Daclatasvir: The First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A

Curr Med Chem. 2013 Dec 28. [Epub ahead of print]

Gentile I, Borgia F, Coppola N, Buonomo AR, Castaldo G, Borgia G.

Abstract

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. It is treated with pegylated-interferon (peg-IFN) and ribavirin, and in the case of patients affected by genotype 1, also with a protease inhibitor (telaprevir or boceprevir). Despite a good success rate, IFN-based combinations are contraindicated in several patients (e.g. decompensated cirrhosis, patients with psychiatric disorders, severe heart diseases or autoimmune disorders) and are associated with frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase of clinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical data regarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profile is good. Clinical data regarding its efficacy in combination with peg-IFN, ribavirin or other direct antiviral agents are impressive (rates of sustained virological response range between 60% and 100% in treatment-naïve patients). The only drawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially in combinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C.

PMID: 24372205 [PubMed - as supplied by publisher]

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Mathematical modeling: A tool for selecting agents with complementary modes of action?

Journal of Hepatology

Volume 59, Issue 6 , Pages 1346-1348, December 2013

Sylvie Deuffic-Burban, Yazdan Yazdanpanah

Received 24 June 2013; received in revised form 14 July 2013; accepted 15 July 2013. published online 29 July 2013.

Keywords: Direct-acting antiviral agents, Mathematical modeling, Viral dynamics

COMMENTARY ON:

Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Guedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, Layden TJ, Uprichard SL, Perelson AS. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3991–6. Copyright © 2013. Abstract reprinted with permission from the National Academy of Sciences.

http://www.ncbi.nlm.nih.gov/pubmed/23431163

Abstract. The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir’s mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6–9h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.

Chronic hepatitis affects nearly 3% of the world population [1]. The landscape of therapy for hepatitis C virus (HCV) infection, where treatment was still suboptimal until recently, is changing rapidly. Specific proteins involved in the replication of the virus have been identified and targeted by drug development. Among these, we can enumerate non-structural (NS) viral proteins with known enzymatic functions, such as the NS3/4A protease [2], [3], and the NS5B polymerase [4], [5] but also non-enzymatic targets such as NS5A proteins [6]. The mode of action of HCV drugs targeting these proteins is not always understood. For example, the mode of action of Daclatasvir (BMS-790052), one of the most promising and expected molecules identified as a potent NS5A inhibitor, is not known [6], [7]. This is related to the uncertain nature of the molecular mechanisms by which NS5A functions and the absence of direct screening assays for NS5A function.

One means of uncovering an antiviral agent’s mode of action is to analyze the kinetics of the response it generates using mathematical modeling. This approach was initiated by Perelson et al. in HIV by characterizing the decline in HIV during antiretroviral therapy [8], [9] and it was then successfully applied to understand HCV kinetics during therapy [10]. In these models, the infected cell is treated as a “black box” that produces/secretes virus particles, which then either are cleared or infect new target cells, and the effect of treatment is to block virus production from infected cells [10]. Clearly, one limitation of these models is that it does not take into account the stages of the (intracellular) viral lifecycle that are yet the main target of DAAs. In a recent study published in PNAS, Guedj et al. introduced a novel generation of models, called “multiscale models” that, in contrast to the standard model, takes into account the dynamics of the intracellular viral RNA and identifies some essential stages of viral replication that can be affected by treatment, namely virion assembly/secretion, viral RNA production, and vRNA degradation (Fig. 1) [11].

Fig. 1. Presentation of the standard and multi-scale model of HCV dynamics, and parameter estimates obtained to fit data from patients treated with daclatasvir[11]. In both models, T and I represent target and infected cells, respectively, and V represents virus. Target cells are created and die with constant rates, s and d, respectively, and are infected by virus, V, with constant rate β. Infected cells, I, are lost with constant rate δ, and virus, V, is cleared from serum with constant rate c. (A) The standard model considers only the level of cell infection and virus in the serum. Treatment (parameters in red) acts by reducing the average number of virions produced by infected cells from p to (1−ε)p. Thus, ε represents a global measure of antiviral effectiveness that does not distinguish the stages of intracellular viral replication that are blocked by treatment. The main estimates are c=23.3d⁻¹, ε=0.997, δ=1.06d⁻¹. (B) The multi-scale model was designed to account for essential features of intracellular HCV RNA replication, R, i.e., production, degradation, and assembly/secretion with rates α, μ, and ρ, respectively. The HCV RNA level within an infected cell (dashed circle) is assumed to increase with time since infection and reach a steady state. Treatment (parameters in red) may block HCV RNA production with effectiveness ε_α and/or virion assembly/secretion with effectiveness ε_s, and/or enhance the degration rate of HCV RNA by a factor κ. The main estimates after fixing δ=0.14d⁻¹, μ=1d⁻¹, α=40d⁻¹ are c=22.3d⁻¹, ε_α=0.99, ε_s=0.998, ρ=8.18d⁻¹, κμ=1.46d⁻¹. Figure reprinted from [11], Copyright © 2013, National Academy of Science.

This model was applied to the comparison of the viral kinetics observed after initiation of three different classes of agents, namely IFN, telaprevir (a protease inhibitor) and daclatasvir (a NS5A inhibitor) and allowed to puzzle out the mode of action of these drugs. The authors showed that the kinetics observed were dependent on the stages of the viral lifecycle where these drugs acted. While all three agents were found to have a high effectiveness in blocking vRNA production, the reason why HCV RNA declines so rapidly with daclatasvir was due to the fact that daclatasvir, unlike IFN and telaprevir to a lower extent, was extremely effective in blocking viral assembly/secretion, with an effectiveness estimated to 99.8% (vs. 39.0% in IFN-treated patients, p<10⁻¹⁰; and 0.94 in telaprevir-treated patients, p<10⁻⁶). As a consequence, the number of viruses newly secreted after initiation of daclatasvir is minimal and thus the viral decline observed in serum provides a good model to estimate HCV half-life in serum. Using this approach, Guedj et al. could demonstrate that the current estimate of 2.7h derived from the analysis of viral kinetics during IFN-based treatment were not accurate and now estimate the mean serum half-life of HCV at 45min. Of note, if HCV half-life is about four times shorter than previously thought, it implies that, in order to maintain a given level of virus, HCV production is also four times larger than initially thought. Thus the risk of generating mutations conferring drug resistance is also larger than previously thought.

The dual mechanism of action of daclatasvir provides a basis to explain why NS5A inhibitors may be good candidates for combination with drugs with complementary mode of actions, such as protease or polymerase inhibitors. Yet, these modeling efforts were based on the analysis of viral kinetics after one single dose of daclatasvir, and important questions on the implications of this dual mode of action remain to be solved. In particular, it is still unclear whether that plays any role in improving the genetic barrier to resistance and how this rapid initial viral decline translates into the long-term viral decline. Clearly, further studies with repeated doses of daclatasvir will be needed to study whether blocking assembly/secretion accelerates only the initial viral decline or also contributes to a faster elimination of the virus in the long run that may allow for shorter treatment duration.

The speed of development of drugs to treat HCV infection is unprecedented and new drugs with high potency, low side effects and requiring short treatment duration are emerging. In this context, mathematical modeling as the one performed by Guedj et al. is a promising tool to better understand the mechanism of action of new DAAs, such as NS5A and NS5B inhibitors, or a new generation of antiprotease inhibitors [12], rationalizing the combination of these agents and eventually selecting agents with complementary modes of action.

