases. The once-daily combination drug (brand name, Mavyret) was approved by the FDA earlier this month to treat all HCV genotypes.

The trial enrolled 146 adults with HCV genotype 1a, 1b, 2, 4, 5, or 6 and compensated cirrhosis who either had not been previously treated, or had not responded to interferon-based treatment or to treatment with sofosbuvir plus ribavirin (with or without pegylated interferon). At 12 weeks after treatment ended, all but one patient had sustained virologic response. A patient with HCV genotype 1a and a history of treatment with pegylated interferon plus ribavirin relapsed at week 8.

Nearly 70% of patients had adverse events, most of which were mild (e.g., fatigue). No serious events were related to the study drug.

Link(s):
The Lancet
Lancet Infectious Diseases article (Free abstract)
Lancet Infectious Diseases comment (Subscription required)
Background: Physician's First Watch coverage of glecaprevir-pibrentasvir (Free)
Source-

Tuesday, May 23, 2017

Updated - HCV Guidance website

In Case You Missed It
Updated Thursday, April 27, 2017



Guidelines
HCV Guidelines
The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) with the International Antiviral Society developed a living document with ever evolving guidelines to treat HCV.
Homepage - HCV Guidelines

Stay current with all guideline updates, click here.

What’s New and Updates/Changes
This version of the Guidance has been updated to reflect several key developments as indicated below. Updated references have been provided throughout the Guidance.

Global Changes Occurring throughout the document:
  • RAV changed to RAS
  • Standardized renal function parameter from CrCI to eGFR
     
Initial Treatment:
Retreatment:
Decompensated:
Renal:
Upcoming Updates:
  • Guidance will be forthcoming regarding treatment of adolescents living with chronic HCV given recent FDA-approvals

Sunday, November 13, 2016

AASLD 2016 Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis

Nov 13
Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis
By Debra Hughes, MS
Patients with chronic hepatitis C virus (HCV) genotypes (GT) 2, 4, 5, or 6 infection without cirrhosis had SVR12 rates of 97% after 8 weeks of treatment with co-formulated glecaprevir/pibrentasvir, investigators from the SURVEYOR-II, Part 4, concluded at The Liver Meeting® 2016.​

Press Release
Nov 11
Update AbbVie's Glecaprevir/Pibrentasvir (G/P) Acheive High SVR12 Rates at 8 Wks Genotypes 1-6
- 97.5 percent of chronic HCV infected patients without cirrhosis and new to treatment across all major genotypes (GT1-6) achieved SVR12 with 8 weeks of G/P
- Across the 8-week arms of three registrational studies, no patients discontinued treatment due to adverse events
- G/P is an investigational, pan-genotypic, once-daily, ribavirin-free regimen for the treatment of chronic HCV

Additional updates @ MPR
Current updates: Conference Reports
Updates On This Blog: AASLD 2016

Thursday, October 6, 2016

Effectiveness of Elbasvir and Grazoprevir, With or Without Ribavirin, Treatment-Experienced Patients with Chronic Hepatitis C Infection

Article summary @ MPR
Fixed-Dose HCV Combo Drug Effective in Hard-to-Treat Patients
For patients with hepatitis C virus (HCV) genotype 1, 4, or 6 infection who have previously failed peg-interferon and ribavirin treatment, the combination of elbasvir and grazoprevir, with or without ribavrin, was effective in inducing sustained virologic response 12 weeks after the end of treatment (SVR12). Results of this study were published online in the journal Gastroenterology.....

Articles in Press

Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients with Chronic Hepatitis C Infection
Paul Kwo, Edward Gane, Cheng-Yuan Peng, Brian Pearlman, John M. Vierling, Lawrence Serfaty, Maria Buti, Stephen Shafran, Paul Stryszak, Li Lin, Jacqueline Gress, Stuart Black, Frank J. Dutko, Michael Robertson, Janice Wahl, Lisa Lupinacci, Eliav Barr, Barbara Haber

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.

PDF - Accepted Manuscript
Download Full Text Article

DOI: http://dx.doi.org/10.1053/j.gastro.2016.09.045

Abstract
Background & Aims

Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population.

