Showing posts with label MK3(MK-3682/grazoprevir/ruzasvir1). Show all posts
Showing posts with label MK3(MK-3682/grazoprevir/ruzasvir1). Show all posts

Tuesday, January 24, 2017

What's Hot in Gastroenterology - New Drug Classes Seek to Further Improve Already Favorable Outcomes in Hepatitis C

New Drug Classes Seek to Further Improve Already Favorable Outcomes in Hepatitis C
William F. Balistreri, MD
January 24, 2017
Editor's Note: Several major themes related to hepatitis C virus (HCV) emerged at The Liver Meeting®, the annual meeting of the American Association for the Study of Liver Diseases, held November 11-15, 2016, in Boston, Massachusetts. With the success of direct-acting antiviral (DAA) regimens, presentations focused on new drugs and ways to integrate existing and upcoming agents into treatment strategies. In addition, new data on the management of patients with HCV infection during the peri-transplant period, as well as the impact of DAAs on recurrent infection after transplantation, were presented. Of special importance was a discussion on the potential reactivation of hepatitis B virus (HBV) infection during the DAA treatment of HCV infection.

Article available at Medscape, free registration required.

Index

  • Introduction
  • Glecaprevir/Pibrentasvir
  • Noncirrhotic Patients with Chronic HCV Genotypes 1 to 6 Infection
  • Chronic HCV Genotype 1 to 6 Infection and Renal Impairment
  • HCV Genotype 3 Infection With Previous Treatment Experience and/or Cirrhosis
  • Sofosbuvir/Velpatasvir/Voxilaprevir
  • DAA-Naive HCV Genotypes 1 to 6
  • Chronic HCV Genotype 1 to 6 Infection and Renal Impairment
  • HCV Genotype 3 Infection With Previous Treatment Experience and/or Cirrhosis
  • Grazoprevir/Elbasvir/Ruzasvir/MK3682
  • HCV Genotype 3 With Cirrhosis
  • Chronic HCV Genotype 1 Infection; Previously Failed DAA Regimen
  • Chronic HCV Genotype 1 Infection; Previously Failed DAA Regimen
  • RG-101: A Novel Approach
  • Impact of DAA Therapy on the HCV-Infected Transplant Candidate
  • HBV Reactivation Associated With DAA Therapy

  • Wednesday, January 18, 2017

    Hepatitis C Treatment: What to Expect in 2017

    Last Updated Feb 2018

    Recommended 
    2018
    HCV Genotypes/Treatment
    Offered on this page is current research 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.

    2018
    Research Articles
    Current full text articles covering every aspect of hepatitis C.

    This article is now archived and will no longer be updated. 

    Conference Coverage
    The Liver Meeting® 2017
    Friday, October 20, 2017 - Tuesday, October 24, 2017

    Liver Meeting 2017: I'm A HCV Patient - Show Me What I Need To Know!
    Quick review of the meeting

    Full Text Articles
    I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about hepatitis C.

    Hepatitis C Treatment: What to Expect in 2017
    *Article; Hepatitis C Treatment: What to Expect in 2017 - is located further down this page following current updates with key data on the treatment and management of the hepatitis C virus.

    Research Articles
    Dec 1, 2017
    2017 December
    Summary from AASLD 2017 for Hepatitis C HCV: Game over?

    November 17, 2017

    October 2017
    The changing HCV treatment cascade
    Although the IDSA/AASLD guidelines provide the map to managing HCV, they do not identify the ideal interferon-free regimen to begin with, nor have they given a clear path to treating genotype 3 and those with decompensated cirrhosis. This ever-changing field will require collaboration among health care providers, including those specializing in infectious diseases, hepatology and gastroenterology, as well as pharmacists, to optimize treatment strategies. As the landscape of HCV continues to update with new literature and new medications, this subspecialty continues to be dynamic.

    High sustained virological response rates using imported generic direct acting antiviral treatment for hepatitis C
    This analysis assessed the efficacy of generic imported DAAs.

    Oct 5, 2017

    September 2017
    AASLD IDSA
    HCV Guidance Updates
    Recommendations Reflecting Vosevi and Mavyret.
    Stay current with all guideline updates, "click here."
    Updated - Geno 1 & 3 Treatment-Naïve & Treatment-Experienced
    Read more click here.....

    September 22, 2017
    Sofosbuvir-Velpatasvir-Voxilaprevir for Chronic Hepatitis C – A Review
    Gastroenterology & Hepatology.