Conflict of interest 

Yazdan Yazdanpanah received travel grants, honoraria for presentations at workshops and consultancy honoraria from Abbott, Bristol-Myers Squibb, Gilead, Merck, Roche, Tibotec and ViiV Healthcare.

Sylvie Deuffic-Burban received grants from Roche, Janssen Pharmaceuticals, and Merck, and consultancy honoraria from Merck, GlaxoSmithKline, and AbbVie.

References

1. World Health Organization. Hepatitis C. Fact sheet N°164. July 2012. [cited May 8, 2013]; Available from:http://www.who.int/mediacentre/factsheets/fs164/en/. View In Article

2. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416 View In Article CrossRef

3. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206 View In Article CrossRef

4. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878–1887 View In Article CrossRef

5. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867–1877 View In Article CrossRef

6. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100 View In Article CrossRef

7. Suk-Fong Lok A. HCV NS5A inhibitors in development. Clin Liver Dis. 2013;17:111–121 View In Article Abstract Full Text Full-Text PDF (208 KB) CrossRef

8. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996;271:1582–1586 View In Article MEDLINE

9. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997;387:188–191 View In Article MEDLINE CrossRef

10. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282:103–107 View In Article MEDLINE CrossRef

G11. uedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, 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 U S A. 2013;110:3991–3996 View In Article CrossRef

12. Rong L, Guedj J, Dahari H, Coffield DJ, Levi M, Smith P, et al. Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model. PLoS Comput Biol. 2013;9:e1002959 View In Article CrossRef

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Daclatasvir: potential role in hepatitis C

Authors: Lee C

Published Date October 2013 Volume 2013:7 Pages 1223 - 1233

DOI: http://dx.doi.org/10.2147/DDDT.S40310

Received: 29 July 2013
Accepted: 29 August 2013
Published: 16 October 2013

Choongho Lee
College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea

Abstract: Chronic hepatitis C virus (HCV) infection is responsible for the development of liver cirrhosis and hepatocellular carcinoma. It has been a tremendous burden on global health care systems. With the advent of a number of new direct-acting and host-targeting antiviral agents, current interferon-a- and ribavirin-based HCV therapy has started to move towards an interferon-sparing or even interferon-free strategy. In this regard, a recently identified NS5A inhibitor, daclatasvir, showed a great promise in clinical trials as another new class of direct-acting anti-HCV therapeutics, with a distinct mechanism of action. In this review, a variety of preclinical as well as clinical proof-of-concept studies of daclatasvir, including the studies of its discovery, mechanism of action, viral resistance, and host polymorphism profiles are reviewed. In addition, a role of daclatasvir in the future therapy for HCV patients is discussed briefly.

Keywords: hepatitis C virus, nonstructural protein 5A, NS5A inhibitor, hepatitis C treatment

Read full article here (PDF)

Interim Analysis of an Interferon (IFN)- And Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 In Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1828. Interim Analysis of an Interferon (IFN)- And Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 In Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients

Session: Oral Abstract Session: Hepatitis C

Saturday, October 5, 2013: 2:45 PM

Room: The Moscone Center: 250-262

Background: The IFN- and RBV-free regimen of DCV (NS5A inhibitor), ASV (protease inhibitor) and BMS-791325 (non-nucleoside NS5B inhibitor, 75mg BID) achieved sustained virologic response (SVR4, SVR12) >90% in treatment-naïve, hepatitis C virus (HCV) genotype (GT) 1 patients. We evaluated this regimen using two BMS-791325 doses (75 vs 150 mg BID).

Methods: HCV GT1, treatment-naïve, non-cirrhotic patients (N=32) were randomized 1:1 to DCV 60mg QD, ASV 200mg BID, and BMS-791325 75mg BID for 24 (Group 1) or 12 (Group 2) weeks. Subsequently, 34 additional patients were randomized to DCV, ASV, and BMS-791325 150mg BID for 24 (Group 3) or 12 (Group 4) weeks. The primary end point was HCV RNA <25 IU/mL at 12 weeks post-treatment (SVR12). Interim results are presented.

Results: Patients were mainly GT1a (74%), white (79%), and IL28Bnon-CC (70%). 64/66 patients had HCV RNA <25 IU/mL by Week 4 (Table). There was no difference in virologic response between 12 and 24 weeks of treatment. Overall, patients achieved SVR4 92% (46/50), SVR12 94% (30/32), and SVR24 94% (15/16). No patient discontinued for adverse events (AEs) related to DCV+ASV+BMS-791325. Most common AEs (≥10% total) were headache, asthenia, and gastrointestinal. Two serious AEs were reported, both unrelated to DCV+ASV+BMS-791325. No hepatotoxicity or Grade 3/4 elevations of ALT/AST or bilirubin were reported.

Conclusion: DCV+ASV+BMS-791325 achieved high rates of SVR4, SVR12, and SVR24 in treatment-naive GT1 patients, characterized by GT1a and IL28Bnon-CC. This regimen was well tolerated with no apparent safety signals. Expansion of the current study is underway to better define the efficacy and safety of this regimen.

Virologic Response During and After Treatment

BMS-791325 Dose		75 mg				150 mg
Duration		24 weeks		12 weeks		24 weeks		12 weeks
Group		1 (N=16)		2 (N=16)		3 (N=16)		4 (N=18)
HCV RNA <25IU/mL, n(%)
Week 4		16(100)		16(100)		16(100)		16(89)a
EOT/Last on-treatment		15(94)b		16(100)		-		17(94)c
SVR4		15(94)b		15(94)d		-		16(89)c,e
SVR12		15(94)b		15(94)d		-		-
SVR24		-		15(94)f		-		-
Virologic breakthrough, n(%)		0		0		1(7)		1(6)
Relapse, n(%)		0		0		-		1(6)
aOne patient with isolated HCV RNA of 43 IU/mL, one patient missing; b Patient withdrew consent; cOne viral breakthrough; dOne missing; eOne relapse; fA second patient missing.

Gregory T. Everson¹, Karen D. Sims², Maribel Rodriguez-Torres, MD³, Christophe Hézode⁴, Eric Lawitz⁵, Marc Bourlière⁶, Veronique Loustaud-Ratti⁷, Vinod Rustgi⁸, Howard Schwartz⁹, Harvey Tatum¹⁰, Patrick Marcellin¹¹, Stanislas Pol¹², Paul J. Thuluvath¹³, Timothy Eley, PhD², Xiaodong Wang², Shu-Pang Huang¹⁴, Fiona Mcphee¹⁵, Megan Wind-Rotolo¹⁴, Ellen Chung², Claudio Pasquinelli², Dennis M. Grasela² and David F. Gardiner², (1)University of Colorado Denver, Aurora, CO, (2)Bristol-Myers Squibb, Hopewell, NJ, (3)Gastroenterology, Fundacion de Investigacion, Rio Piedras, PR, (4)CHU Henri Mondor, Service d’Hépato-Gastroentérologie, Créteil, France, (5)Alamo Medical Research, San Antonio, TX, (6)Hôpital Saint Joseph, Service d’Hépato-Gastroentérologie, Marseille, France, (7)University Hospital of Limoges, Limoges, France, (8)Metropolitan Research, Arlington, VA, (9)Miami Research Associates, South Miami, FL, (10)Options Health Research, Tulsa, OK, (11)Hôpital Beaujon, Clichy, France, (12)Université Paris Descartes, INSERM U1610 and Liver Unit, Hôpital Cochin, Paris, France, (13)Mercy Medical Center, Baltimore, MD, (14)Bristol-Myers Squibb, Princeton, NJ, (15)Bristol-Myers Squibb, Wallingford, CT

