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GT 1 OR 3 Advanced Cirrhosis
and Post-transplant
Efficacy & Study Design

ALLY 1 Study Design: Advanced cirrhosis/post-transplant1,2

A phase 3, open-label, two-cohort (advanced cirrhosis in GT 1-4 and post-transplant in GT 1, 3, 6), 12-week study* to assess the efficacy of treatment in 113 chronic HCV patients taking Daklinza plus sofosbuvir and ribavirin.

*Subjects were monitored for 24 weeks after the end of treatment.
Patients with chronic HCV GT 1-6 were allowed to enroll in both cohorts.
Starting at ≤600 mg/day, ribavirin dosage was adjusted as needed based on Hgb levels and CrCl.

Immunosuppressives included: cyclosporine, tacrolimus, sirolimus, and mycophenolic acid.

Primary endpoint: Sustained viral response§ at post-treatment Week 12 (SVR12) in each cohort of patients with genotype 1 infection treated for 12 weeks (82% SVR12 in advanced cirrhotics and 95% in post-transplants).

§SVR defined as HCV RNA <25 IU per milliliter

Selected secondary endpoints: SVR12 for each individual GT 2, 3, 4, 5, 6 in both cohorts.

Selected subject inclusion criteria: Age ≥18 years, HCV infection (any genotype), direct-acting antiviral therapy failures allowed except NS5A. For patients with advanced cirrhosis: Child-Pugh score A, B, or C; model for end-stage liver disease (MELD) score 8-40; hepatocellular carcinoma allowed. For post-liver transplant patients: ≥3 months post-transplant; no evidence of rejection at time of enrollment; the following immunosuppressants were studied in ALLY 1: cyclosporine, tacrolimus, sirolimus, everolimus, corticosteriods, mycophenolate mofetil (mycophenolic acid).

Available data from ALLY 1 on GT 2 (n=5) and 4 (n=4) in the advanced cirrhosis cohort, and GT 6 (n=1) in the post-transplant cohort, were insufficient to provide treatment recommendations, and efficacy results for these genotypes are not included in the Daklinza PI.

ALLY 1 Baseline Characteristics

Efficacy in advanced cirrhotic patients in ALLY 1**

82% SVR12 in GT 1 advanced cirrhotic patients with 12 weeks of treatment

  • 83% SVR12 in difficult-to-treat GT 3 advanced cirrhotics
  • SVR12 rates were comparable regardless of gender, age, baseline HCV RNA levels, or IL28B status

**Available data from ALLY 1 on GT 2 (n=5) and 4 (n=4) in the advanced cirrhosis cohort, and GT 6 (n=1) in the post-transplant cohort, were insufficient to provide treatment recommendations, and efficacy results for these genotypes are not included in the Daklinza PI.
aSVR defined as HCV RNA <25 IU per milliliter.

93% SVR12 achieved in GT 1 & 3 Child-Pugh B1,2

aSVR defined as HCV RNA <25 IU per milliliter.
b77% of GT 1 & 3 Child-Pugh C patients in the ALLY 1 study had a MELD score >15; 23% were ≥20.

Efficacy in post-transplant patients in ALLY 1††

95% SVR12 in GT 1 post-transplant patients with 12 weeks of treatment1

  • 91% SVR12 achieved in GT 3 patients
  • SVR12 rates were comparable regardless of gender, age, baseline HCR RNA levels, or IL28B status

††Available data on subjects with GT 6 (n=1) are insufficient to provide treatment recommendations. Daklinza is indicated to treat GT 1 & 3.
aSVR defined as HCV RNA <25 IU per milliliter.

Learn more about Daklinza and the ALLY studies:

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

  • Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Daklinza. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate management for HBV infection as clinically indicated.

CONTRAINDICATIONS

  • When used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen; refer to the respective prescribing information.
  • 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 Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV (additional information): HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation may be increased in these patients.
  • 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 5.3 of the prescribing information.
    • 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.
    • Bradycardia generally resolved after discontinuation of HCV treatment.
  • Risks Associated with Ribavirin Combination Treatment: If ribavirin is used as part of the regimen, the warnings and precautions for ribavirin, particularly the pregnancy avoidance warning, apply. See the ribavirin full prescribing information for complete information.