Methods
We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA below 15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was was greater than the reference rate (58%).

Results
With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Also among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotype 1 and 7.5% infected with HCV genotype 4, respectively, who relapsed after completing peg-interferon and ribavirin or with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%).

Conclusions
The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov no: NCT02105701.

Gastroenterology - Full Text Article

Sunday, July 31, 2016

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

Articles In Press

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
Open Access
Preview 
Download Full Text  - PDF

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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Saturday, January 16, 2016

HCV NEXT January Issue - 2015: The Good The Bad The Ugly

Responsive to Treatment Elusive to Detection: 
HCV Genotypes 5 and 6

"HCV Next" offers information on a range of topics, which include diagnosis, new combination therapies, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.

The following articles appeared in the January print edition of HCV NEXT, provided online at Healio.

EDITORIAL
Looking Back, Looking Ahead at Treatment Developments
2015: The Good The Bad The Ugly
HCV Next, January 2016

After 2014, a year of first implementations of direct-acting antiviral therapies, 2015 brought even more changes and challenges in hepatitis C virus research, diagnosis, treatment and access.

We saw much good: approvals in difficult-to-treat genotypes, breakthrough designations for soon-to-come drugs that hold promise for underserved populations and a successful continuous updating of the HCV guidelines document jointly maintained by the AASLD and IDSA.

Yet there was the bad: real-world experiences with rapidly approved drugs proven to produce drug-drug interactions and unforeseen toxicities.

And the ugly seems to be getting uglier, with ongoing denials of treatment for patients who have not yet progressed in severity of their disease.

Please see my Looking Back, Looking Ahead article for a more detailed breakdown on what 2015 brought to our community and what I foresee in the coming year.

— Michael S. Saag, MD
Co-Chief Medical Editor
HCV Next

Table of Contents

MEETING NEWS COVERAGE

SPECIAL SERIES

THE BIG PICTURE

TREND WATCH


Thursday, November 12, 2015

FDA Approves New Indications for Harvoni®, Gilead's Once-Daily Single Tablet Regimen for Chronic Hepatitis C

U.S. FDA Approves New Indications for Harvoni®, Gilead's Once-Daily Single Tablet Regimen for Chronic Hepatitis C

Date(s): 12-Nov-2015 5:54 PM

For a complete listing of our news releases, please click here

- Label Expanded to Include Patients with Genotypes 4, 5 and 6 and Patients Co-Infected with HIV -

- Use of Harvoni in Combination with Ribavirin for 12 Weeks Can be Considered for Treatment-Experienced Genotype 1 Patients with Cirrhosis -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Nov. 12, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Harvoni® (ledipasvir/sofosbuvir) for expanded use in patients with genotype 4, 5 and 6 chronic hepatitis C virus (HCV) infection and in patients co-infected with HIV. In addition, Harvoni plus ribavirin (RBV) for 12 weeks was approved as an alternate therapy to 24 weeks of Harvoni for treatment-experienced, genotype 1 patients with cirrhosis. Harvoni received regulatory approval for the treatment of chronic HCV genotype 1 infection in adults in the United States in October 2014.

"Harvoni - the first and only single-tablet regimen for the treatment of HCV - continues to demonstrate high cure rates and a tolerable side effect profile across a range of patient populations, including those who have historically been considered among the most difficult to cure," said Norbert Bischofberger, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. "We are pleased that the Harvoni label and prescribing information now includes guidance for health care providers on its use in these important HCV patient populations."

Genotypes 4, 5 and 6

The supplemental new drug application (sNDA) approval for HCV genotypes 4-6 was supported by data from the open-label trials 1119 and ELECTRON-2. Study 1119 evaluated Harvoni for 12 weeks in patients with HCV genotype 4 or 5 who were treatment-naïve and treatment-experienced with or without cirrhosis. Results showed that 93 percent (41/44) of those with genotype 4 and 93 percent (38/41) of those with genotype 5 achieved SVR12. ELECTRON-2 evaluated Harvoni for 12 weeks in treatment-naïve or previously-treated patients with genotype 6 HCV infection with or without cirrhosis. In this study, 96 percent (24/25) of patients achieved SVR12.

