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European Commission Approves Daklinza (daclatasvir) for the Treatment of Genotype 1, 3 and 4 Chronic Hepatitis C Patients with HIV Coinfection, Advanced Cirrhosis and Post-liver Transplant Recurrence of HCV

Hepatitis C Blog Posted on January 28, 2016 by AlanJanuary 28, 2016

Updated label provides additional treatment options for multiple HCV patient populations, including difficult-to-treat patients with decompensated cirrhosis

HIV/HCV coinfected patients experience more rapid fibrosis progression than mono-infected HCV patients

Thursday, January 28, 2016 12:41 pm EST 
“The European Commission’s approval of these new indications for Daklinza is an important step forward for a significant group of patients with chronic hepatitis C who are still in need of treatment options that can deliver high cure rates”

PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers Squibb Company(NYSE:BMY) announced today that the European Commission has approved Daklinza for the treatment of chronic hepatitis C (HCV) in three new patient populations. The expanded label allows for the use of Daklinza in combination with sofosbuvir (with or without ribavirin, depending on the indication and HCV genotype) in HCV patients with decompensated cirrhosis, HIV-1 (human immunodeficiency virus) coinfection, and post-liver transplant recurrence of HCV in all 28 Member States of the European Union.

“The European Commission’s approval of these new indications for Daklinza is an important step forward for a significant group of patients with chronic hepatitis C who are still in need of treatment options that can deliver high cure rates,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “The complex clinical considerations for physicians treating HCV/HIV coinfected patients and patients with cirrhosis, decompensated cirrhosis or post-transplant recurrence of HCV reinforces the vast diversity of this disease, and we have worked hard to continue to identify and address those patients who require additional solutions for cure.”

Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A and P-glycoprotein transporter, as this may lead to lower exposure and loss of efficacy of Daklinza. Daklinzamust not be administered as a monotherapy.

Daklinza is already approved by the European Commission for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic HCV infection in adults, and the Daklinza + sofosbuvir regimen is the only approved 12-week, all-oral treatment for genotype 3 HCV patients without cirrhosis. The new indications are based on data from the ALLY-1 clinical trial (in post-transplant patients and patients with advanced cirrhosis) and ALLY-2 clinical trial (in HIV-coinfected patients). The recommended treatment regimens and durations are as follows:

Patient population* Regimen and duration
HCV GT 1 or 4
Patients without cirrhosis

Daklinza + sofosbuvir for 12 weeks

Patients with cirrhosis
Child-Pugh Class (CP) A or B

Daklinza + sofosbuvir + ribavirin for 12 weeks

or

Daklinza + sofosbuvir (without ribavirin) for 24 weeks

CP C

Daklinza + sofosbuvir +/- ribavirin for 24 weeks

HCV GT 3
Patients without cirrhosis Daklinza + sofosbuvir for 12 weeks

Patients with cirrhosis

Daklinza + sofosbuvir +/- ribavirin for 24 weeks

(see section 5.1 of the Summary of Product Characteristics)

Recurrent HCV infection post-liver transplant (GT 1, 3 or 4)
Patients without cirrhosis Daklinza + sofosbuvir + ribavirin for 12 weeks
Patients with CP A or B cirrhosis
GT 1 or 4

Daklinza + sofosbuvir + ribavirin for 12 weeks

GT 3

Daklinza + sofosbuvir +/- ribavirin for 24 weeks

Patients with CP C cirrhosis Daklinza + sofosbuvir +/- ribavirin for 24 weeks
*

Includes patients coinfected with human immunodeficiency virus (HIV). For dosing recommendations with HIV antiviral agents, refer to full Summary of Product Characteristics.

ALLY-2 Study Design

In the ALLY-2 Phase 3 open-label clinical trial, 153 patients with chronic HCV coinfected with HIV (101 treatment-naïve patients and 52 treatment-experienced patients) received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks, and 50 treatment-naïve patients received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 8 weeks. Patients with genotypes 1-6 were eligible to enroll, including those with compensated cirrhosis (Child-Pugh A), and the dose of Daklinza was adjusted for concomitant antiretroviral use. The co-primary endpoints were defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12 (SVR12) in each treatment group. The 153 patients who received 12 weeks of treatment had a median age of 53 years (range, 24-71); 63% of the patients were white and 33% were black. Sixty-eight percent of patients had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Sixteen percent of all patients had compensated cirrhosis.

In the 12-week arms, the Daklinza plus sofosbuvir regimen demonstrated overall SVR12 in 97% of patients, including 100% in genotype 3. SVR12 rates were greater than 94% across all combination antiretroviral therapy (cART) regimens, including boosted-protease inhibitor-, NNRTI-, and integrase inhibitor-based therapies.