Disclosures:

G. T. Everson, Bristol-Myers Squibb: Investigator, Research support

K. D. Sims, Bristol-Myers Squibb: Employee, Salary

M. Rodriguez-Torres, Bristol-Myers Squibb: Investigator, Research support

C. Hézode, Bristol-Myers Squibb: Investigator, Research support

E. Lawitz, Bristol-Myers Squibb: Investigator, Research support

M. Bourlière, Bristol-Myers Squibb: Investigator, Research support

V. Loustaud-Ratti, Bristol-Myers Squibb: Investigator, Research support

V. Rustgi, Bristol-Myers Squibb: Investigator, Research support

H. Schwartz, Bristol-Myers Squibb: Investigator, Research support

H. Tatum, Bristol-Myers Squibb: Investigator, Research support

P. Marcellin, Bristol-Myers Squibb: Investigator, Research support

S. Pol, Bristol-Myers Squibb: Investigator, Research support

P. J. Thuluvath, Bristol-Myers Squibb: Investigator, Research support

T. Eley, Bristol-Myers Squibb: Employee, Salary

X. Wang, Bristol-Myers Squibb: Employee, Salary

S. P. Huang, Shu-Pang Huang: Employee, Salary

F. Mcphee, Bristol-Myers Squibb: Employee, Salary

M. Wind-Rotolo, Bristol-Myers Squibb: Employee, Salary

E. Chung, Bristol-Myers Squibb: Employee, Salary

C. Pasquinelli, Bristol-Myers Squibb: Employee, Salary

D. M. Grasela, Bristol-Myers Squibb: Employee, Salary

D. F. Gardiner, Bristol-Myers Squibb: Employee, Salary

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Bristol-Myers Squibb to Present Range of New Hepatitis C Data at the 2013 American Association for the Study of Liver Diseases (AASLD) Annual Meeting

• Phase III SVR24 data on daclatasvir + asunaprevir, an investigational, interferon-free and ribavirin-free treatment regimen, in Japanese HCV patients with high unmet needs selected to lead off this year’s Presidential Plenary session
• Data presentations provide further insight on dosing, tolerability and safety of multiple daclatasvir-based investigational HCV regimens
• 16 accepted abstracts on HCV and HBV underscore the breadth of the company’s hepatitis portfolio

Tuesday, October 1, 2013 11:46 am EDT  

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that 16 abstracts have been accepted for presentation at The Liver Meeting^® 2013, the 64th Annual Meeting of The American Association for the Study of Liver Diseases (AASLD), in Washington D.C., November 1 – 5. These abstracts include new data supporting the company’s broad pipeline of hepatitis C (HCV) compounds.

Key presentations include:

• Results from a Phase III study of an all-oral combination of daclatasvir (DCV) and asunaprevir (ASV) in Japanese HCV genotype 1b patients who are either ineligible or intolerant to interferon-based therapies or who are non-responders to both interferon and ribavirin. This is the first presentation of a Phase III study evaluating an all-oral, interferon-free and ribavirin-free regimen. Presentation of complete SVR₂₄ results from this study will lead the Viral Hepatitis Presidential Plenary session on Tuesday, November 5.
• Additional dosing, safety and efficacy data on DCV, ASV and BMS-791325, several BMS investigational HCV compounds that are being studied as a fixed-dose combination.
• Findings from health economics and outcomes research studies including long-term morbidity and mortality in chronic hepatitis C patients in the U.S. Veterans Health Administration; and an analysis of the burden of alfa-interferon based therapies on chronic hepatitis C patients in Japan.

“The wealth of Bristol-Myers Squibb data at this year’s AASLD meeting reflects our long-standing commitment to researching the unmet medical needs of patients with hepatitis C. We are particularly excited about our investigational, all-oral regimen of daclatasvir and asunaprevir and its potential for HCV patients, including many in Japan who currently have no treatment options,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “Just 25 years after the discovery of the hepatitis C virus, the HCV research community is on the cusp of a cure for more patients than ever before. Bristol-Myers Squibb is proud to be among the companies standing at the forefront of this major shift in the treatment paradigm.”

Bristol-Myers Squibb is studying a broad portfolio of new compounds in hopes of providing flexible treatment options which aim to help address the diverse unmet medical needs of a global HCV patient population. These investigational compounds include DCV, ASV, BMS-791325, and peginterferon lambda-1a (Lambda). The company also continues to study the full potential of Baraclude^® (entecavir), an oral antiviral agent with selective activity against HBV. Baraclude is a leading treatment for chronic hepatitis B and is approved in more than 90 countries.

The complete list of Bristol-Myers Squibb data presentations is below. Abstracts can be accessed on the AASLD website at www.aasld.org/livermeeting.

 

Title			Date/Time
Hepatitis C: Direct-Acting Antiviral Data
Presidential Plenary: All-oral Combination of Daclatasvir plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase III Trial			Tuesday, November 5, 8 – 8:15 a.m.
Asunaprevir Pharmacokinetics and Safety in Subjects With Impaired Renal Function			Saturday, November 2, 5:30 p.m. – 7:00 p.m.
Lack of Pharmacokinetic Interaction Between the HCV Protease Inhibitor MK-5172 and HCV NS5A Inhibitor Daclatasvir In Normal Healthy Volunteers
No Clinically-Relevant Interactions Between Asunaprevir and Selective Serotonin Reuptake Inhibitors (Escitalopram and Sertraline) in Healthy Subjects
Daclatasvir Pharmacokinetics in Healthy Subjects: No Clinically-Significant Drug-Drug Interactions with Cyclosporine or Tacrolimus			Sunday, November 3, 12:30 p.m. – 2 p.m.
Analysis of HCV Resistance Variants in a Phase III Trial of Daclatasvir Combined With Asunaprevir for Japanese Patients with Genotype 1b Infection
Safety and Efficacy of BMS-791325, a Non-Nucleoside NS5B Polymerase Inhibitor, Combined with Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve Patients Infected with Hepatitis C Virus Genotype 1
Hepatitis C and B: PEG-Interferon Lambda Data
Inverse Modulation in Hepatic Expression of Interferon Receptor Complexes for Alpha and Lambda during HCV Infection are Associated with Altered Interferon Signaling Induction upon Treatment with Peginterferon Alfa-2a Compared to Peginterferon Lambda-1a			Saturday, November 2, 5:30 p.m. – 7 p.m.
Safety Profile of Peginterferon Lambda for Treatment of Chronic Hepatitis B Virus (HBV) or Chronic Hepatitis C Virus (HCV) Infection: Cross-Study Analysis of Patients Treated in Three Phase 2 Studies			Sunday, November 3, 12:30 p.m. – 2 p.m.
Hepatitis C: Outcomes Research / Real-World Data
Impact of Treatment on Long-Term Morbidity and Mortality in Chronic Hepatitis C Patients Receiving Care Through the U.S. Veterans Health Administration			Tuesday, November 5, 12:30 p.m. – 12:45 p.m.
Using Laboratory Data to Predict Long-Term Morbidity and Mortality in Chronic Hepatitis C Patients Through The U.S. Veterans Health Administration			Tuesday, November 5, 10:30 a.m. – 12 p.m.
Patient Burden of Peginterferon Alfa (Alfa)-Based Therapy Among Patients with Chronic Hepatitis C Infection in Japan: Report from a 2013 National Survey Study
The Comparative Effectiveness of Daclatasvir Plus Asunaprevir vs Telaprevir Triple Therapy in Nonresponder Japanese Patients Chronically Infected With HCV Genotype 1b: Results from a Bayesian Meta-Analysis
A Meta-Analysis Platform for the Continuous Updating of Knowledge Regarding Treatment Regimens for Hepatitis C Virus Infection
Chronic Hepatitis B: BARACLUDE (entecavir) Clinical Data
The Safety and Efficacy of Entecavir and Tenofovir Combination Therapy for Chronic Hepatitis B in Patients with Previous Nucleos(t)ide Treatment Failure			Sunday, Nov. 3, 8 a.m. – 5:30 p.m.
Entecavir Pharmacokinetics Among Nucleos/tide-Naїve Pediatric Subjects