The most common adverse events (in at least 10 percent of subjects) were asthenia (18 percent), headache (14 percent) and fatigue (10 percent).

Patients Co-Infected with HIV

Patients with HCV/HIV co-infection represent approximately 30 percent of the total HIV-infected population in the United States. Compared with HCV infection alone, HIV/HCV co-infection is associated with an increased risk of cirrhosis and the subsequent complications of end-stage liver disease and hepatocellular carcinoma (liver cancer).

The sNDA approval for patients with HCV/HIV-1 co-infection was supported by data from the Phase 3 open-label ION-4 study, which evaluated Harvoni for 12 weeks for the treatment of genotypes 1 or 4 chronic HCV infection among patients co-infected with HIV. Data demonstrate that 96 percent (321/335) of patients achieved SVR12. The study included HCV treatment-naïve (45 percent) and treatment-experienced (55 percent) patients, including patients with compensated cirrhosis (20 percent). The majority of patients were taking one of three HIV antiretroviral (ARV) regimens: tenofovir disoproxil fumarate (TDF) and emtricitabine with efavirenz (Atripla®), raltegravir or rilpivirine (Complera®).

The most common adverse events (in at least 10 percent of subjects) were headache (20 percent) and fatigue (17 percent).

Treatment-Experienced Patients with Cirrhosis

The sNDA approval of Harvoni with RBV for 12 weeks for genotype 1 treatment-experienced HCV patients with cirrhosis was supported by data from the Phase 2 SIRIUS study, which evaluated Harvoni plus RBV for 12 weeks or Harvoni without RBV for 24 weeks in genotype 1 HCV-infected patients with compensated cirrhosis who failed prior therapy. Ninety six percent (74/77) of patients treated with Harvoni plus RBV for 12 weeks, and 97 percent (75/77) of patients treated with Harvoni for 24 weeks without RBV, achieved SVR12.

The most common adverse reactions (occurring in at least 10 percent of subjects) among patients receiving Harvoni plus RBV for 12 weeks were asthenia (36 percent), headache (13 percent) and cough (11 percent). In patients receiving Harvoni for 24 weeks, these were asthenia (31 percent), headache (29 percent) and fatigue (18 percent).

The European Medicines Agency also recently approved updates to the Harvoni label to allow for the use of shorter durations of therapy with Harvoni in combination with RBV. Specifically, these include the use of Harvoni plus RBV for 12 weeks in genotypes 1 and 4 HCV-infected patients with compensated cirrhosis, decompensated cirrhosis and post-liver transplant patients. The new label also includes data further supporting use of Harvoni for 12 weeks in patients with genotypes 1 or 4 who are co-infected with HIV and in patients who had previously failed treatment with sofosbuvir plus RBV with or without pegylated interferon.

Important Safety Information for Harvoni

Contraindications

If Harvoni is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions

Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Harvoni due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John's wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (=10%, all grades) adverse reactions were fatigue, headache and asthenia.

Drug Interactions

In addition to rifampin and St. John's wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

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 physicians may not see the benefits of prescribing Harvoni. 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 September 30, 2015, 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 Harvoni is available at www.gilead.com.

US full Prescribing Information for Atripla and Complera, including BOXED WARNING for both products, are also available at www.gilead.com.

Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

Complera, Sovaldi and Harvoni are registered trademarks 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.

View source version on businesswire.com: http://www.businesswire.com/news/home/20151112006728/en/

Source: Gilead Sciences, Inc.
Gilead Sciences, Inc.
Patrick O'Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

Tuesday, July 28, 2015

FDA Acceptance of NDA for Merck's Grazoprevir/Elbasvir Treatment of Hepatitis C Genotypes 1, 4 and 6 Infection

Merck Announces U.S. Food and Drug Administration Acceptance of New Drug Application for Grazoprevir/Elbasvir, an Investigational Therapy for Treatment of Chronic Hepatitis C Genotypes 1, 4 and 6 Infection

Company Granted FDA Priority Review with Target Action Date of January 28, 2016

Tuesday, July 28, 2015 6:30 am EDT

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application for grazoprevir/elbasvir (100mg/50mg), an investigational, once-daily, single-tablet combination therapy for the treatment of adult patients infected with chronic hepatitis C virus (HCV) genotypes (GT) 1, 4 or 6.1 The FDA granted Priority Review for grazoprevir/elbasvir (100mg/50mg), with a Prescription Drug User Fee Act (PDUFA) action date of January 28, 2016.

