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All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase 3 Study
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Download the PDF here
Scroll down below study to see- European Medicines Agency. Daklinza (daclatasvir) summary of product characteristics. Package leaflet: Information for the patient
Daklinza 60 mg film-coated tablets
daclatasvir
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AASLD: All-Oral 12-Week Combination Treatment With Daclatasvir and Sofosbuvir in Patients Infected With HCV Genotype 3: ALLY-3 Phase 3 Study - (11/11/14)
Study to Evaluate the Safety and Efficacy of Daclatasvir/Sofosbuvir/Ribavirin for 16 Versus 24 Weeks for HCV Genotype 3 Cirrhotics - (01/12/15)
AASLD: High Efficacy of LDV/SOF Regimens for 12 Weeks for Patients With HCV Genotype 3 or 6 Infection - (11/11/14)
AASLD: High Efficacy of Treatment With Sofosbuvir + GS-5816 ± Ribavirin for 12 Weeks in Treatment-Experienced Patients With Genotype 1 or 3 HCV Infection - (11/12/14)
AASLD: Safety and Efficacy of Treatment with Sofosbuvir + GS-5816 ± Ribavirin for 8 or 12 Weeks in Treatment-Na•ve Patients with Genotype 1-6 HCV Infection - (11/10/14)
AASLD: Once-Daily Sofosbuvir With GS-5816 for 8 Weeks With or Without Ribavirin in Patients With HCV Genotype 3 Without Cirrhosis Result in High Rates of SVR12: The ELECTRON-2 Study - (11/10/14)
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All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase 3 Study
Hepatology
Accepted Article
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record
23 JAN 2015
Authors: David R. Nelson,1 James N. Cooper,2 Jacob P. Lalezari,3 Eric Lawitz,4 Paul J.
Pockros,5 Norman Gitlin,6 Bradley F. Freilich,7 Ziad H. Younes,8 William Harlan,9 Reem Ghalib,10
Godson Oguchi,11 Paul J. Thuluvath,12 Grisell Ortiz-Lasanta,13 Mordechai Rabinovitz,14 David
Bernstein,15 Michael Bennett,16 Trevor Hawkins,17 Natarajan Ravendhran,18 Aasim M. Sheikh,19
Peter Varunok,20 Kris V. Kowdley,21 Delphine Hennicken,22 Fiona McPhee,23 Khurram Rana,24
Eric A. Hughes,25 on behalf of the ALLY-3 Study Team
Abstract
Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin.
This phase 3 study (ALLY-3; http://www.ClinicalTrials.gov NCT02032901) evaluated the 12-week regimen of daclatasvir (pangenotypic NS5A inhibitor) plus sofosbuvir (pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment-naive (n=101) or treatment-experienced (n=51) and received daclatasvir 60mg plus sofosbuvir 400mg once daily for 12 weeks.
Co-primary endpoints were the proportions of treatment-naive and treatment-experienced patients achieving a sustained virologic response at posttreatment Week 12 (SVR12). SVR12 rates were 90% (91/101) and 86% (44/51) in treatment-naive and treatment-experienced patients, respectively; no virologic breakthrough was observed, and ≥99% of patients had a virologic response at the end of treatment.
SVR12 rates were higher in patients without cirrhosis (96% [105/109]) than in those with cirrhosis (63% [20/32]).
Five of 7 patients who previously failed treatment with a sofosbuvir-containing regimen and 2 of 2 patients who previously failed treatment with an alisporivir-containing regimen achieved SVR12.
Baseline characteristics, including gender, age, HCV RNA levels, and IL28B genotype, did not impact virologic outcome. Daclatasvir plus sofosbuvir was well tolerated; there were no adverse events leading to discontinuation and only 1 serious adverse event on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient.
Conclusion: A 12-week regimen of daclatasvir plus sofosbuvir achieved SVR12in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway. This article is protected by copyright. All rights reserved.
The relationship between resistance-associated variants (RAVs) at NS5A amino acid positions M28, A30, L31, and Y93 at baseline and SVR12 was assessed. No patients had L31 polymorphisms at baseline; one patient without cirrhosis had M28V at baseline and achieved SVR12. NS5A-A30 polymorphisms were detected in 14 of 147 patients at baseline. Of the 14 patients with A30 polymorphisms, 9 of 9 patients without cirrhosis and 1 of 5 with cirrhosis achieved SVR12. Among the 4 cirrhotic patients with baseline A30 polymorphisms who did not achieve SVR12, 2 also had Y93H at baseline, 1 had A30T which has no effect on daclatasvir potency in vitro, and 1 had A30K which was associated with SVR12 in the 5 remaining patients with this polymorphism.18 NS5A-Y93H was detected in 13 of 147 patients who had NS5A sequence at baseline; of these 13 patients, 6 of 9 patients without cirrhosis and 1 of 4 patients with cirrhosis achieved SVR12. No NS5B RAVs were detected at amino acid positions associated with resistance to sofosbuvir (159, 282, or 321) at baseline.