    Chronic hepatitis C virus infection: Everyone should be treated
    Authors Steven Flamm
    First Published: 29 September 2017
    Abstract
    Full Text (HTML)
    PDF (91.3KB)
    PDF (91.3KB)
    References
    Watch
    a video presentation of this article
    Watch the interview with the author

    Aug 26, 2017
    The new paradigm in the treatment of chronic hepatitis C disease: Faster, Higher and Stronger

    Systematic review: cost-effectiveness of DAAs for treatment of HCV genotypes 2-6

    Aug 17, 2917
    Which Hepatitis C Treatment to Start in 2017 - Are All Treatments Created Equal?

    FDA Update
    Aug 3, 2107
    FDA Approved - MAVYRET AbbVie Receives U.S. FDA Approval of MAVYRET™ (glecaprevir/pibrentasvir)

    Aug 1, 2017
    FDA Approves Expanded Labeling for Epclusa® for Hepatitis C in Patients Co-Infected with HIV

    FDA Update
    July 18, 2017
    FDA Approved Gilead's VoseviTM
    Sofosbuvir/Velpatasvir/Voxilaprevir
    Genotype 1, 2, 3, 4, 5 or 6 - Re-treatment of chronic hepatitis C virus

    Research Articles
    Aug 1, 2017
    Viral Hepatitis: The Search for a Cure

    Liver International
    SOF/VEL in patients with HCV GT 1-6 & compensated cirrhosis or advanced fibrosis

    Curr Hepatology Rep
    Next-generation direct-acting antiviral drug-based regimens for HCV

    Link to PDF full text articles provided by @HenryEChang via Twitter

    In chronic HCV infection, oral DAAs have high sustained virologic response
    In patients with chronic hepatitis C virus (HCV) infection, what are the efficacy and safety of oral direct-acting antiviral (DAA) regimens?

    All patients with chronic HCV infection should undergo a thorough renal survey at diagnosis and receive regular follow-up.

    July/August 2017
    Understanding HCV drug resistance: Clinical implications for current & future regimens
    IAS–USA Topics in Antiviral Medicine

    July - 2017
    Hepatitis C Therapies Perform Well in Challenging Patients
    William F. Balistreri, MD
    At this year's Digestive Disease Week, several studies looked into the nuances of treating hepatitis C virus (HCV)infection. Of particular interest were new data regarding difficult-to-treat groups and the validation of shorter, simpler regimens

    2017 - June
    June 30
    Clinical Liver Disease (CLD) just launched; Pangenotypic regimens and the next generation hepatitis C virus therapy a multimedia overview of: Three new antiviral therapies for viral hepatitis C anticipated in the next several months: GP, glecaprevir (protease inhibitor [PI])/pibrentasvir (NS5A inhibitor); SOF/VEL/VOX, sofosbuvir (NS5B inhibitor)/velpatasvir (NS5A)/voxilaprevir (NS3); and MK3, grazoprevir (NS3) + MK-3682 (NS5B) + NS5A inhibitor (elbasvir or Ruzasvir).

    June 27
    Impact of DAA therapy for treatment of HCV genotypes 1,3 & 4: A real life experience from India

    June 22
    Listen Or Watch: Mark Sulkowski, MD discuss current treatment options for all HCV genotypes
    Listen to Mark Sulkowski, MD discuss HCV screening, diagnosis, noninvasive tests for assessing liver fibrosis and current treatment options for all HCV genotypes (1-6).

    June 13, 2017
    Digestive Disease Week (DDW) 2017
    Nancy S. Reau, MD
    Despite the incredible evolution in hepatitis C (HCV) therapeutics, much remains to be done to affect the incidence, prevalence, and morbidity caused by this silent but curable disease. Several presentations at the recent Digestive Disease Week (DDW) meeting offer new perspectives in screening, reinfection, and therapy.

    2017 - May Updates
    May 27
    May 2017 - Hepatitis C in a New Era: A Review of Current Therapies
    Review of recommended HCV regimens according to genotype or comorbid patient conditions

    Oral direct-acting agent therapy for HCV infection: A systematic review
    To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection.

    May 26
    Current therapy for chronic hepatitis C: The role of direct-acting antivirals.
    Antiviral Res. 2017 Jun;142:83-122. doi: 10.1016/j.antiviral.2017.02.014. Epub 2017 Feb 24.
    Highlights
    • HCV genotype-specific drugs evolve to pan-genotypic drugs.
    • Drug potency increases from moderate (∼60%) to high (>90%) levels of sustained virologic response.
    • Treatment durations are shortened from a 48-week to 12-week or 8-week period.
    • HCV therapies based upon multiple pills per day are simplified to a single pill per day.
    • HCV therapies are administered orally regardless of prior treatment history and cirrhotic status.

    May 18
    The Changing HCV Landscape: Pangenotypic Regimens

    Conference Updates
    The International Liver CongressTM 2017
    April 19-23, 2017
    Investigational Regimen of Glecaprevir/Pibrentasvir

    April 2017
    Direct-acting antivirals: the endgame for hepatitis C?