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb’s hepatitis C pipeline includes compounds with different mechanisms of action, pursuing both biologics as well as small molecule direct-acting antivirals. These compounds are being studied as part of multiple treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies.

• Our investigational NS5A replication complex inhibitor daclatasvir (DCV) has been extensively studied in thousands of patients to date as a foundational agent for multiple DAA-based combination therapies and is currently in Phase III development. DCV has shown antiviral potency and pan-genotypic activity across HCV genotypes in vitro. DCV has a drug-drug interaction profile that supports its continued study in a variety of HCV combination regimens
• Asunaprevir (ASV) is an NS3 protease inhibitor in Phase III development for hepatitis C as a component of DCV-based treatment regimens
• BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase II development for hepatitis C as a component of DCV-based treatment regimens
• Lambda is an investigational type III interferon that has the potential to offer an alternative to alfa-interferon in patients for whom an interferon-based regimen is required or preferred

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. According to the World Health Organization, 20 percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. In Japan, the hepatitis C virus is the most common cause of chronic hepatitis and cirrhosis, and approximately 1.2 million people there are living with the hepatitis C virus.

INDICATION and IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) 0.5mg/1mg Tablets:

INDICATION

BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

The following points should be considered when initiating BARACLUDE:

1. This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naïve and lamivudine-resistant adult subjects with HBeAg-positive or HBeAg-negative chronic HBV infection and compensated liver disease.

2. Virologic, biochemical, serologic, and safety data are available from a controlled study in adult subjects with chronic HBV infection and decompensated liver disease.

3. Virologic, biochemical, serologic, and safety data are available for a limited number of adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy.

IMPORTANT SAFETY INFORMATION

WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY

• Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

• Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, alone or in combination with antiretrovirals.

Warnings and Precautions

• Before initiating BARACLUDE (entecavir) therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.

• Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. BARACLUDE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Adverse Reactions

• In clinical trials in patients with compensated liver disease, the most common (≥3%) adverse reactions of any severity with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. In these trials, the most common adverse reactions of moderate to severe intensity (grades 2-4) were diarrhea, dyspepsia, nausea, vomiting, fatigue, headache, dizziness, somnolence, and insomnia.

• In the decompensated liver disease trial, the most common adverse reactions of any severity among patients treated with BARACLUDE (entecavir), regardless of causality, included: peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). In this trial, 18% (18/102) of BARACLUDE patients and 20% (18/89) of adefovir patients died during the first 48 weeks of therapy. The majority of those deaths were due to liver related causes.

Drug Interactions

BARACLUDE is primarily eliminated by the kidneys, therefore coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either BARACLUDE or the coadministered drug. Patients should be monitored closely when receiving BARACLUDE with other renally-eliminated drugs.

Pregnancy and Nursing Mothers

• There are no adequate and well-controlled studies of BARACLUDE (entecavir) in pregnant women. BARACLUDE should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.

• There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.

• It is not known whether BARACLUDE is excreted into human milk; however, many drugs are excreted into breast milk. Due to the potential for serious adverse reactions in nursing infants from BARACLUDE, risks and benefits should be considered when deciding whether to discontinue breast-feeding or discontinue BARACLUDE in nursing women.

Pediatric Use

• Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have not been established.

Renal Impairment

• Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance <50 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis.

Liver Transplant Recipients

• Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus.

Dosage and Administration

BARACLUDE (entecavir) should be administered on an empty stomach (at least 2 hours after a meal and at least 2 hours before the next meal).

The recommended dose of BARACLUDE:

• in nucleoside-naïve adults and adolescents (16+ yrs) with compensated liver disease is 0.5 mg once daily

• in adults and adolescents (16+ yrs) with compensated liver disease, and refractory to lamivudine or with known lamivudine or telbivudine resistance mutations (rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L) is 1 mg once daily

• in adults with decompensated liver disease is 1 mg once daily

The optimal duration of treatment with BARACLUDE (entecavir) for patients with chronic HBV infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

Additional Information

BARACLUDE is not a cure for HBV. Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.

Please see accompanying Full Prescribing Information, including Boxed WARNINGS click here.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://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. Among other risks, there can be no guarantee that the clinical trials of these compounds will support regulatory filings, or that the compounds described in this release will receive regulatory approvals or, if approved, that they will become commercially successful products. 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, 2012, 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.

BARACLUDE^® (entecavir) is a registered trademark of Bristol-Myers Squibb Company

Contact:

Bristol-Myers Squibb
Media:
Carrie Fernandez, 609-252-4831
carrie.fernandez@bms.com
Julie Ferguson, 609-252-5597
julie.ferguson@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
Ryan Asay, 609-252-5020
ryan.asay@bms.com

Source

Gilead HCV Program, GS-7977

Provided by NATAP

(All links open in new windows)

from Jules od NATAP: Gilead submitted to the FDA approval for the Gilead nucleotide GS-7977+Peg/Rbv 12 weeks for Gt1, and for GS7977+Rbv for Gt2/3 and I think 4/6. They have been studying HIV/HCV coinfection in Gt2 and I think Gt1. The FDA hearing for TMC435 & for GS-7977 appears to be Oct 24/25 2013. There is a lot of research & studies that have been conducted so there is a lot below, you can look at the phase 3 results presented at EASL 2013, link below. Gilead has a protease inhibitor & a non-nuc as well in clinical development, studies presented at EASL 2013. GS-7977 has been studied in combination with BMS' NS5A inhibitor in naives & telaprevir/boceprevir failures with 95-100% SVR rates. In 2014 by June Gilead is expected to submit phase 3 study results to the FDA for their fixed dose combination go GS-7977 + their 1st generation NS5A with and w/o RBV, 12 weeks therapy. At the same time Abbvie will be submitting their Phase 3 study results for their INF-free oral regimen which includes their protease inhibitor, NS5A inhibitor & their non-nuc with & w/o RBV, 12 weeks therapy; GS-7977 mono therapy data is reported in study links below.