In the trial, there were no treatment-related serious adverse events (SAEs) and no discontinuations due to adverse events (AEs). The most common treatment-related AEs (≥10%) were fatigue (17%), nausea (13%), and headache (11%).

ALLY-1 Study Design

In the ALLY-1 Phase 3 open-label clinical trial, 113 patients with chronic HCV and Child-Pugh A, B or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53) received Daklinza 60 mg plus sofosbuvir 400 mg once daily with ribavirin (600 mg starting dose) for 12 weeks. Patients with genotypes 1-6 were eligible to enroll. The co-primary endpoints were defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12 (SVR12) in each treatment group. Among the 53 post-liver transplant patients: the median age was 59; 96% were white, 2% were black, and 2% were defined as other; and, 58% of patients had HCV genotype 1a, 19% had genotype 1b, 21% had genotype 3, and 2% had genotype 6. Among the 60 cirrhotic patients: the median age was 58; 95% were white and 5% were black; 20% were Child-Pugh class A, 53% were Child-Pugh class B, and 27% were Child-Pugh class C; and, 57% of patients had HCV genotype 1a, 18% had genotype 1b, 8% had genotype 2, 10% had genotype 3, and 7% had genotype 4. In the same cohort, median baseline Model for End-Stage Liver Disease (MELD) score was 13. Most (55%) of the 53 patients in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE® results). The trial permitted a wide variety of immunosuppressants in the post-transplant cohort, including cyclosporine, tacrolimus, sirolimus, everolimus, corticosteroids, or mycophenolate mofetil.

In the trial, 94% of post liver-transplant patients and 83% of patients in the cirrhosis cohort achieved SVR12, including 92-94% of patients with Child-Pugh A or B. In the cirrhosis cohort, 4 subjects with hepatocellular carcinoma underwent liver transplantation after 1 to 71 days of treatment; 3 of the 4 subjects received 12 weeks of post-liver transplant treatment extension and 1 subject, treated for 23 days before transplantation, did not receive treatment extension. All 4 subjects achieved SVR12.

In the trial, there were no treatment-related SAEs, and 16 patients discontinued study drugs due to AEs; 14 discontinued ribavirin only, and 2 discontinued the entire regimen. The most common treatment-related AEs (≥10%) in either cohort of ALLY-1 were headache (15%, 36%), fatigue (18%, 28%), anemia (20%, 19%), diarrhea (8%, 19%), nausea (17%, 6%) and arthralgia (2%, 13%) in the advanced cirrhotic and post-transplant treatment groups, respectively. The updated Summary of Product Characteristics will be available at www.ema.europa.eu.

About Bristol-Myers Squibb in HCV

Bristol-Myers Squibb is focused on helping to eradicate hepatitis C around the world, with a primary emphasis on difficult-to-treat patients, including those millions in countries where population-based HCV solutions remain a high unmet need.

In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic hepatitis C. Since then, daclatasvir-based regimens have been approved in more than 50 countries across Europe, Central and South America, the Middle East and the Asia-Pacific region.

U.S. Indication and Important Safety Information (ISI) – Daklinza™ (daclatasvir)

The following ISI is based on information from U.S. Prescribing Information for Daklinza. Please consult the full Prescribing Information for all labeled safety information.

INDICATION

Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.

Limitations of Use:

  • Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

  • Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
    • Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).

WARNINGS and PRECAUTIONS

  • Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
  • Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
    • Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
    • Bradycardia generally resolved after discontinuation of HCV treatment.
    • Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.

ADVERSE REACTIONS

  • The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).

DRUG INTERACTIONS

  • CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
  • P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.

See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.

Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.

Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.

Please click here for the Daklinza full prescribing information.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global pharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact: 

Bristol-Myers Squibb Company
Media:
Robert Perry,  407-492-4616
rob.perry@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
Bill Szablewski, 609-252-5894
william.szablewski@bms.com

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Posted in daclatasvir, Genotype 2, Genotype 3 | Tagged 3, 4, Daklinza, EU Approval, Genotype 1, Genotype 2, Genotype 3, HIV/HCV coinfection

ALLY 3+ Trial Investigating Daklinza (daclatasvir) in Combination with Sofosbuvir and Ribavirin Demonstrates High Cure Rates in Chronic Hepatitis C Genotype 3 Patients with Advanced Fibrosis or Cirrhosis