    March 2017
    Review FDA Approved Therapies
    2017 / Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV

    Of Interest - Mar 2017
    Care of Patients Who Have Achieved a Sustained Virologic Response (SVR) Following Antiviral Therapy for Chronic Hepatitis C Infection
    Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C
    Delaying HCV treatment regardless of fibrosis stage may be detrimental given increased risk of mortality

    November 2016
    Summary for AASLD 2016 for Hepatitis C - New HCV two and three drug regimens on their way: what do they promise? And what do clinicians need to look out for under DAA combination therapy and beyond SVR?
    Abbvie dual combination Glecaprevir /Pibrentasvir
    Gilead fixed dose combination SOF/VEL/VOX
    Merck fixed-dose combination tablet MK3 (MK-3682/grazoprevir/ruzasvir)
    _______________________________________________

    ARC Journal of Hepatology and Gastroenterology
    Volume-1 Issue-1, 2016, Page No: 9-16

    Hepatitis C Treatment: What to Expect in 2017
    Andreia Gi1, Ana Miguel Matos1,2, Cristina Luxo1,2


    Abstract
    Hepatitis C virus infection is a substantial health problem on a global scale [1] It is estimated that approximately 185 million people live with hepatitis C worldwide, with 350,000–500,000 patients dying each year from liver disease associated with hepatitis C[2]. However, something is about to change. In the latest years, there has been a shift in treatment paradigm due to the discovery and approval of direct-acting antiviral agents [3]. Nevertheless, these regimens still included ribavirin, which increased side effects, cost, and inconvenience of treatment. Moreover, improved treatment options for patients who did not respond to prior direct-acting antiviral agents (and may have drug-resistant virus) and for hepatitis C virus genotype 3 infection, with or without cirrhosis, were desirable. Thus, three new promising direct-acting antiviral agents were developed to fulfill these significant unmet medical needs [4,5]

    In many countries, sustainability has been the buzzword across all stakeholders. Still, direct-acting antiviral agents have demonstrated a favorable cost-effectiveness profile [6] and their exceptional cure rates have already helped establish the concept that chronic hepatitis C virus infection can be cured in most, if not all, affected individuals.

    This review summarizes the clinical potential of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir-pibrentasvir, discussing key results and future directions. Its aim is to highlight the significance of a future free from hepatitis C.

    Keywords: Hepatitis C Virus, Direct-Acting Antiviral Agents, Sustained Virologic Response, Cure, Difficult-To- Treat Populations

    Abbreviations
    HCV - Hepatitis C virus
    HCC - Hepatocellular carcinoma
    SVR - Sustained Virologic Response
    IFN - Interferon
    RBV - Ribavirin
    DAAs - Direct-acting antiviral agents
    SOF – Sofosbuvir
    VEL – Velpatasvir
    VOX - Voxilaprevir

    Introduction
    The Hepatitis C virus (HCV) is a small-enveloped virus of the Flaviridae family and genus Hepacivirus, [7] with a single-stranded positive RNA molecule of approximately 9.6 kb [8]. Prior to the discovery of the viral agent, HCV was mainly transmitted via blood products. Since then, injection drug use has arisen as the major mode of transmission in developed countries [2]

    The main problem is that, following exposure to HCV, only a minority of patients clears the acute infection, whereas 80% persist with life-long chronic viremia[9] Chronic HCV infection is a serious, progressive, and potentially life-threatening disease [10,11] If left untreated, over time it can cause liver damage or failure due to the development of cirrhosis. This liver complication can lead patients at substantial risk of decompensated disease and hepatocellular carcinoma (HCC), [12] which impose a considerable burden on affected people, healthcare systems and society [13,14] Early diagnosis could help prevent these consequences, but HCV infection is often undiagnosed because it is usually asymptomatic during decades and so, the majority of HCV-infected individuals are unaware of their infection [15].

    The goal of treatment in all infected individuals, regardless of which of the six major genotypes are present, remains the achievement of a sustained virologic response (SVR) in which circulating HCV RNA is undetectable (with the use of a highly sensitive assay) following treatment. When a SVR is achieved, there is a 99% chance that the hepatitis C infection is cured [13,16]. Historically, SVR was defined as HCV RNA levels below a designated threshold of quantification 24 weeks after completion of treatment (SVR24)[17]. However, more recent data shows that viral clearance 12 weeks post-treatment (and sometimes, even 8 weeks) correlates closely to SVR24[18]. Therefore, an undetectable HCV RNA at 12 weeks after treatment (SVR12) is considered an appropriate primary efficacy endpoint [19] and translates into “cure” for nearly all patients[13]

    2. Direct-Acting Antiviral Agents Versus Interferon-Based Therapies
    The new regimens for HCV mean a breakthrough novelty in the history of anti-HCV treatment. Previous treatments for HCV were often long and difficult. Many lasted from 24 to 48 weeks and showed suboptimal efficacy in viral response with a range of commonly occurring significant side effects, which impaired therapeutic compliance[20]. Nowadays, HCV patients can benefit from a less complex administration schedule and expect interferon (IFN) and even ribavirin (RBV)-free combinations. This results in a reduction of the incidence and severity of adverse events, optimizing quality of life during therapy and improving adherence to direct-acting antiviral agents (DAAs).