“The U.S. FDA’s Priority Review designation for grazoprevir/elbasvir underscores how innovative treatment approaches for chronic hepatitis C are still needed for many patient populations,” said Dr. Roy Baynes, senior vice president of clinical development, Merck Research Laboratories. “Our clinical data for grazoprevir/elbasvir in broad and diverse patient populations with chronic hepatitis C are very encouraging, and we look forward to continuing our dialogue with the FDA to bring this novel combination medicine to the appropriate patients with chronic hepatitis C.”

The New Drug Application for grazoprevir/elbasvir (100mg/50mg) is based in part upon data from the pivotal C-EDGE clinical trials program, as well as the C-SURFER and C-SALVAGE trials. Data from these trials were previously presented at The International Liver Conference 2015™. Collectively, these trials evaluated treatment regimens of grazoprevir/elbasvir (100mg/50mg), with or without ribavirin, in multiple genotypes (GT1, 4 and 6) including patient populations who were previously treated, and those with cirrhosis or certain co-morbidities (e.g., HIV/HCV co-infection, chronic kidney disease stages 4 and 5).

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir is Merck’s investigational, once-daily, single-tablet combination therapy consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of Merck’s broad clinical trials program, grazoprevir/elbasvir is being evaluated in multiple HCV genotypes including patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.

In April 2015, the FDA granted Breakthrough Therapy designation status for grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT1 with end stage renal disease on hemodialysis, and Breakthrough Therapy designation status for grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT4. Breakthrough Therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

About Merck

Today’s Merck is a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement of Merck & Co. Inc., Kenilworth, NJ, USA

This news release of Merck & Co., Inc., Kenilworth, NJ, USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include, but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation in the United States and internationally; global trends toward healthcare cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2014 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

1 Grazoprevir is an HCV NS3/4A protease inhibitor and elbasvir is an HCV NS5A replication complex inhibitor

Press Release 

Friday, May 29, 2015

Grazoprevir/Elbasvi - Merck Submits NDA To FDA For HCV Genotypes 1,4 and 6

Grazoprevir/Elbasvi - Merck Submits NDA To FDA

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the company has submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for grazoprevir/elbasvir (100mg/50mg), an investigational once-daily, single tablet combination therapy for the treatment of adult patients with chronic hepatitis C genotypes (GT) 1, 4 or 6 infection. Within 60 days of submission, the FDA will determine whether it will accept for review Merck's application as filed. The company plans to submit additional license applications in the European Union and other markets by the end of 2015.

“This submission to the U.S. FDA is an important milestone as we seek to provide patients with a new treatment option for this serious infection.”

“Merck's submission is based on evidence from our wide-ranging clinical program assessing the efficacy and tolerability profile of grazoprevir/elbasvir in populations with chronic hepatitis C,” said Dr. Roy Baynes, senior vice president of clinical development, Merck Research Laboratories. “This submission to the U.S. FDA is an important milestone as we seek to provide patients with a new treatment option for this serious infection.”

The FDA has previously granted Breakthrough Therapy designation status for grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT1 with end stage renal disease on hemodialysis, and for patients infected with chronic HCV GT4. Breakthrough Therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

The New Drug Application for grazoprevir/elbasvir (100mg/50mg) is based in part upon data from the pivotal C-EDGE clinical trials program, as well as the C-SURFER and C-SALVAGE trials, evaluating grazoprevir/elbasvir (100mg/50mg), with or without ribavirin, in patients with chronic hepatitis C infection. Data from these trials were presented at The International Liver CongressTM 2015 in April 2015.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir is an investigational, once-daily single tablet regimen consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of Merck’s broad clinical trials program, grazoprevir/elbasvir is being studied in multiple HCV genotypes and in patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.