GS-7977 & HIV ARTs PK - No Clinically Significant Pharmacokinetic Interactions Between Sofosbuvir (GS-7977) and HIV Antiretrovirals Atripla, Rilpivirine, Darunavir/Ritonavir, or Raltegravir in Healthy Volunteers
http://www.natap.org/2012/AASLD/AASLD_64.htm

GILEAD SUBMITS NEW DRUG APPLICATION TO U.S. FDA FOR SOFOSBUVIR FOR THE TREATMENT OF HEPATITIS C http://www.natap.org/2013/HCV/040813_01.htm

Antiviral Drugs Advisory Committee .........October 24-25 http://www.fda.gov/AdvisoryCommittees/Calendar/ucm153468.htm

Gilead Reports Interim Data From Phase 2 LONESTAR Study - (05/03/13)

EASL 2013
Gilead reported 7 studies results including 4 phase 3 studies and others including their HCV protease inhibitor, 1st & 2nd generation NS5A inhibitors and their non-nuc, ALL with links to each presentation within this report http://www.natap.org/2013/HCV/050313_02.htm

Clin Pharm Workshop at EASL Amsterdam 2013 - Clinical Pharmacology of DAA's for HCV:
What's New and What's in the Pipeline
Gilead Sciences A. Mathias Pres. DATA FROM PHASE 3 STUDIES OF GILEAD'S SOFOSBUVIR FOR HEPATITIS C TO BE PRESENTED AT 48TH ANNUAL EASL MEETING; FINDINGS PUBLISHED ONLINE TODAY IN THE NEW ENGLAND JOURNAL OF MEDICINE - Press Release http://www.natap.org/2013/EASL/EASL_02.htm

Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection: 2 phase 3 studies - FISSION (gt2/3), NEUTRINO (gt1) http://www.natap.org/2013/EASL/EASL_32.htm

Gilead's HCV Pipeline Unveiled at EASL http://www.natap.org/2011/EASL/EASL_97.htm

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13) EASL/2012: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders http://www.natap.org/2013/CROI/croi_34.htm

AASLD/2012: High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3 - (11/13/12)

EASL: No S282T Mutation Detected by Deep Sequencing in a Large Number of HCV Patients Who Received Sofosbuvir With RBV and/or GS-0938: the Quantum Study - (04/29/13)

EASL: GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier - (04/29/13)

EASL: Healthy Volunteer First-in-Human Evaluation of GS-5816, a Novel Second Generation Broad-Genotypic NS5A Inhibitor With Potential for Once-Daily Dosing - (04/29/13)

GILEAD PROVIDES UPDATE ON HEPATITIS C DEVELOPMENT PROGRAMS - update on GS-7977+GS-5885+Rbv in null responders in Electron http://www.natap.org/2013/HCV/010713_02.htm

GS-7977 400 mg QD Safety and Tolerability in the Over 500 Patients Treated for at Least 12 Weeks http://www.natap.org/2012/EASL/EASL_55.htm

Once Daily Sofosbuvir (GS-7977) Regimens in HCV Genotype 1-3: The ELECTRON Trial http://www.natap.org/2012/AASLD/AASLD_31.htm

AASLD: Once Daily Sofosbuvir (GS-7977) plus PEG/RBV In Treatment-Na•ve Patients With HCV Genotype 1, 4, and 6 Infection: The ATOMIC Study http://www.natap.org/2012/AASLD/AASLD_21.htm
http://www.natap.org/2013/HCV/033113_02.htm

Nucleotide Polymerase Inhibitor Sofosbuvir (GS-7977) plus Ribavirin for Hepatitis C - new published study http://www.natap.org/2013/HCV/010413_04.htm

ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 AND PSI-7977 PROVIDES 94% HCV RNA < LOD AT DAY 14: FIRST PURINE/PYRIMIDINE CLINICAL COMBINATION DATA (THE NUCLEAR STUDY) http://www.natap.org/2011/EASL/EASL_07.htm

Pharmasset Announces Results of a 28-day Phase 2a Study with PSI-7977 for the Treatment of Chronic Hepatitis C Infection http://www.natap.org/2010/HCV/102810_04.htm

AASLD: PSI-7977: ELECTRON Interferon is not required for Sustained Virologic Response in Treatment-Na•ve Patients with HCV GT2 or GT3 - (11/07/11) Lack of Effect of the Nucleotide Analog Polymerase Inhibitor PSI-7977 on Methadone PK and PD http://www.natap.org/2011/AASLD/AASLD_104.htm

PSI-7977 Has No Effect on QTcF Intervals at Therapeutic or Supratherapeutic Doses http://www.natap.org/2011/AASLD/AASLD_103.htm

PSI-7977 with PEG/RBV Elicits Rapid Declines in HCV RNA in Patients with HCV GT-4 and GT-6 http://www.natap.org/2011/hepDART/hepDART_01.htm

High Rapid Virologic Response (RVR) with PSI-7977 Daily Dosing plus PEG-IFN/RBV in a 28-day Phase 2a Trial http://www.natap.org/2010/AASLD/AASLD_49.htm

Gilead Acquires Pharmasset $11 Billion http://www.natap.org/2011/HCV/112111_02.htm

TMC435+GS7977 (Rbv) New Study in Advanced Hepatic Fibrosis- Null Responders & Naives http://www.natap.org/2013/HCV/012213_03.htm

Combination of two complementary nucleotide analogues, PSI-7977 and PSI-938, effectively clears wild type and NS5b: S282T HCV replicons - Comparison with combinations of other antiviral compounds http://www.natap.org/2010/EASL/EASL_28.htm

 

New HCV Treatments and Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial

Provided by NATAP

Download the PDF here

The Lancet, 15 June 2013

Kris V Kowdley, Eric Lawitz, Israel Crespo, Tarek Hassanein, Mitchell N Davis, Michael DeMicco, David E Bernstein, Nezam Afdhal, John M Vierling, Stuart C Gordon, Jane K Anderson*, Robert H Hyland, Hadas Dvory-Sobol, Di An, Robert G Hindes*, Efsevia Albanis*, William T Symonds, M Michelle Berrey, David R Nelson, Ira M Jacobson