    3. Sofosbuvir-Velpatasvir
    Sofosbuvir-velpatasvir (EPCLUSA®) is a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with or without cirrhosis (compensated). In clinical studies, sofosbuvir-velpatasvir (SOF-VEL) had high overall cure rates. (Table 1) The most common side effects were headache and tiredness [21].

    Clinical Study (Reference)Number of patients (% cirrhosis)HCV genotype (%)Treatment HistorySVR12 by Genotype, Cirrhosis and Treatment Experience
    ASTRAL-1 (22)740 (19%)1
    2
    4
    5
    6
    Treatment-naïve and treatment- experiencedSOF - VEL, 12 weeksGenotype 1a98% (206/210)
    Genotype 1b99% (117/118)
    Genotype  2100% (104/104)
    Genotype  4100% (116/116)
    Genotype  597% (34/35)
    Genotype  6100% (41/41)
    Without Cirrhosis99% (496/501)
    With Cirrhosis99% (120/121)
    Treatment- naïve99% (418/423)
    Treatment- experienced99% (200/201)
    ASTRAL-2 (23)266(14%)2(100%)Treatment-naïve and treatment- experienced SOF - VEL, 12weeksTreatment- naïve without cirrhosis99% (99/100)
    SOF + RBV, 12 weeksTreatment- naïve without cirrhosis96% (92/96)
    SOF - VEL, 12 weeksTreatment- naïve with cirrhosis100% (15/15)
    SOF + RBV, 12 weeksTreatment- naïve with cirrhosis93% (14/15)
    SOF - VEL, 12 weeksTreatment- experienced without cirrhosis100% (15/15)
    SOF + RBV, 12 weeksTreatment- experienced without cirrhosis81% (13/16)
    SOF - VEL, 12 weeksTreatment- experienced with cirrhosis100% (4/4)
    SOF + RBV, 12 weeksTreatment- experienced with cirrhosis100% (4/4)
    ASTRAL-3 (23)552(30%)3(100%)Treatment-naïve and treatment- experiencedSOF - VEL, 12 weeksTreatment- naïve without cirrhosis98% (160/163)
    SOF + RBV, 24 weeksTreatment- naïve without cirrhosis90% (141/156)
    SOF - VEL, 12 weeksTreatment- naïve with cirrhosis93% (40/43)
    SOF + RBV, 24 weeksTreatment- naïve with cirrhosis73% (33/45)
    SOF - VEL, 12 weeksTreatment- experienced without cirrhosis91% (31/34)
    SOF + RBV, 24 weeksTreatment- experienced without cirrhosis71% (22/31)
    SOF - VEL, 12 weeksTreatment- experienced with cirrhosis89% (33/37)
    SOF + RBV, 24 weeksTreatment- experienced with cirrhosis


    4. Sofosbuvir-Velpatasvir-Voxilaprevir
    Four Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluated a 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 1,2,3,4,5 and 6 chronic HCV infection. (Table 3)

    The most common adverse events among patients who received SOF-VEL-VOX were headache, fatigue, diarrhea and nausea. The overall incidence of adverse events was similar to placebo or SOF- VEL. Among the 1,056 patients who received SOF-VEL-VOX in the four studies, only a patient receiving SOF-VEL-VOX for 12 weeks discontinued due to an adverse event[26]. These results show that this new three-drug co-formulation with different mechanisms of action and high barrier to resistance can provide high cure rates for patients who had previously failed treatment with other DAAs.

    Table 2. Summary of clinical studies of sofosbuvir-velpatasvir in special populations
                          

    3. Summary of clinical studies of sofosbuvir-velpatasvir-voxilaprevir
                          


    5. Glecaprevir-Pibrentasvir

    Glecaprevir-pibrentasvir is an investigational, pan-genotypic regimen that is being evaluated (table 4) not only as a potential cure in 8 weeks for HCV patients without cirrhosis and who are new to treatment, but also in patients with specific treatment challenges, such as genotype 3, patients who were not cured with previous DAA treatment and those with chronic kidney disease, including patients on dialysis.

    This investigational, pan-genotypic regimen of glecaprevir-pibrentasvir is showing to be well tolerated with a favorable safety profile in these difficult-to-treat populations. The most commonly reported adverse events included fatigue and nausea.