Sunday, April 26, 2015

Single Pill Combination Therapy For Some Hepatitis C Subtypes

Single Pill Combination Therapy For Some Hepatitis C Subtypes
Posted on April 26, 2015
Source-

Interview with:
Stefan Zeuzem, MD
Professor of Medicine
Chief Department of Medicine
Goethe University Hospital
Frankfurt

Medical Research: What is the background for this study? What are the main findings?


Dr. Zeuzem: Interferon- and ribavirin-free regimens are needed to treat HCV infection. The objective of the study was to evaluate the safety and efficacy of grazoprevir (NS3/4A-protease-inhibitor) and elbasvir (NS5A-inhibitor) in previously untreated patients with chronic hepatitis C (without and with liver cirrhosis). Among 421 participants, 194 (46%) were women, 157 (37%) were non-white, 382 (91%) had genotype-1 infection, and 92 (22%) had cirrhosis. 

Of 316 patients receiving immediate treatment, 299/316 achieved SVR12 (undetectable HCV 12 weeks after treatment), including 144/157 with genotype-1a, 129/131 with genotype-1b, 18/18 with genotype-4, 8/10 with genotype-6, 68/70 with cirrhosis, and 231/246 without cirrhosis. 

Virologic failure occurred in 13 patients including 1 breakthrough and 12 relapses, and was associated with baseline NS5A-polymorphisms and emergent NS3- and/or NS5A-variants. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo arms, respectively; none were considered drug-related.


Medical Research: What should clinicians and patients take away from your report?


Dr. Zeuzem: Various interferon-free regimen are available for patients with chronic hepatitis C. Grazoprevir and Elbasvir are co-formulated and will be the second available treatment regimen with a single pill per day. The new treatment is restricted to patients infected with HCV genotypes 1, 4, and 6. In previously untreated patient the addition of ribavirin to this regimen is not required

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Zeuzem: Future research should explore the higher virologic relapse rate in high-viraemic, HCV-1a infected patients with pre-existent resistance-associated variants against elbasvir. The requirement of molecular tests to test for these variants before initiation of theray should be carefully defined.

Citation:

Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic HCV Genotype 1, 4, or 6 Infection: A Randomized Trial

Stefan Zeuzem, MD; Reem Ghalib, MD; K. Rajender Reddy, MD; Paul J. Pockros, MD; Ziv Ben Ari, MD; Yue Zhao, PhD; Deborah D. Brown, BS; Shuyan Wan, PhD; Mark J. DiNubile, MD; Bach-Yen Nguyen, MD; Michael N. Robertson, MD; Janice Wahl, MD; Eliav Barr, MD; and Joan R. Butterton, MD

Ann Intern Med. Published online 24 April 2015 doi:10.7326/M15-0785

Friday, January 9, 2015

Hepatitis C Update-Treatment Of Genotypes 1,2,3,4,5,and 6

HCV Treatment and Genotypes 

Good day folks, we have a few website updates from Hepatitis C Online, an interactive website from the University of Washington.

The site has comprehensive information on the diagnosis, monitoring, treatment and management of hepatitis C and offers a free online Hepatitis C Course, using AASLD/IDSA/IAS-Recommendations for Testing, Managing, and Treating Hepatitis C.

The hepatitis C patient will have an opportunity to the explore over 7 different modules, slide lectures, and read key data from published studies using new direct-acting antiviral agents.

Updated January 9 2015 
This month, Hepatitis C Online updated Module 5;Treatment of Chronic Hepatitis C Infection.

Click on each lesson to review the course module, or download PDF, I highly suggest the latter for easy viewing.