Hepatitis C Blog Posted on November 16, 2015 by HCV AdvocateDecember 1, 2015

Daclatasvir+sofosbuvir+ribavirin regimen achieves SVR12 rates of 88% and 92% overall for 12 or 16 weeks of therapy respectively in GT-3 patients with advanced fibrosis or cirrhosis

MONTREAL, Nov. 16, 2015 /CNW/ – Bristol Myers-Squibb today announced late-breaking data from the Phase 3 ALLY-3+ Trial investigating a regimen of Daklinza™ (daclatasvir, DCV) in combination with sofosbuvir (SOF) and ribavirin (RBV) in genotype 3 hepatitis C (HCV) patients with advanced fibrosis or cirrhosis, for treatment durations of 12 and 16 weeks. This patient population is one of the most difficult to treat, among whom sustained virologic response (SVR) rates, or cure, have proved harder to achieve with existing therapies.

The results show that SVR12 rates in cirrhotic patients only were 83 per cent  and 89 per cent in the 12- and 16-week arms, respectively. Results will be presented at The Liver Meeting® 2015, the Annual Meeting of The American Association for the Study of Liver Diseases (AASLD), in San Francisco, CA, November 13 – 17.

Daklinza is a potent, pan-genotypic NS5A replication complex inhibitor (in vitro) that has been approved for use in combination with sofosbuvir (marketed in Canada by Gilead Sciences Canada Inc. as SOVALDI™) as a convenient, all-oral, once-daily regimen for the treatment of adult patients with hepatitis C genotypes 1 and 2 with compensated liver disease including cirrhosis. Daklinza has also received a Notice of Compliance with conditions (NOC/c) from Health Canada for the treatment of genotype 3 patients with compensated liver disease including cirrhosis. In Canada, genotypes 3 accounts for 20 per cent of hepatitis C infections.

Read more…

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Tagged BMS, Genotype 3

SNAPSHOTS —Alan Franciscus, Editor-in-Chief

Hepatitis C Blog Posted on October 14, 2015 by HCV AdvocateDecember 1, 2015

This month’s (October 2015) column features a variety of studies, including treatment of people with advanced liver disease, treating people who have not achieved a cure with direct acting antiviral therapy, including people who had developed RAVs.

Article:  Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease—M Charlton et al. 
Source:  Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.
Results and Conclusions
This was a phase 2 study of 337 patients with decompensated cirrhosis with genotype 1 (332 patients) and genotype 4 (5 patients) who received 12 or 24 weeks of Harvoni plus ribavirin twice daily.  None of the patients previously treated developed resistance to sofosbuvir.  People who had been previously treated with an NS5A inhibitor were excluded from the study. 
There were two groups in the study:
  •  Group A, who had NOT had a liver transplant: 59 patients with Child-Pugh class B cirrhosis and 49 patients with Child-Pugh class C  cirrhosis*
  •  Group B who HAD undergone liver transplantation:  111 patients without cirrhosis, 51 patients with Child-Pugh class A cirrhosis, 52 with Child-Pugh class B cirrhosis, 9 with Child-Pugh class C cirrhosis, and 6 with fibrosing cholestatic hepatitis*

 *Child-Pugh cirrhosis scoring is a system that uses various types of blood markers and liver disease progression such as ascites to evaluate a patient to establish the severity of cirrhosis and long-term patient survival.  The classes are A, B and C with A as the less severe and C as the most severe.  Cholestatic hepatitis is bile duct blockage with fibrosis.
Group A and B had 12- and 24-week treatment arms, but cure rates were similar regardless of treatment duration.
     
 The Bottom Line
In group A (those who had not received a liver transplant), the cure rate was 86% to 89%.  In group B (transplant group) the people who did not have cirrhosis or Class A cirrhosis—the cure rate was 96% to 98%.  Furthermore, in group B with class B cirrhosis (compensated) the cure rate was 85% to 88%, and those with class C cirrhosis (moderate impairment) achieved 60% to 75% cure rates. The people who had fibrosing cholestatic hepatitis achieved 100% cure rates.  There were 13 patients (4%) who discontinued treatment.  Ten patients died in the trial.  The deaths were mainly attributed to complications from hepatic decompensation or end-stage liver disease.
Editorial Comment
In the past, people with these types of severe disease progression have been very difficult to cure or even treat, but now with these ‘miracle’ drugs many people now have a second chance at life.  Now if we could just get these drugs to everyone with hepatitis C before this stage, we would eliminate the need to treat at these stages of disease severity. 
___________
Article:  Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent—X Forns et al.
Source:  J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.
Results and Conclusions
There were 79 HCV genotype 1 patients in the study. 
  • Sixty-six patients who had been previously treated patients with an NS3/4A protease inhibitor but had not been cured. 
  • Of the 13 remaining patients, 12 had discontinued treatment due to side-effect(s). 
  • Thirty-four patients had NS3 resistance-associated variants (RAVs), and eight patients had NS5A RAVs. 
  • Eight patients treated with the combination of grazoprevir and elbasvir plus ribavirin twice daily.