    Table 4. Summary of clinical studies of glecaprevir-pibrentasvir
                          

    6. Discussion
    Although the post-marketing phase always requires a careful evaluation of data from the “everyday” clinical practice experience, clinical trials have showed that these new DAA combinations have resolved most issues related to HCV treatment compared with the past regimens. Despite the approval of the first DAAs which have provided high cure rates and simplified treatment for most HCV patients, HCV genotype 3-infected patients with cirrhosis, patients with chronic kidney disease and those who have failed previous treatment with DAAs continued to represent an unmet medical need. In the era of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir- pibrentasvir, DAA therapy provides a new way to manage these difficult-to-treat HCV-infected patients, who are at a high risk of serious conditions[30]. They are now contemplated and are therefore expected to have a much better prognosis than they have had until very recently. Perhaps, soon, we may no longer have difficult-to-treat populations.

    The advent of new generation oral antiviral therapy has led to major improvements in efficacy and tolerability but has also resulted in an explosion of data with increased treatment choice complexity [31].

    Thus, clinicians need more detailed, accurate and timely information in order to choose the right regimen for individual patients and educate them. When they counsel and guide their patients, these ones are less likely to be anxious or resistant about taking steps toward possible cure. However, cure does not prevent reinfection and so, it is crucial to advise patients on measures that will reduce their risk (avoid alcohol intake and sexual and injection risk behaviors, eat a balanced diet and take exercise are some examples).

    7. Conclusion
    DAAs have shown that it is possible to minimize the spread of HCV and the morbidity and mortality associated with HCV infection[32].

    Despite the financial controversy around their high costs, which have served as a major barrier for more widespread use, many stakeholders recognize now their long-term cost-benefits and the advantages of a future free from hepatitis C are manifest.

    It is true that patients undergoing treatment need systematic monitoring before, during and after therapy, but these new treatment options have offered them hope and re-awakening. It is a clear evolution compared with the previous IFN-based therapies.

    8. Future Directions
    At a future time, treatment failure and resistance can occur and become a clinical challenge to be solved[30,33].

    However, before them, there are already some questions that should concern us. First one is why is the association of RBV with DAAs, in some cases, increasing the SVR12 rate and shortening the duration of treatment? Then, at what point is it no longer worth treating a patient? Will we have the financial capacity to treat reinfected-patients? Will this simplicity of therapeutic regimen encourage risk behaviors in the future?

    References
    Download PDF | Full Text HTML

    Sunday, November 13, 2016

    AASLD 2016 Merck's HCV Triple-Combination High Rates of SVR In Genotypes 1, 2 or 3 Infection

    Related
    AASLD - Slides available @ NATAP
    Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/MK-8408 (Ruzasvir) With or Without Ribavirin in Non-cirrhotic or Cirrhotic Patients with Chronic HCV GT1, 2 or 3 Infection (Part B of C-CREST-1 & -2)

    High Sustained Virologic Response Rates in Patients with Chronic HCV GT1, 2 or 3 Infection Following 16 Weeks of MK-3682/Grazoprevir/MK-8408 (Ruzasvir) Plus Ribavirin After Failure of 8 Weeks of Therapy (Part C of C-CREST-1 & 2) 

    Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682 / Grazoprevir / MK-8408 (Ruzasvir) in Cirrhotic or Non-cirrhotic Patients with Chronic HCV GT1 Infection who Previously Failed a Direct-acting Antiviral Regimen (C-SURGE) 

    View all conference coverage at NATAP

    Merck Announces Findings for Investigational Triple-Combination Chronic Hepatitis C Therapy Showing High Rates of Sustained Virologic Response in People with Genotypes 1, 2 or 3 Infection

    Phase 2 Data Presentations at The Liver Meeting® Detail SVR12 Rates from Two Studies as Well as SVR8 Rates in Patients for Whom Direct-Acting Antiviral Treatment Previously Failed

    November 13, 2016 08:00 AM Eastern Standard Time
    KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced the presentation of results from three Phase 2 clinical trials evaluating MK-3682B (MK-3682/grazoprevir/ruzasvir1), the company’s investigational all-oral, triple-combination regimen for the treatment of chronic hepatitis C (HCV) infection (informally referred to as MK3). Results from Part B of C-CREST 1 & 2 demonstrated high rates of sustained virologic response2 (SVR) 12 weeks after the completion of therapy (SVR12, considered virologic cure) in patients with chronic HCV genotype (GT) 1 or GT3 infection who received eight weeks of treatment with MK-3682B. Findings from C-CREST 1 & 2 Part B also demonstrated high rates of SVR12 in GT1, GT2 and GT3-infected patients who received MK3 for 12 or 16 weeks. Findings from Part C of C-CREST 1 & 2 and interim results from the ongoing C-SURGE study showed high rates of SVR12 and SVR8, respectively, in chronic HCV patients who had failed prior treatment with investigational or approved direct-acting antiviral regimens. These results will be announced in oral presentations at The Liver Meeting® 2016 today (C-CREST 1 & 2 Parts B and C) and tomorrow (C-SURGE).