Genotype 1
PDF - Treatment of HCV Genotype 1
Lesson 1: Treatment of HCV Genotype 1
Contents: Introduction
Genotype 1: Initial Treatment and Retreatment with Prior Relapse
Genotype 1: Retreatment of Patients with prior Treatment Failure
Genotype 1: Future Treatment Options
Summary Points
Reference

Genotype 2
Contents: Introduction
Genotype 2: Initial Treatment and Retreatment with Prior Relapse
Genotype 2: Retreatment of Prior Nonresponders
Genotype 2: Future Treatment Options
Summary Points

Genotype 3
PDF - Treatment of HCV Genotype 3
Lesson 3: Treatment of HCV Genotype 3
Contents: Introduction
Genotype 3: Initial Treatment and Retreatment with Prior Relapse
Genotype 3: Retreatment of Prior Nonresponders
Genotype 3: Future Treatment Options
Summary Points

Genotype 4
Contents: Introduction
Genotype 4: Initial Treatment and Retreatment with Prior Relapse
Genotype 4: Retreatment of Prior Nonresponders
Genotype 4: Future Treatment Options
Summary Points

Genotype 5 or 6
Genotype 5 or 6: Initial Treatment and Retreatment with Prior Relapse
Genotype 5 or 6: Retreatment of Prior Nonresponders
Genotype 5 or 6: Future Treatment Options
Summary Points

Index
Genotypes 1-6
Module 5; Treatment of Chronic Hepatitis C Infection

Liver International
Volume 35, Issue Supplement s1, pages 1–3, January 2015

A special supplement of Liver InternationalProceedings of the 8th Paris Hepatitis Conference International Conference on the Management of Patients with Viral Hepatitis, is open access this month. This issue will include review articles on both HCV and HBV, with treatment strategies for HCV genotype 2, 4, and HCV-1b. Additional articles include HIV/HCV co-infection, end stage liver disease, liver cancer, and the dire universal need for affordable IFN-free regimens. 

Highlights
Optimal IFN-free therapy in treatment-naïve patients with HCV genotype 1 infection
Optimal therapy in genotype 4 chronic hepatitis C: finally cured?
Optimal therapy of genotype-2 chronic hepatitis C: what's new?
How to optimize current therapy in hepatitis C virus genotype 1 patients. Predictors of response to interferon-based therapy with second wave direct acting antivirals
Pegylated interferon based therapy with second-wave direct-acting antivirals in genotype 1 chronic hepatitis C

In Case You Missed It

November 2014
Hepatitis C Genotype 3
Written by Mr. Alan Franciscus, published in HCV Advocate's November Newsletter.
In the past, HCV genotype 3 was thought to be one of the easiest to cure. As a result there was little incentive to develop newer therapies especially since there were fewer people with genotype 3 in developed countries. Now it has turned out that treatment of genotype 3 is the hardest to cure with HCV inhibitor therapy compared to HCV genotypes 1, 2 and 4. 

Of Interest
AASLD @ HepMag.com
Eight weeks of Gilead Sciences’ Sovaldi and GS-5816, with or without ribavirin, cured high rates of people with genotype 3 of hepatitis C virus (HCV), but yielded unsatisfactory results among those with genotypes 1 and 2.

Genotypes 3 and 6
Harvoni Posts Good Cure Rates for Hepatitis Genotypes 3 and 6
Twelve weeks of Gilead Sciences’ Harvoni (ledipasvir/sofosbuvir) plus ribavirin cured 73 percent to 89 percent of people with genotype 3 of hepatitis C virus (HCV), while 96 percent of people with genotype 6 were cured without ribavirin in a recent trial, the National AIDS Treatment Advocacy Project (NATAP) reports.

Insulin resistance and liver steatosis in HCV genotype 3
Three main types of steatosis in the patients with Hepatitis C virus (HCV) infection are known: a metabolic type associated with metabolic syndrome and two viral types: one that seems to be directly triggered by the virus and one that could originate from the interference of the virus in the mechanisms of insulin resistance. The first viral type is particularly widely considered to be predominant and, perhaps, strictly linked to HCV genotype 3 infection and its intra-hepatic viral load. This evidence is supported by the resolution of steatosis in most patients infected with genotype 3 virus after HCV eradication by antiviral therapy.

Enjoy the weekend!
Tina