 The Bottom Line
The overall cure rates were 96% (76 of 79 patients)—this included 93% (63 of 66 patients) of the genotype 1a, one hundred percent of the patients (43 of 43 patients) who DID NOT have RAVs achieved a cure.  Ninety-one percent of those who DID have NS3 RAV’s were cured and 75% (6 of 8 patients) of those who had NS5A RAVs were cured.  Of those with cirrhosis 94% were cured with this combination. 
Editorial Comment
The addition of ribavirin to grazoprevir and elbasvir works to help cure resistance-associated variants in people who have been previously treated but who have not been cured.  It is also good strategy to treat other negative predictors to current  medications.
____________________
Article:  Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens—D Wyles et al.  
Source:  Hepatology. 2015 Jun;61(6):1793-7. doi: 10.1002/hep.27814. Epub 2015 Apr 27.
Results and Conclusions
There were 51 genotype 1 patients enrolled in the study (Note: one patient was incorrectly typed as genotype 1, but was subsequently correctly genotyped as genotype 3).  All of the patients in this trial were previously treated with a sofosbuvir containing regimes in Gilead’s phase 1 or phase 2 studies.  The treatment duration in this study was 12 weeks. 
Breaking it down by type of prior type of non-response:
  • 25 pts (49%) had previously received sofosbuvir plus pegylated interferon plus ribavirin
  • 20 pts (39%) had previously received sofosbuvir plus ribavirin
  • 5 pts (10%) received sofosbuvir (sugar pill/placebo) plus pegylated interferon and ribavirin
  • 1 pt (2%) received GS-0938 only fourteen patients (27%) had compensated cirrhosis.

 The Bottom Line
The total number of patients who achieved a cure was 98% (50 of 51 patients).  Among those who had received a prior course of sofosbuvir 98% (44 of 45) were cured.  The only patient who did not achieve a cure was the patient who was originally misdiagnosed as a genotype 1. 
The most common side effects were fatigue, headache and diarrhea.  The patients in this trial are considered some the most difficult to treat—those who have not achieved a cure with a previous course of a direct acting antiviral medication, those with cirrhosis, and people with resistant antiviral variants (RAVs). 
Editorial Comment
The addition of ledipasvir and ribavirin to sofosbuvir increased the cure rates to 100% for genotype 1.  Excellent results!  This is a good strategy with another type of direct acting antiviral to stop the virus from replicating and escaping.
Gilead, Merck, AbbVie, Janssen, and Achillion are working on other HCV drugs that have a higher barrier to resistance to avoid the development of resistance and to work for people who are not responding to the current medications.
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Tagged cirrhosis, elbasvir, Genotype 1, genotype 1a, Genotype 3, grazoprevir, ledipasvir, Liver Transplant, NS5A inhibitor, pegylated interferon, RAV, ribavirin, Sofosbuvir

SNAPSHOTS —Alan Franciscus, Editor-in-Chief

Hepatitis C Blog Posted on October 14, 2015 by HCV AdvocateDecember 13, 2015

This month’s (October 2015) column features a variety of studies, including treatment of people with advanced liver disease, treating people who have not achieved a cure with direct acting antiviral therapy, including people who had developed RAVs.

Article:  Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease—M Charlton et al. 
Source:  Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.
Results and Conclusions
This was a phase 2 study of 337 patients with decompensated cirrhosis with genotype 1 (332 patients) and genotype 4 (5 patients) who received 12 or 24 weeks of Harvoni plus ribavirin twice daily.  None of the patients previously treated developed resistance to sofosbuvir.  People who had been previously treated with an NS5A inhibitor were excluded from the study. 
There were two groups in the study:
  •  Group A, who had NOT had a liver transplant: 59 patients with Child-Pugh class B cirrhosis and 49 patients with Child-Pugh class C  cirrhosis*
  •  Group B who HAD undergone liver transplantation:  111 patients without cirrhosis, 51 patients with Child-Pugh class A cirrhosis, 52 with Child-Pugh class B cirrhosis, 9 with Child-Pugh class C cirrhosis, and 6 with fibrosing cholestatic hepatitis*

 *Child-Pugh cirrhosis scoring is a system that uses various types of blood markers and liver disease progression such as ascites to evaluate a patient to establish the severity of cirrhosis and long-term patient survival.  The classes are A, B and C with A as the less severe and C as the most severe.  Cholestatic hepatitis is bile duct blockage with fibrosis.
Group A and B had 12- and 24-week treatment arms, but cure rates were similar regardless of treatment duration.
     