ADVERSE REACTIONS

  • In clinical trials (ALLY 2, 3) with the Daklinza and sofosbuvir regimen, the most common adverse reactions (≥5%) were, respectively: headache (8%, 14%), fatigue (15%, 14%), nausea (9%, 8%), diarrhea (7%, 5%).
  • In clinical trials (ALLY 1) with Daklinza, in combination with sofosbuvir and ribavirin, the most common adverse reactions (≥5%) were, in the cirrhosis cohort and the post-liver transplantation cohort, respectively: headache (12%, 30%), anemia (20%, 19%), fatigue (15%, 17%), nausea (15%, 6%), rash (8%, 2%), diarrhea (3%, 6%), insomnia (3%, 6%), dizziness (0, 6%), somnolence (5%, 0).

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 Sections 4, 7, and 12.3 of the Daklinza Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations. Refer to the prescribing information for other agents in the regimen for drug interaction information.

DAKLINZA IN PREGNANCY

  • No adequate human data are available to determine whether or not Daklinza poses a risk to pregnancy outcomes. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity.
  • If Daklinza and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to the ribavirin prescribing information.

LACTATION

  • It is not known whether Daklinza is present in human milk, affects human milk production, or has effects on the breastfed infant. Daklinza was present in the milk of lactating rats. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Daklinza and any potential adverse effects on the breastfed child from Daklinza or from the underlying condition.
  • When Daklinza is administered with ribavirin, the nursing mothers' information for ribavirin also applies to this combination regimen. Refer to the nursing mothers' information in the ribavirin prescribing information.

Please see
Full Prescribing Information, including Boxed WARNING.

References: 1. Daklinza [package insert]. Princeton, NJ; Bristol-Myers Squibb Company. 2. Ampuero J, Romero-Gomez J-M, Reddy KR. HCV genotype 3: the new treatment challenge. Aliment Pharmacol Ther. 2014;39(7):686-698. 3. Kanwal F, Kramer JR. Ilyas J, et al. HCV genotype 3 is associated with an Increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. veterans with HCV. Hepatology. 2014;60:98-105. 4. Tapper EB, Afdhal NH. Is 3 the new 1: perspectives on virology, natural history and treatment for hepatitis C genotype 3. J Virol Hepat. 2013;20:669-677. 5. Rockstroh JK, Bhagani S. Managing HIV/hepatitis C co-infection in the era of direct acting antivirals. BMC Medicine. 2013;11:234-243. 6. Thein H-H, Yi Q, Dore GJ, Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS. 2008;22:1979 -1991. 7. Gambato M, Lens S, Navasa M, Forns X. Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation. Journal of Hepatology. 2014;61:S120 -S131. 8. Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. Journal of Hepatology. 2013;58:1028 -41. 9. Demetris A. Evolution of hepatitis C virus in liver allografts. Liver Transplantation. 2009;15(2):S35-S41

Reference: 1. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb.

References: 1. Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci. 2013;110(10):3991-3996. 2. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.

References: 1. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral, 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61(4):1127-1135.

References: 1. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral, 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase 3 study. Hepatology. 2015;61(4):1127-1135. doi:10.1002/hep.27726. 2. Daklinza (daclatasvir) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 3. Data on file, DACL 032, Bristol-Myers Squibb Company. 4. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725. 5. Supplementary Appendix to Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725. 6. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir, Sofosbuvir, and Ribavirin Combination for HCV Patients with Advanced Cirrhosis or Post-transplant Recurrence: ALLY-1 Phase 3 Study. Presented at The International Liver Congress 2015, 50th Annual Meeting of the European Association for the Study of the Liver: April 22-26, 2015; Vienna, Austria.

References: 1. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral, 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase 3 study. Hepatology. 2015;61(4):1127-1135. doi:10.1002/hep.27726. 3. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725. 4. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir, Sofosbuvir, and Ribavirin Combination for HCV Patients with Advanced Cirrhosis or Post-transplant Recurrence: ALLY-1 Phase 3 Study. Presented at The International Liver Congress 2015, 50th Annual Meeting of the European Association for the Study of the Liver: April 22-26, 2015; Vienna, Austria.