Gilead submitted their New Drug Application (NDA) to the FDA this past Spring for several uses, indications of Sofosbuvir (GS7977) including for gt1 with SOF+Peg/Rbv for 12 weeks duration of therapy and also for Gt2/3 with SOF+Rbv for 12 weeks. As well Janssen submitted their NDA for Simeprevir (protease)+Peg/Rbv this past Spring. Boehringer Ingelheim will soon follow in step with their NDA submission for Faldaprevir (protease)+Peg/Rbv. FDA approvals are expected later this year or soon thereafter. Next year by the end of 1st half 2014 several more NDA submissions are expected including by Abbott for their 4-drug IFN-free regimen of ABT450/r(protease)+ABT267(NS5A)+ABT333(non-nuc)+/-Rbv for 12 weeks duration of therapy for Gt1; also Gilead is expected to submit their NDA for their IFN-free regimen of Sofosbuvir+GS5885(Ledipasvir)+/- Rbv for 12 weeks for Gt1; as well, BMS is expected to submit several NDAs for several different combinations including for their potent first-in-class NS5A BMS052 (Daclatasvir). Of note 3 IFN-free & Rbv free studies have been conducted but they were relatively small phase 2 studies: Daclatasvir+Sofosbuvir in treatment-naives & separate study in boceprevir & telaprevir failures with 100% SVR rates, and the COSMOS Study of Simeprevir+Sofosbuvir for 12 weeks in null responders with a 96% SVR rate. By the end of this year both Simeprevir+Sofosbuvir are expected to be approved by the FDA but not for this indication, i.e. not to be used together in this 2-drug combination which is IFN & Rbv free because the study was relatively small, it was not a phase 3 study. This is unfortunate for patients who would like to use this regimen & for those who might need such a regimen. Of note, there are many additional IFN-free regimens in research & development now using 2-4 potent HCV orally administered antivirals by Boehringer Ingelheim, Merck, Vertex, Roche, Janssen, BMS, Achillion and in collaboration with big pharma Presidio & Idenix. Some of these oral antivirals are 2nd generation meaning they are more potent & effective against resistant virus. These ongoing or soon to start studies will include 2-4 different oral HCV drugs, will be 12 week regimens & be IFN-free and are a few years away, maybe 2-3 additional years away. What we need is to conduct HCV screening projects that include linkage to care, we need federal, state & city support to conduct these studies, as it is estimated that as many as 75% of HCV-infected individuals remain undiagnosed

COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders
http://www.natap.org/2013/CROI/croi_34.htm

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)

AASLD/2012: High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3 - (11/13/12)

EASL: SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY - (04/25/13)

Gilead Reports Interim Data From Phase 2 LONESTAR Study

from Jules: this ATOMIC Study is the forerunner for the NEUTRINO Study which is the phase 3 study for this very same regimen of SOF+Peg/rbv in gt1/4/5/6.

HERE in this link is the Phase 3 NEUTRINO data reported at EASL:

EASL: Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study - (04/27/13)

Here are NATAP EASL & CROI/HCV Reports--

EASL: New Oral HCV Drugs at EASL - Report 4A

Summary from EASL 2013 for Hepatitis C - New HCV DAAs on their way soon: what do the phase III studies tell us? - written by Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany (05/16/13)

New HCV Drugs - EASL & Beyond - (05/11/13)

EASL 48th Annual Meeting
April 24th - 28th 2013
The Netherlands, Amsterdam

HCV at CROI - (03/17/13)

Summary

Background

The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.

Methods

For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978.

Results

We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5).

In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C.

We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug-anaemia and neutropenia-were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event.

Interpretation

Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis.

Funding

Gilead Sciences.

Introduction

For previously untreated patients with chronic hepatitis C virus (HCV) genotype-1 infection, the standard of care is one of two HCV protease inhibitors-telaprevir or boceprevir-in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin for up to 48 weeks.1 Duration of treatment is defined by patients' on-treatment response; the dosing schedules for both drugs allow the shortening of treatment duration to 24-28 weeks in patients with no liver cirrhosis who achieve and maintain undetectable HCV RNA in the first 8 weeks of treatment.2, 3 The potential to shorten duration of treatment is important because it can reduce the occurrence of the serious side-effects associated with peginterferon and ribavirin (headache, fever, cytopenia, autoimmunity disorders, and depression).4, 5 Unfortunately, many patients do not qualify for shortened regimens and need 48 weeks of treatment.6, 7 Data beginning to emerge since the approval of the protease inhibitors suggest that discontinuation rates from these regimens have been high.8-11 Other limitations of treatment with the available protease inhibitors are their low barrier to resistance,12 potential for drug interactions, and complex regimens with high pill burdens. Thus, a clear need exists for a shorter, simpler, better tolerated, and effective regimen with a high barrier to resistance for treatment-naive patients with chronic HCV infection.

Sofosbuvir (formerly known as GS-7977; Gilead Sciences, Foster City, CA, USA) is a selective, pangenotypic nucleotide inhibitor of NS5B-directed HCV RNA replication. In another phase 2 trial,13 43 (91%; 95% CI 80-98) of 47 treatment-naive patients with HCV genotype-1 receiving 400 mg sofosbuvir in combination with peginterferon and ribavirin for 12 weeks followed by 12 weeks of peginterferon and ribavirin had sustained virological response at post-treatment week 12 (SVR12).13 These results, along with the rapidity of the recorded on-treatment virological suppression (nearly all patients had undetectable concentrations by week 4) and the lack of viral breakthrough in this trial and other studies of sofosbuvir, including the exploratory ELECTRON phase 2 trial,14 indicate the need to assess shorter durations of treatment with sofosbuvir plus peginterferon and ribavirin in the treatment of patients with chronic HCV. The ATOMIC trial was designed to assess whether a 12-week treatment regimen of sofosbuvir plus peginterferon and ribavirin is as effective as a 24-week regimen. Additionally, we explored whether or not 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by an additional 12 weeks of sofosbuvir monotherapy or sofosbuvir and ribavirin offers any benefit compared with the 12-week regimen of sofosbuvir plus peginterferon and ribavirin.

Methods

Study design and participants

We did this randomised, open-label phase 2 study at 42 centres: 41 in the USA and one in Puerto Rico. Study screening began on March 23, 2011, with the last patient enrolled on Sept 21, 2011; the last patients' final follow-up visit was on Aug 27, 2012. Eligible patients were at least 18 years of age, had not been treated previously for HCV infection, and had chronic genotype 1, 4, 5, or 6 HCV infection with serum HCV RNA concentrations of 50 000 IU/mL or greater. Exclusion criteria included histological evidence of cirrhosis (patients had to have had a liver biopsy done within 36 months of entry) or other clinically important chronic liver disease, a body-mass index of 18 kg/m2 or lower, or co-infection with hepatitis B or HIV. Patients with a history of psychiatric illness were eligible if approved by a psychiatrist or licensed mental health professional.

Before enrolment and before any procedures were done, written informed consent was obtained from all patients. The study was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. A safety review committee consisted of a group of Pharmasset employees (including a clinical scientist, safety scientist, medical monitor, medical advisor, and chief medical officer) who met on a monthly basis to review the ongoing safety of the study; additionally, a group of four external members (including the committee chairman) were available on an as-needed basis.

Randomisation and masking

Using an interactive web-based response system, we randomly allocated patients with HCV genotype-1 in a 1:2:3 ratio to cohorts A, B, or C. Randomisation was stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients with genotype 4, 5, or 6 (or indeterminate genotype) were enrolled into cohort B. This study was an open-label study. For the study to have been blinded, patients in cohorts A and C would have had to receive placebo injections for 12 weeks after the conclusion of their planned dosing. We decided that the potential benefits of blinding did not warrant the risk and inconvenience to patients. Patients as well as individuals providing study treatment, assessing outcomes, or analysing data were not masked to group assignment at any point during the study.

Procedures

Individuals in cohort A received sofosbuvir 400 mg orally once daily, peginterferon 180 μg subcutaneously once a week, and ribavirin orally as a divided weight-based daily dose (ie, patients <75 kg received 1000 mg and those ≥75 kg received 1200 mg) for 12 weeks. Patients in cohort B received the same drugs at the same doses for 24 weeks. Patients in cohort C received the same regimen as individuals in cohort A followed by an additional 12 weeks of sofosbuvir monotherapy for half the patients, or sofosbuvir plus ribavirin for the other half (with patients randomly allocated to these subcohorts). Patients in cohort A who did not achieve a rapid virological response (defined as HCV RNA <15 IU/mL at week 4) continued to receive sofosbuvir plus peginterferon and ribavirin for an additional 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment until week 24.