 The Bottom Line
In group A (those who had not received a liver transplant), the cure rate was 86% to 89%.  In group B (transplant group) the people who did not have cirrhosis or Class A cirrhosis—the cure rate was 96% to 98%.  Furthermore, in group B with class B cirrhosis (compensated) the cure rate was 85% to 88%, and those with class C cirrhosis (moderate impairment) achieved 60% to 75% cure rates. The people who had fibrosing cholestatic hepatitis achieved 100% cure rates.  There were 13 patients (4%) who discontinued treatment.  Ten patients died in the trial.  The deaths were mainly attributed to complications from hepatic decompensation or end-stage liver disease.
Editorial Comment
In the past, people with these types of severe disease progression have been very difficult to cure or even treat, but now with these ‘miracle’ drugs many people now have a second chance at life.  Now if we could just get these drugs to everyone with hepatitis C before this stage, we would eliminate the need to treat at these stages of disease severity. 
___________
Article:  Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent—X Forns et al.
Source:  J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.
Results and Conclusions
There were 79 HCV genotype 1 patients in the study. 
  • Sixty-six patients who had been previously treated patients with an NS3/4A protease inhibitor but had not been cured. 
  • Of the 13 remaining patients, 12 had discontinued treatment due to side-effect(s). 
  • Thirty-four patients had NS3 resistance-associated variants (RAVs), and eight patients had NS5A RAVs. 
  • Eight patients treated with the combination of grazoprevir and elbasvir plus ribavirin twice daily.

 The Bottom Line
The overall cure rates were 96% (76 of 79 patients)—this included 93% (63 of 66 patients) of the genotype 1a, one hundred percent of the patients (43 of 43 patients) who DID NOT have RAVs achieved a cure.  Ninety-one percent of those who DID have NS3 RAV’s were cured and 75% (6 of 8 patients) of those who had NS5A RAVs were cured.  Of those with cirrhosis 94% were cured with this combination. 
Editorial Comment
The addition of ribavirin to grazoprevir and elbasvir works to help cure resistance-associated variants in people who have been previously treated but who have not been cured.  It is also good strategy to treat other negative predictors to current  medications.
____________________
Article:  Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens—D Wyles et al.  
Source:  Hepatology. 2015 Jun;61(6):1793-7. doi: 10.1002/hep.27814. Epub 2015 Apr 27.
Results and Conclusions
There were 51 genotype 1 patients enrolled in the study (Note: one patient was incorrectly typed as genotype 1, but was subsequently correctly genotyped as genotype 3).  All of the patients in this trial were previously treated with a sofosbuvir containing regimes in Gilead’s phase 1 or phase 2 studies.  The treatment duration in this study was 12 weeks. 
Breaking it down by type of prior type of non-response:
  • 25 pts (49%) had previously received sofosbuvir plus pegylated interferon plus ribavirin
  • 20 pts (39%) had previously received sofosbuvir plus ribavirin
  • 5 pts (10%) received sofosbuvir (sugar pill/placebo) plus pegylated interferon and ribavirin
  • 1 pt (2%) received GS-0938 only fourteen patients (27%) had compensated cirrhosis.

 The Bottom Line
The total number of patients who achieved a cure was 98% (50 of 51 patients).  Among those who had received a prior course of sofosbuvir 98% (44 of 45) were cured.  The only patient who did not achieve a cure was the patient who was originally misdiagnosed as a genotype 1. 
The most common side effects were fatigue, headache and diarrhea.  The patients in this trial are considered some the most difficult to treat—those who have not achieved a cure with a previous course of a direct acting antiviral medication, those with cirrhosis, and people with resistant antiviral variants (RAVs). 
Editorial Comment
The addition of ledipasvir and ribavirin to sofosbuvir increased the cure rates to 100% for genotype 1.  Excellent results!  This is a good strategy with another type of direct acting antiviral to stop the virus from replicating and escaping.
Gilead, Merck, AbbVie, Janssen, and Achillion are working on other HCV drugs that have a higher barrier to resistance to avoid the development of resistance and to work for people who are not responding to the current medications.
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Tagged cirrhosis, elbasvir, Genotype 1, genotype 1a, Genotype 3, grazoprevir, ledipasvir, Liver Transplant, NS5A inhibitor, pegylated interferon, RAV, ribavirin, Sofosbuvir

FDA approves new treatment for chronic hepatitis C genotype 3 infections

Hepatitis C Blog Posted on July 24, 2015 by HCV AdvocateDecember 1, 2015

The Food and Drug Administration today approved Daklinza
(daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV)
genotype 3 infections. Daklinza is the first drug that has demonstrated
safety and efficacy to treat genotype 3 HCV infections without the need
for co-administration of interferon or ribavirin, two FDA-approved drugs
also used to treat HCV infection.