SVR12 rates with daclatasvir plus sofosbuvir were higher in patients without cirrhosis than in those with cirrhosis, and in patients with a fibrosis stage (based on FibroTest scores) of F0 to F3 than in those with F4. However, the 63% SVR12 rate in patients with cirrhosis is comparable to that achieved with 16 weeks (61%) or 24 weeks (67%) of sofosbuvir plus ribavirin, with the advantages of an interferon-free and shorter-duration regimen.7 On-treatment and end-of-treatment response rates were similar in patients with or without cirrhosis, with relapse accounting for all but one of the treatment failures: among the 16 patients with relapse, 11 had cirrhosis. Relapse was more frequent in the 4 patients with cirrhosis who had Y93H RAVs at baseline, although these RAVs did not measurably affect on-treatment response. Other possible reasons for the higher relapse rate in genotype 3-infected patients with cirrhosis remain uncertain. Since high relapse rates have also been observed with other all-oral regimens following treatment of genotype 3 infection,14,18 this HCV genotype may be more difficult than others to eradicate with direct-acting antivirals, particularly in patients with cirrhosis. Multiple factors may contribute to this effect and require further study.
The robust on-treatment virologic response with daclatasvir plus sofosbuvir, with nearly all virologic failures due to posttreatment relapse, suggests that optimizing treatment outcomes in patients with cirrhosis could include the addition of ribavirin or a longer treatment duration. A randomized study has been initiated (http://www.ClinicalTrials.gov NCT02319031)19 in which patients with genotype 3 infection and compensated advanced cirrhosis are receiving daclatasvir in
combination with sofosbuvir and ribavirin for 12 or 16 weeks, with the objective of determining whether adding ribavirin and extending treatment will improve the durability of response posttreatment. This strategy has been successful with other all-oral regimens. A recent report regarding a phase 2 study of sofosbuvir plus GS-5816, with or without ribavirin, suggests that the addition of ribavirin improves response rates in genotype 3Šinfected patients with cirrhosis. In treatment-experienced patients with cirrhosis treated for 12 weeks, SVR12 rates were higher with sofosbuvir plus GS-5816 with the addition of ribavirin (85%-96%) than with sofosbuvir plus GS-5816 alone (58%-88%).20 The combination of ledipasvir plus sofosbuvir with ribavirin for 12 weeks has been reported to provide SVR12 rates of 89% in genotype 3Šinfected, treatment-experienced patients without cirrhosis and a lower rate of 77% in those with cirrhosis.21 Because daclatasvir has shown greater potency in vitro against genotype 3 compared with ledipasvir,11, 22-24 the combination of daclatasvir plus sofosbuvir, with the addition of ribavirin, may be expected to provide improved response rates relative to the current results in patients with
cirrhosis. Daclatasvir plus sofosbuvir, with or without ribavirin, is also being evaluated in additional patient populations with high unmet medical needs in other studies of the ALLY phase 3 program. These include patients who have cirrhosis or who are postŠliver transplant (ALLY-1; ClinicalTrials.gov NCT02032875) and patients who are coinfected with HIV (ALLY-2; ClinicalTrials.gov NCT02032888). Daclatasvir has been approved in combination with other anti-HCV agents in Europe and Japan.
European Medicines Agency. Daklinza (daclatasvir) summary of product characteristics.
2014; http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003768/WC500172848.pdf.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003768/WC500172848.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003768/WC500172848.pdf
Package leaflet: Information for the patient
Daklinza 60 mg film-coated tablets
daclatasvir
Download the PDF here
Daklinza is indicated in combination with other medicinal products for the treatment of chronic
hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1).
Antiviral activity in cell culture
Daclatasvir is an inhibitor of HCV genotypes 1a and 1b replication in cell-based replicon assays with effective concentration (50% reduction, EC50) values of 0.003-0.050 and 0.001-0.009 nM, respectively, depending on the assay method. The daclatasvir EC50 values in the replicon system were 0.003-1.25 nM for genotypes 3a, 4a, 5a and 6a, and 0.034-19 nM for genotype 2a as well as 0.020 nM for infectious genotype 2a (JFH-1) virus.
Daclatasvir showed additive to synergistic interactions with interferon alfa, HCV nonstructural protein 3 (NS3) protease inhibitors, HCV nonstructural protein 5B (NS5B) non-nucleoside inhibitors, and HCV NS5B nucleoside analogues in combination studies using the cell-based HCV replicon system. No antagonism of antiviral activity was observed.
No clinically relevant antiviral activity was observed against a variety of RNA and DNA viruses, including HIV, confirming that daclatasvir, which inhibits a HCV-specific target, is highly selective for HCV.
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