We measured plasma HCV RNA concentrations using the COBAS AmpliPrep/COBAS Taqman HCV test (Roche; Indianapolis, IN, USA) with a limit of detection of 15 IU/mL. We defined virological breakthrough as the presence, during treatment, of detectable HCV RNA in serum samples after previous documentation of HCV RNA concentrations lower than 15 IU/mL; we defined virological rebound as a greater than 1 log10 increase in HCV RNA from the lowest point while on treatment. Relapse was defined as presence of detectable HCV RNA at any time during the 24-week post-treatment follow-up after documentation of HCV RNA less than 15 IU/mL in serum samples at the end of treatment. We discontinued treatment in patients who did not respond by week 12 (ie, <2 log10 decrease in HCV RNA) or who had confirmed viral breakthrough or rebound at any time during the trial.

We monitored patients for virological breakthrough during the 12-24 weeks of treatment and for relapse after treatment discontinuation. We did a confirmatory HCV RNA test in any patient with virological breakthrough and all treatment was discontinued if breakthrough was confirmed. Blood samples were obtained at each study visit for population sequencing of the NS5B-encoding region with a detection limit of 15-25% of the viral population. Samples were sequenced by dideoxy sequencing (DDL Diagnostic Laboratory; Rijswijk, Netherlands) at baseline for all patients, and at failure timepoints for those who had virological breakthrough or relapse.

For virological failures, phenotypic analysis of NS5B was done by Janssen Diagnostics BVBA (Beerse, Belgium), with a replicon-based HCV assay containing the NS5B regions of HCV derived from plasma sequences from patients and quantitatively measured differences in sofosbuvir susceptibility compared with corresponding baseline samples or respective wild-type reference replicon.

Safety was assessed by review of adverse events and concomitant drugs, blood samples for serum tests and haematological assessments, and physical examinations including vital signs and electrocardiograms. Patients with decreases in haemoglobin concentrations to lower than 100 g/L during treatment received reduced peginterferon or ribavirin dosing. The use of erythropoiesis-stimulating agents was not allowed.

Statistical analysis

The primary efficacy endpoint of the study was sustained virological response 24 weeks after discontinuation of all treatment (SVR24). The intention-to-treat analysis included all patients who were enrolled and received at least one dose of study drug. The primary analysis compared the proportion of patients in each treatment group with HCV RNA concentrations lower than 15 IU/mL (or undetectable) at week 24 after the end of treatment. We calculated point estimates and two-sided 95% CIs of between-group differences in SVR24 using stratum-adjusted Mantel-Haenszel proportions. Secondary endpoints were the proportion of patients with undetectable HCV RNA at all timepoints throughout the study (eg, rapid virological response and SVR12) with point estimates and exact 95% CIs.

We estimated that a sample size of 50 patients and 100 patients or a sample size of 75 patients and 100 patients would be sufficient to achieve 90% power to detect a 30% or 25% difference in SVR24 rates between two treatment groups with the χ2 and a 5% two-sided significance level. We used SAS (version 9.2) for all statistical analyses.

Role of the funding source

The sponsor of the study contributed to recruitment of patients, trial management, data collection, statistical analyses, and the writing and review of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

We screened 588 patients with HCV genotypes 1, 4, and 6, of whom 332 were eligible and enrolled in the study (figure 1). No patients with HCV genotype 5 were enrolled into this study. Characteristics of patients were much the same between groups at baseline, with a mean age of about 50 years and most patients being men, being white, and carrying a non-CC IL28 B genotype (table 1).

Because efficacy results for patients in cohort C who were randomly allocated into two subgroups for the second 12 weeks of treatment-those who received sofosbuvir monotherapy (cohort C1) and those who received sofosbuvir plus ribavirin (cohort C2)-were very similar, their data were pooled when assessing efficacy. However, we analysed the two subcohorts separately when assessing adverse events.

Patients in all groups had rapid and substantial reductions in HCV RNA after beginning treatment (table 2). At the end of the first week of dosing, median decreases in HCV RNA in all three cohorts were greater than 4·5 log10 IU/mL. By the second week of treatment, 79% of patients (259 of 328) receiving treatment had undetectable HCV RNA, a proportion that increased to 99% (323 of 326 patients; 97% by intention-to-treat analysis [323 of 332 patients]) at week 4 of treatment. One patient in cohort A did not have undetectable HCV RNA by week 4. Because of an administrative error, this patient did not receive an extra 12 weeks of treatment as specified by the protocol, but did achieve SVR24.

We recorded high rates of SVR12 and SVR24 in all three groups (table 2). We noted no difference in the proportions of patients achieving SVR24 between cohorts A and B (p=0·94) or between cohorts A and C (p=0·78), suggesting no additional benefit of treatment durations of longer than 12 weeks.

Of the 11 patients with genotype 4 HCV, nine (82%, 95% CI 48-98%) achieved both SVR12 and SVR24. We recorded no virological failure in these 11 patients-the other two patients were lost to follow-up at the end of treatment. All five of the patients with genotype 6 HCV achieved SVR12 and SVR24 (100%, 48-100%).

Factors shown to be associated with reduced response to treatment did not seem to greatly affect response to this regimen: rates of SVR24 for patients with high baseline HCV RNA (≥800 000 IU/mL) were 89% in cohort A (40 of 45 patients), 90% in cohort B (81 of 92 patients), and 87% in cohort C (110 of 127 patients); rates of SVR24 for patients carrying non-CC IL28B genotypes were 87% in cohort A (34 of 39 patients), 90% in cohort B (80 of 89 patients), and 88% in cohort C (96 of 116 patients); and rates of SVR24 for patients with bridging fibrosis versus those without bridging fibrosis were 100% (all seven patients) versus 87% (19 of 23 patients) in cohort A, 88% (15 of 17 patients) versus 89% (96 of 108 patients) in cohort B, and 83% (19 of 23 patients) versus 88% (116 of 132 patients) in cohort C.

No patients had viral breakthrough during treatment. Of the 11 patients who had a return of detectable HCV RNA after stopping treatment, seven relapsed after completing their assigned treatment regimen (table 2). Of these seven patients, relapse occurred by post-treatment follow-up week 4 in four patients, by follow-up week 8 in two patients, and by follow-up week 12 in one patient. All but one patient who had viral relapse carried a non-CC IL28B allele. The slightly fewer number of individuals achieving SVR12 than those receiving SVR24 in each group was not because of relapse but because of patients lost to follow-up after 12 weeks. The rate of relapse did not seem to be higher in patients who received ribavirin dose reductions during treatment (data not shown). The remaining four patients who had virological failure did not complete their assigned course of treatment. All four achieved undetectable HCV RNA during treatment, but had detectable viraemia within 8 weeks after early treatment discontinuation.

Changes in the NS5B polymerase in clinical isolates from the 11 patients who either relapsed after a full course of treatment or after early discontinuation were assessed by population sequencing. We detected neither the Ser282Thr or Met289Leu mutations at the time of virological failure. We detected no change in susceptibility to sofosbuvir compared with their corresponding baselines or in the wild-type 1b Con-1 replicon with any of the 11 patients at the time of relapse.