References: 1. Daklinza [package insert]. Princeton, NJ; Bristol-Myers Squibb. 2. Eley T, You X, Wang R, et al. Daclatasvir: Overview of drug-drug interactions with antiretroviral agents and other common concomitant drugs. HIV DART: Frontiers in Drug Development for Antiretroviral Therapies. Miami, FL; December 9-12, 2014. Poster 63. 3. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725.

References: 1. Daklinza [package insert]. Princeton, NJ; Bristol-Myers Squibb. 2. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725. 3. Supplement to Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725. 4. Eley T, You X, Wang R, et al. Daclatasvir: Overview of drug-drug interactions with antiretroviral agents and other common concomitant drugs. HIV DART: Frontiers in Drug Development for Antiretroviral Therapies. Miami, FL; December 9-12, 2014. Poster 63.

References: 1. Daklinza [package insert]. Princeton, NJ; Bristol-Myers Squibb. 2. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725.

References: 1. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for HCV infection with advanced cirrhosis or post-liver transplant recurrence. Hepatology. In press. doi:10.1002/hep.28446.

References: 1. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for HCV infection with advanced cirrhosis or post-liver transplant recurrence. Hepatology. In press. doi:10.1002/hep.28446.

Reference: 1. Daklinza [package insert]. Princeton, NJ; Bristol-Myers Squibb.

References: 1. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2. Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc. 3. Rebetol [package insert]. Whitehouse Station, NJ: Merck & Co. 4. Eley T, You X, Wang RL, et al. Daclatasvir: Overview of drug-drug interactions with antiretroviral agents and other common concomitant drugs. HIV DART: Frontiers in Drug Development for Antiretroviral Therapies. Miami, FL; December 9-12, 2014. Poster 63. 5. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725.

1392US1502415-03-02 05/16

More Important Safety Information 

SELECTED IMPORTANT SAFETY INFORMATION

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

  • Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Daklinza. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate management for HBV infection as clinically indicated.

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 Sections 4, 7, and 12.3 of the Daklinza Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations. Refer to the prescribing information for other agents in the regimen for drug interaction information.

DAKLINZA IN PREGNANCY

  • No adequate human data are available to determine whether or not Daklinza poses a risk to pregnancy outcomes. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity.
  • If Daklinza and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to the ribavirin prescribing information.

LACTATION

  • It is not known whether Daklinza is present in human milk, affects human milk production, or has effects on the breastfed infant. Daklinza was present in the milk of lactating rats. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Daklinza and any potential adverse effects on the breastfed child from Daklinza or from the underlying condition.
  • When Daklinza is administered with ribavirin, the nursing mothers' information for ribavirin also applies to this combination regimen. Refer to the nursing mothers' information in the ribavirin prescribing information.

WARNINGS AND PRECAUTIONS (continued)

  • Risks Associated with Ribavirin Combination Treatment: If ribavirin is used as part of the regimen, the warnings and precautions for ribavirin, particularly the pregnancy avoidance warning, apply. See the ribavirin full prescribing information for complete information.

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.

ADVERSE REACTIONS

  • In clinical trials (ALLY 2, 3) with the Daklinza and sofosbuvir regimen, the most common adverse reactions (≥5%) were, respectively: headache (8%, 14%), fatigue (15%, 14%), nausea (9%, 8%), diarrhea (7%, 5%).
  • In clinical trials (ALLY 1) with Daklinza, in combination with sofosbuvir and ribavirin, the most common adverse reactions (≥5%) were, in the cirrhosis cohort and the post-liver transplantation cohort, respectively: headache (12%, 30%), anemia (20%, 19%), fatigue (15%, 17%), nausea (15%, 6%), rash (8%, 2%), diarrhea (3%, 6%), insomnia (3%, 6%), dizziness (0, 6%), somnolence (5%, 0).

WARNINGS AND PRECAUTIONS (continued)

  • 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.

WARNINGS AND PRECAUTIONS

  • Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV (additional information): HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation may be increased in these patients.

CONTRAINDICATIONS

  • When used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen; refer to the respective prescribing information.
  • 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

  • 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.

CONTRAINDICATIONS

  • When used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen; refer to the respective prescribing information.
  • 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 (continued)

  • 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 5.3 of the prescribing information.
    • 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.
    • Bradycardia generally resolved after discontinuation of HCV treatment.

ADVERSE REACTIONS

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