    “Across the chronic hepatitis C treatment landscape, incredible progress has been made in a remarkably short amount of time, but there remains a need for more options, particularly for patients who do not achieve sustained virologic response with treatment regimens available today,” said Dr. Eliav Barr, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories. “The strong findings observed following treatment with MK-3682B are an encouraging step towards Merck’s goal of developing and delivering a shorter-duration, pan-genotypic next-generation treatment regimen for more patients with chronic hepatitis C infection.”

    C-CREST 1 & 2 Part B Overview and Findings

    Part B of C-CREST 1 & 2 – ongoing, open-label Phase 2 clinical trials – was designed to evaluate the safety and efficacy of MK-3682B in patients with chronic HCV GT1, GT2 or GT3 infection, with or without cirrhosis. Patients with GT2 or GT3 infection received MK-3682B with or without RBV. All patients with GT1 or GT2 infection were treatment-naïve. Fifty six percent (189/337) of patients with GT3 infection were treatment naïve and 44 percent (148/337) were previously treated with peginterferon/ribavirin (RBV). The primary endpoint of the study was the proportion of patients in each treatment arm who achieved SVR12.

    Eight weeks of treatment with MK-3682B resulted in SVR12 rates of 95 percent, 86 percent and 95 percent in GT1, GT2 and GT3 patients, respectively. A 12-week treatment duration resulted in high SVR12 rates in all genotypes (GT1, 99%; GT2, 97%; GT3, 97%). Efficacy was comparable in patients with and without cirrhosis. There were no virologic failures in the patients with GT1 or GT2 infection who received 12 weeks of MK-3682B. Efficacy results are presented in the table below. Results from Part A of C-CREST 1 & 2 were previously reported at The Liver Meeting® in November 2015.   
     
    Summary of SVR12 Findings
                   
    Population     N     MK-3682B
    +/- RBV
    8 weeks
        MK-3682B
    +/- RBV
    12 weeks
        MK-3682B
    +/- RBV
    16 weeks
    GT1a     90     93% (39/42)     98% (47/48)     -
    GT1b     86     98% (45/46)     100% (40/40)     -
    GT2     151     86% (54/63)     97% (60/62)     100% (26/26)
    GT3*     337     95% (98/103)     97% (155/159)     96% (72/75)
    *28 percent (29/103), 36 percent (58/159) and 81 percent (61/75)
    of patients with GT3 infection receiving eight, 12 or 16 weeks
    of therapy, respectively, were previously treated with peginterferon/RBV
     
      
    Among patients who received at least one dose of MK-3682B with or without RBV, the overall most common adverse events (AEs) reported (greater than 10% incidence in either treatment arm) were headache (22%), fatigue (19%) and nausea (13%). There were two drug-related serious AEs, both considered related to RBV only. Nine patients discontinued study drug due to AEs, four of whom discontinued RBV only. One patient died due to AEs not related to the study drug.

    “As a scientist and physician who regularly treats patients with chronic hepatitis C, the importance of continuing to research this complex disease and its many complications is evident,” said Dr. Eric Lawitz, vice president, scientific and research development, The Texas Liver Institute and clinical professor of medicine, The University of Texas Health Science Center, San Antonio. “The virologic cure rates observed in Part B of C-CREST 1 & 2 clearly demonstrate the potential for MK3 and support further study of this investigational regimen.”

    C-SURGE Overview and Preliminary Findings

    C-SURGE is an ongoing, open-label Phase 2 clinical trial designed to evaluate MK-3682B with or without RBV in chronic HCV GT1 patients who previously failed therapy with either ledipasvir/sofosbuvir (LDV/SOF) or ZEPATIER™ (elbasvir and grazoprevir). The study enrolled 94 patients randomized to receive 16 weeks of MK-3682B plus RBV (n=45) or 24 weeks of MK-3682B without ribavirin (n=49); one patient in the 16 week arm withdrew prior to starting treatment. Of the 93 patients who received treatment in this study, 61 percent (57/93) had previously received 12 to 24 weeks of treatment with LDV/SOF; 15 percent (14/93) had received 8 weeks of LDV/SOF; and 24 percent (22/93) had received 12 weeks of ZEPATIER. A majority of patients (84%, 78/93) had at least one baseline NS5A resistance-associated variant (RAV) at positions 28, 30, 31 or 93.