Hepatitis C is a viral disease
that causes inflammation of the liver that can lead to diminished liver
function or liver failure. Most people infected with HCV have no
symptoms of the disease until liver damage becomes apparent, which may
take several years. Some people with chronic HCV infection develop
scarring and poor liver function (cirrhosis) over many years, which can
lead to complications such as bleeding, jaundice (yellowish eyes or
skin), fluid accumulation in the abdomen, infections or liver cancer.
According to the Centers for Disease Control and Prevention,
approximately 2.7 million Americans are infected with HCV of which,
approximately 10 percent are genotype 3.

“Today’s approval
provides a new option for patients with genotype 3 HCV, including those
patients who cannot tolerate ribavirin,” said Edward Cox, M.D., director
of the Office of Antimicrobial Products in the FDA’s Center for Drug
Evaluation and Research.

The safety and efficacy of Daklinza in
combination with sofosbuvir were evaluated in a clinical trial of 152
treatment-naive and treatment-experienced participants with chronic HCV
genotype 3 infection. Participants received Daklinza 60 mg plus
sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24
weeks post treatment. The studies were designed to measure whether a
participant’s hepatitis C virus was no longer detected in the blood 12
weeks after finishing treatment (sustained virologic response),
suggesting a participant’s infection had been cured.

Results
showed that 98 percent of the treatment-naive participants with no
cirrhosis of the liver and 58 percent of the treatment-naive
participants with cirrhosis achieved sustained virologic response. Of
the participants who were treatment-experienced, 92 percent with no
cirrhosis of the liver and 69 percent with cirrhosis achieved sustained
virologic response. Daklinza labeling carries a Limitations of Use
statement to inform prescribers that sustained virologic response rates
are reduced in HCV genotype 3 infected patients with cirrhosis.

Safety
information was available for approximately 1,900 patients with HCV
treated with the recommended dose of Daklinza in combination with other
anti-HCV drugs in clinical trials. The most common side effects of
Daklinza with sofosbuvir were fatigue and headache.

Daklinza
carries a warning for patients and health care providers that serious
slowing of the heart rate (symptomatic bradycardia) and cases requiring
pacemaker intervention have been reported when amiodarone is
co-administered with sofosbuvir in combination with another HCV
direct-acting antiviral, including Daklinza. Co-administration of
amiodarone with Daklinza in combination with sofosbuvir is not
recommended.

Daklinza was reviewed under the FDA’s priority review
program, which provides for an expedited review of drugs that treat
serious conditions and, if approved, would provide significant
improvement in safety or effectiveness.

Daklinza is marketed by Bristol-Myers Squibb, based in Princeton, New Jersey.

The
FDA, an agency within the U.S. Department of Health and Human Services,
protects the public health by assuring the safety, effectiveness, and
security of human and veterinary drugs, vaccines and other biological
products for human use, and medical devices. The agency also is
responsible for the safety and security of our nation’s food supply,
cosmetics, dietary supplements, products that give off electronic
radiation, and for regulating tobacco products.

Press Release Source:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455888.htm

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Tagged daklinza + sofosbuvir, FDA Approval, Genotype 3, GT3

FDA approves new treatment for chronic hepatitis C genotype 3 infections

Hepatitis C Blog Posted on July 24, 2015 by HCV AdvocateDecember 13, 2015

The Food and Drug Administration today approved Daklinza (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, approximately 2.7 million Americans are infected with HCV of which, approximately 10 percent are genotype 3.

“Today’s approval provides a new option for patients with genotype 3 HCV, including those patients who cannot tolerate ribavirin,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

The safety and efficacy of Daklinza in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis.

Safety information was available for approximately 1,900 patients with HCV treated with the recommended dose of Daklinza in combination with other anti-HCV drugs in clinical trials. The most common side effects of Daklinza with sofosbuvir were fatigue and headache.

Daklinza carries a warning for patients and health care providers that serious slowing of the heart rate (symptomatic bradycardia) and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct-acting antiviral, including Daklinza. Co-administration of amiodarone with Daklinza in combination with sofosbuvir is not recommended.