    Interim results from the modified full analysis set (mFAS), which excludes one patient in the 16-week arm who withdrew due to administrative reasons after receiving three doses of study medication, show all patients (43/43) who have completed treatment with MK-3862B plus RBV for 16 weeks achieved SVR8. All patients (49/49) in the mFAS who received MK-3682B for 24 weeks have completed treatment and remain subject to follow-up; the interim results show of those in the 24-week arm who have reached follow-up weeks four and eight, 100 percent have achieved SVR4 (38/38) and SVR8 (30/30), respectively. SVR12 is the primary outcome measure of this ongoing trial. Final results will be presented at a future scientific congress.

    Among patients who received at least one dose of MK-3682B with or without RBV, the overall most common AEs reported were fatigue (35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%). There were no drug-related serious AEs, and no patients discontinued due to a drug-related AE.

    C-CREST 1 & 2 Part C Overview and Findings

    Part C of C-CREST 1 & 2 was designed to evaluate retreatment with MK-3682B plus RBV for 16 weeks among patients who previously failed an investigational triple-therapy regimen (MK-3682/grazoprevir/ruzasvir or MK-3682/grazoprevir/elbasvir). The study enrolled 24 patients with GT1 (n=2), GT2 (n=14) or GT3 (n=8) infection. All patients (23/23) who completed treatment achieved SVR12. One GT2 patient discontinued treatment after a single dose due to drug-related serious AEs. Among patients who received at least one dose of MK-3682B plus RBV, the most common AEs reported (greater than 20% incidence) were headache (33%), fatigue (25%), nausea (25%), rash (21%) and insomnia (21%).

    About MK-3682B

    MK-3682B (informally referred to as MK3) is Merck’s investigational triple-combination therapy in Phase 2 development for the treatment of chronic HCV infection. MK-3682B combines an HCV nucleotide analogue NS5B polymerase inhibitor (MK-3682), an HCV NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A inhibitor (ruzasvir, MK-8408).

    About ZEPATIER™ (elbasvir and grazoprevir) 50 mg/100mg tablets

    ZEPATIER is a fixed-dose combination product containing elbasvir, an HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. ZEPATIER is indicated with or without ribavirin (RBV) for treatment of chronic HCV genotypes 1 or 4 infection in adults.

    Selected Safety Information about ZEPATIER

    ZEPATIER is not for use in patients with moderate or severe hepatic impairment (Child Pugh B or C). ZEPATIER is also not for use with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors (e.g., atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A) inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz. If ZEPATIER is administered with RBV, healthcare professionals should refer to the prescribing information for RBV as the contraindications, warnings and precautions, adverse reactions and dosing for RBV also apply to this combination regimen.

    Elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Healthcare professionals should perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic lab testing should be performed at treatment week 12.

    Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Healthcare providers should consider discontinuing ZEPATIER if ALT levels remain persistently greater than 10 times ULN. ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.

    The concomitant use of ZEPATIER with certain drugs may lead to adverse reactions or reduced therapeutic effect due to drug interactions. Certain strong CYP3A inhibitors may increase the plasma concentration of ZEPATIER, leading to possibly clinically significant adverse reactions. Moderate CYP3A inducers may decrease the plasma concentration of ZEPATIER, leading to reduced therapeutic effect and possible development of resistance. Coadministration of ZEPATIER with these drugs is not recommended. Physicians should consult the Prescribing Information for potential drug interactions.

    In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.

    Selected Dosage and Administration Information for ZEPATIER (elbasvir and grazoprevir)

    ZEPATIER is a single tablet taken once daily. The recommended dosing is 12 or 16 weeks with or without RBV, depending on HCV genotype, prior treatment history and, for patients with genotype 1a infection, presence of certain baseline NS5A resistance-associated polymorphisms. See Prescribing Information for ZEPATIER for specific dosage regimens and durations. Refer to RBV prescribing information for RBV dosing and dosage modifications when ZEPATIER is given with RBV. To determine dosage regimen and duration of ZEPATIER for genotype 1a patients, testing for the presence of virus with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, or 93 is recommended prior to initiating treatment.

    http://www.businesswire.com/news/home/20161113005036/en/Merck-Announces-Findings-Investigational-Triple-Combination-Chronic-Hepatitis

    Monday, November 16, 2015

    AASLD 2015 - Merck Announces Results from Two Phase 2 Studies of Investigational Triple-Combination Chronic Hepatitis C Therapy

    Merck Announces Presentation of Results from Two Phase 2 Studies of Investigational Triple-Combination Chronic Hepatitis C Therapy at The Liver Meeting®

    Merck Advances to Part B of C-CREST Phase 2 Clinical Development Program

    November 16, 2015 08:30 AM Eastern Standard Time
    KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of results from the initial phase (Part A) of the company’s C-CREST 1 and 2 Phase 2 clinical development program evaluating two investigational all-oral, triple-combination treatment regimens – a regimen of grazoprevir1, MK-36822 and elbasvir3; and a regimen of grazoprevir, MK-3682 and MK-84084 – in treatment-naïve patients with chronic hepatitis C virus (HCV) genotypes (GT) 1, 2 or 3 infection. These data will be presented today during a late-breaking abstract session at The Liver Meeting® (Abstract #LB-15). Based on the results of this initial trial, Merck has initiated further study of grazoprevir (100mg), MK-3682 (450mg) and MK-8408 (60mg) in the second phase (Part B) of the C-CREST Phase 2 clinical development program.