Daklinza was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Daklinza is marketed by Bristol-Myers Squibb, based in Princeton, New Jersey.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Press Release Source:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455888.htm

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Tagged daklinza + sofosbuvir, FDA Approval, Genotype 3, GT3

Genotype 3: An Unmet Treatment Need for Some, by Alan Franciscus, Editor-in-Chief

Hepatitis C Blog Posted on July 21, 2015 by HCV AdvocateDecember 1, 2015
 Originally Published June 15, 2015
 
While conducting a workshop in New England, I was
asked a question about genotype 3 treatment for people who are
treatment experienced and had cirrhosis—a question I am frequently
asked.  At this time, we do not have an interferon-free treatment with
high cure rates for this particular group of people with hepatitis C. 
This is an unmet medical need for a large group of people in the United
States and Worldwide.  I am asked this question at almost every
workshop, which surprises me. 
There are many drugs in
development that hold the promise to solve this problem.  In the
meantime, there is a solution—the combination of Sovaldi, pegylated
interferon and ribavirin.   When I bring up interferon, I get the cringe
reaction.  It is a very understandable reaction. However, there are a
couple of serious points to consider:
  • Cirrhosis can be a
    life-threatening event.  You do not want to wait—If you have genotype 3
    and cirrhosis you should consider taking action now
  • Genotype 3 leads to the formation of steatosis (fatty liver)—successful treatment reduces or eliminates steatosis
  • Steatosis can accelerate HCV disease progression—by itself steatosis can lead to cirrhosis
  • People with genotype 3 are at increased the risk for liver disease progression and liver cancer
  • Pegylated interferon and ribavirin can be difficult to tolerate, but the majority of side effects occur after 12 weeks
  • The side effects of pegylated
    interferon and ribavirin can be managed successfully especially if the
    medical provider and patient are proactive
Interferon-Free Therapy
The current standard of care for genotype 3 is the
combination of Sovaldi (sofosbuvir) plus ribavirin for 24 weeks.  The
cure rates for treatment experienced patients without cirrhosis are
85%, but for treatment experienced patients with cirrhosis the cure
rates are 60%.  Clearly, genotype 3 patients who are treatment
experienced with cirrhosis are in need of better treatment options.  I
have listed below two studies that include treatment of Sovaldi,
pegylated interferon plus ribavirin.  Note:  I only
included the information about the cure rates of the genotype 3
treatment experience patients with cirrhosis treated for 12 weeks.
Sovaldi/Peg/RBV
A recently published study in Hepatology
“Sofosbuvir with Peginterferon-Ribavirin for 12 Weeks in Previously
Treated Patients with Hepatitis C Genotype 2 or 3 and Cirrhosis,” –E
Lawitz et al. showed very high cure rates. 
Note:  There were 47 genotype 2 and 3 patients included in the study.  Only genotype 3 results are listed below. 
There were a total of 24
genotype 3 patients with and without cirrhosis.  All were treated for
12 weeks with Sovaldi (sofosbuvir), pegylated interferon plus
ribavirin. 
The cure rates were the same for
those with cirrhosis 83% (10 of 12 pts) and without 83% (10 of 12 pts)
in the genotype 3 patients. 
The second study was presented
at EASL 2015 “Sofosbuvir Plus Peg-IFN/RBV for 12 Weeks vs
Sofosbuvir/RBV for 16 or 24 Week in Genotype 3 HCV Infected Patients
and Treatment-Experienced Cirrhotic Patients with Genotype 2 HCV:  The
BOSON Study,” –R Graham et al. 
Note:  This
study was a large study of 592 genotype 3 treatment naïve/experienced
patients without and without cirrhosis.  I will only list the treatment
experienced patients with cirrhosis who were treated for 12 weeks with
Sovaldi (sofosbuvir), pegylated interferon plus ribavirin and the
comparator arm of the treatment experienced patients with cirrhosis who
received Sovaldi plus ribavirin without pegylated interferon. 
After 12 weeks of treatment the
group of patients who were treated with Sovaldi, pegylated interferon
plus ribavirin achieved a cure rate of 86% (30 of 35 pts) compared to a
cure rate of 47% (17 of 36 pts) for those who received Sovaldi plus
ribavirin but without pegylated interferon. 
The most common side effects were flu-like symptoms, fatigue, and anemia. 