    “The strong results observed in this study support the further investigation of the novel triple-combination regimen of grazoprevir, MK-3682 and MK-8408 in patients with chronic hepatitis C.”

    “Merck’s chronic hepatitis C development program continues to focus on the goal of advancing a short-duration treatment regimen that offers high virologic cure rates across all viral genotypes,” said Dr. Roy Baynes, senior vice president and head of global clinical development, Merck Research Laboratories. “The strong results observed in this study support the further investigation of the novel triple-combination regimen of grazoprevir, MK-3682 and MK-8408 in patients with chronic hepatitis C.”

    In these randomized, open-label clinical trials, C-CREST 1 evaluated treatment-naive, non-cirrhotic patients with chronic HCV GT1 or 2 infection and C-CREST 2evaluated treatment-naive, non-cirrhotic patients with chronic HCV GT3 infection. The primary efficacy endpoint was sustained virologic response 12 weeks after the completion of treatment (SVR12, or virologic cure). All 240 enrolled patients completed eight weeks of treatment and reached follow-up 12 weeks after end of treatment. Treatment with grazoprevir (100mg), MK-3682 (450mg) and MK-8408 (60mg), without ribavirin (RBV), for eight weeks resulted in virologic cure rates of greater than 90 percent across chronic HCV patients with GT1, 2 or 3 infection, which supported the decision to advance this regimen into Part B of the C-CREST Phase 2 clinical trial program.
    Summary of SVR12 Findings Following 8 Weeks of Treatment*: C-CREST 1 and 2 Part A
    PopulationN
    Grazoprevir
    + Elbasvir
    + MK-3682
    300mg
    Grazoprevir
    + Elbasvir
    + MK-3682
    450mg
    Grazoprevir
    + MK-8408
    + MK-3682
    300mg
    Grazoprevir
    + MK-8408
    + MK-3682
    450mg
    GT193100% (23/23)100% (23/23)100% (24/24)91% (21/23)
    GT26169% (11/16)60% (9/15)71% (10/14)94% (15/16)
    GT38690% (19/21)86% (19/22)95% (20/21)91% (20/22)
    *Treatment-naive, non-cirrhotic patients
    The most commonly reported adverse events across all regimens (greater than 10% incidence) were headache (23%), fatigue (20%) and nausea (13%). There were no drug-related serious adverse events and no discontinuations due to adverse events.

    About the C-CREST Program
    The C-CREST Phase 2 clinical development program is designed to evaluate the safety and efficacy of Merck’s triple-combination treatment regimens in patients with chronic HCV GT1, 2 or 3 infection. The investigational medicines studied in the initial phase (Part A) of the C-CREST program included:
    Grazoprevir (MK-5172), an HCV NS3/4A protease inhibitor
    MK-3682, an oral prodrug HCV nucleotide analogue NS5B polymerase inhibitor
    Elbasvir (MK-8742), an HCV NS5A replication complex inhibitor
    MK-8408, an HCV NS5A replication complex inhibitor

    Based on the results from the initial phase (Part A) in treatment-naive, non-cirrhotic chronic HCV patients, Merck has initiated further study of grazoprevir, MK-3682 and MK-8408 in the second phase (Part B) of the C-CREST Phase 2 program. Part B will evaluate the safety and efficacy of this regimen with or without RBV in chronic HCV patients with GT1, 2 or 3 infection for different treatment durations. The various study arms will include treatment-naive patients with or without compensated cirrhosis or with HIV/HCV co-infection, as well as treatment-experienced patients (previously treated with pegylated interferon/RBV) with GT3 infection.

    Merck’s Commitment to HCV
    For nearly 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to deliver innovative healthcare solutions that support people living with HCV worldwide.

    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, visitwww.merck.com and connect with us on Twitter, Facebook, YouTube and LinkedIn.

    Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA
    This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. 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 health care legislation in the United States and internationally; global trends toward health care 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 (100mg).
    2 MK-3682 is an oral prodrug HCV nucleotide analogue NS5B polymerase inhibitor (300mg or 450mg).
    3 Elbasvir is an HCV NS5A replication complex inhibitor (50mg).
    4 MK-8408 is an HCV NS5A replication complex inhibitor (60mg).