 
Comments: The
addition of pegylated interferon to Sovaldi and ribavirin almost
doubled the cure rates for people with genotype 3 in both studies who
had cirrhosis and who were treatment experience.  The best strategy is
to talk with your medical provider and come up with a plan to get
treated as soon as possible, seek a possible cure and stop hepatitis C
in its tracks.

http://hcvadvocate.org/news/newsLetter/2015/advocate0615_mid.html#2

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Tagged Genotype 3, GT3

Genotype 3: An Unmet Treatment Need for Some, by Alan Franciscus, Editor-in-Chief

Hepatitis C Blog Posted on July 21, 2015 by HCV AdvocateDecember 13, 2015
 Originally Published June 15, 2015
 
While conducting a workshop in New England, I was asked a question about genotype 3 treatment for people who are treatment experienced and had cirrhosis—a question I am frequently asked.  At this time, we do not have an interferon-free treatment with high cure rates for this particular group of people with hepatitis C.  This is an unmet medical need for a large group of people in the United States and Worldwide.  I am asked this question at almost every workshop, which surprises me. 
There are many drugs in development that hold the promise to solve this problem.  In the meantime, there is a solution—the combination of Sovaldi, pegylated interferon and ribavirin.   When I bring up interferon, I get the cringe reaction.  It is a very understandable reaction. However, there are a couple of serious points to consider:
  • Cirrhosis can be a life-threatening event.  You do not want to wait—If you have genotype 3 and cirrhosis you should consider taking action now
  • Genotype 3 leads to the formation of steatosis (fatty liver)—successful treatment reduces or eliminates steatosis
  • Steatosis can accelerate HCV disease progression—by itself steatosis can lead to cirrhosis
  • People with genotype 3 are at increased the risk for liver disease progression and liver cancer
  • Pegylated interferon and ribavirin can be difficult to tolerate, but the majority of side effects occur after 12 weeks
  • The side effects of pegylated interferon and ribavirin can be managed successfully especially if the medical provider and patient are proactive
Interferon-Free Therapy
The current standard of care for genotype 3 is the combination of Sovaldi (sofosbuvir) plus ribavirin for 24 weeks.  The cure rates for treatment experienced patients without cirrhosis are 85%, but for treatment experienced patients with cirrhosis the cure rates are 60%.  Clearly, genotype 3 patients who are treatment experienced with cirrhosis are in need of better treatment options.  I have listed below two studies that include treatment of Sovaldi, pegylated interferon plus ribavirin.  Note:  I only included the information about the cure rates of the genotype 3 treatment experience patients with cirrhosis treated for 12 weeks.
Sovaldi/Peg/RBV
A recently published study in Hepatology “Sofosbuvir with Peginterferon-Ribavirin for 12 Weeks in Previously Treated Patients with Hepatitis C Genotype 2 or 3 and Cirrhosis,” –E Lawitz et al. showed very high cure rates. 
Note:  There were 47 genotype 2 and 3 patients included in the study.  Only genotype 3 results are listed below. 
There were a total of 24 genotype 3 patients with and without cirrhosis.  All were treated for 12 weeks with Sovaldi (sofosbuvir), pegylated interferon plus ribavirin. 
The cure rates were the same for those with cirrhosis 83% (10 of 12 pts) and without 83% (10 of 12 pts) in the genotype 3 patients. 
The second study was presented at EASL 2015 “Sofosbuvir Plus Peg-IFN/RBV for 12 Weeks vs Sofosbuvir/RBV for 16 or 24 Week in Genotype 3 HCV Infected Patients and Treatment-Experienced Cirrhotic Patients with Genotype 2 HCV:  The BOSON Study,” –R Graham et al. 
Note:  This study was a large study of 592 genotype 3 treatment naïve/experienced patients without and without cirrhosis.  I will only list the treatment experienced patients with cirrhosis who were treated for 12 weeks with Sovaldi (sofosbuvir), pegylated interferon plus ribavirin and the comparator arm of the treatment experienced patients with cirrhosis who received Sovaldi plus ribavirin without pegylated interferon. 
After 12 weeks of treatment the group of patients who were treated with Sovaldi, pegylated interferon plus ribavirin achieved a cure rate of 86% (30 of 35 pts) compared to a cure rate of 47% (17 of 36 pts) for those who received Sovaldi plus ribavirin but without pegylated interferon. 
The most common side effects were flu-like symptoms, fatigue, and anemia. 

 
Comments: The addition of pegylated interferon to Sovaldi and ribavirin almost doubled the cure rates for people with genotype 3 in both studies who had cirrhosis and who were treatment experience.  The best strategy is to talk with your medical provider and come up with a plan to get treated as soon as possible, seek a possible cure and stop hepatitis C in its tracks.

http://hcvadvocate.org/news/newsLetter/2015/advocate0615_mid.html#2

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Tagged Genotype 3, GT3

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