Most patients (97-99%) had at least one adverse event during the study. The most common adverse events were those consistent with the known safety profile for peginterferon and ribavirin: fatigue, headache, and nausea, with most of these adverse events rated by treating clinician as mild in severity (table 3). 30 patients had adverse events leading to discontinuation of any study drug. The proportion of patients with genotype-1 who discontinued any study drug because of an adverse event was greater in cohort B than in either of the other two cohorts (18% vs 5-6%; three [6%] of 52 patients in cohort A, 19 [18%] of 106 patients in cohort B, and seven [5%] of 155 patients in cohort C). The most common adverse events that led to the discontinuation of any study drug-anaemia and neutropenia-are associated with peginterferon and ribavirin treatment. Anaemia leading to dose modification or interruption seemed to be more common in cohort B (25 [20%] of 125 patients) and cohort C2 (17 [23%] of 75 patients) than it was in cohort A (five [10%] of 52 patients) and cohort C1 (eight [11%] of 75 patients), which might be a consequence of the longer treatment duration with ribavirin. Adverse events that led to treatment discontinuation in more than two patients were neutropenia, nausea, and anxiety (four patients for each), and anaemia (three patients).

13 treatment-emergent serious adverse events were reported in 12 patients: two (4%) in cohort A, six (5%) in cohort B, and four (3%) in cohort C (two each in cohorts C1 and C2). Nine serious adverse events were thought to be unrelated to study drug treatment (arrhythmia, ischaemic colitis, chest pain, acute cholecystitis, cholelithiasis, alcohol poisoning, road-traffic accident, costochondritis, and hip arthroplasty). Four serious adverse events-anaemia, autoimmune hepatitis, pyelonephritis, and pancytopenia-were reported as related to peginterferon and ribavirin (but unrelated to sofosbuvir). Two of the 13 serious adverse events (automimmune hepatitis and chest pain) led to permanent discontinuation of study drug. Subsequent testing confirmed that the case of autoimmune hepatitis was an undiagnosed pre-existing disorder. No patients died during the study period.

Across all treatment groups, we recorded a decrease in neutrophils, haemoglobin, platelets, and lymphocytes, consistent with the known effects of peginterferon and ribavirin (figure 2). The most common grade 3 or 4 laboratory abnormality was neutropenia (table 4). Recovery of neutrophil counts to baseline values occurred promptly after discontinuation of peginterferon in patients continuing on sofosbuvir or sofosbuvir plus ribavirin (figure 2). Additionally, we detected rapid increase of haemoglobin and lymphocyte counts to baseline values in patients receiving sofosbuvir monotherapy; improvement of these indices occurred at a slower rate and to a lesser extent in the group randomised to receive sofosbuvir plus ribavirin (figure 2). Although mean serum ALT concentrations decreased in all cohorts B, C1, and C2 (figure 2) during the first 12 weeks of treatment, we saw further improvements after discontinuation of peginterferon at week 12.

Discussion

Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending sofosbuvir treatment beyond 12 weeks. Furthermore, patients in the groups receiving longer durations of peginterferon generally had higher rates of adverse effects without an attendant increase in efficacy.

The uniformly high rates of SVR24 with sofosbuvir plus peginterferon plus ribavirin also suggest that there would be no need to tailor either the treatment duration or regimen to individual patients on the basis of early response or baseline characteristics. Protease inhibitor regimens (approved in April, 2011) use response-guided treatment to shorten treatment duration from 48 weeks to 24-28 weeks in patients who fulfil predefined criteria for early response.2, 3 Our results indicate that response-guided treatment might not be needed for treatment with sofosbuvir. Moreover, on the basis of our findings, other factors previously shown to be predictive of response to treatment-IL28B CC versus non-CC genotype, high versus low baseline viral load, and genotype 1a versus genotype 1b-are of doubtful use with this sofosbuvir regimen. Although all but one patient who relapsed carried non-CC IL28B alleles, the predictive value of this index for response seems insufficient to base treatment decisions on. However, the small numbers of patients in some of these subgroups do not allow definitive conclusions.

The advent of direct-acting antivirals has been accompanied by concerns about the development of drug resistance.7 In phase 3 trials of the protease inhibitors telaprevir and boceprevir, resistance-associated mutations were detected in up to 75% of patients who did not achieve SVR.12 More than 90% of patients who had virological failure in these trials were shown to harbour drug-resistant variants.12 Our findings seem to lend support to the claim that sofosbuvir has a high barrier to resistance. We detected no virological breakthrough or treatment-emergent resistance in this trial. Relapse after treatment was rare, and no patients who had relapse showed the presence of the signature Ser282Thr mutation in population sequencing.

Sofosbuvir-based treatment seemed to be safe and well tolerated. Most of the adverse events and laboratory abnormalities seen during this study were characteristic of peginterferon or ribavirin. Patients in cohort C who received sofosbuvir monotherapy after 12 weeks of triple therapy showed prompt improvement in haemoglobin and neutrophil values towards baseline values, suggesting little or no haematological toxicity that could be ascribed solely to sofosbuvir. Patients in the third cohort who received sofosbuvir and ribavirin combination treatment after 12 weeks of triple therapy also showed improvement in haematological indices, although recovery was slower, consistent with the effect of ribavirin.

In terms of its rate of response, resistance profile, and safety characteristics, sofosbuvir plus peginterferon plus ribavirin for 12 weeks seems to compare favourably with those seen with present standard-of-care treatments for treatment-naive patients with HCV genotype-1 (panel).

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Panel

Research in context

Systematic review

We consulted a review of treatment of hepatitis C in adults,14 which systematically assessed a large body of evidence concerning outcomes of clinical trials of approved drug regimens for the treatment of hepatitis C virus (HCV). We searched PubMed in December, 2012, using the search term "HCV treatment", searching for studies written in English. We also consulted treatment guidelines for hepatitis C.1, 15

Interpretation

For previously untreated patients with genotype-1 hepatitis C infection, standard-of-care treatment is one of the recently approved (April, 2011) protease inhibitors-telaprevir or boceprevir-plus peginterferon and ribavirin. Our findings lend support to the phase-3 assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. Furthermore, the exploration of the combination of sofosbuvir with other direct-acting antiviral agents is warranted.

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Sofosbuvir-based combination treatment also seemed to be effective in patients with HCV genotypes 4 and 6; however, the small numbers of patients in the study with genotype 4 and 6 preclude any definitive conclusions. Nor do our data allow us to address whether 12 weeks of treatment is sufficient for patients with these genotypes, because all patients with genotypes 4 or 6 received 24 weeks of triple therapy. However, we saw no breakthrough or relapse in any patient with HCV genotype 4 or 6. The only two patients (both genotype 4) who did not achieve SVR24 were lost to follow-up.

This study was limited by its exclusion of patients that are historically more difficult to treat-namely, those with cirrhosis and advanced liver disease. Ongoing phase 3 trials (NCT01497366, NCT01641640, NCT01542788, and NCT01604850) of sofosbuvir include patients with cirrhosis. We have planned future studies to examine the effectiveness of this agent in patients who have failed to respond to telaprevir-based or boceprevir-based combination treatment.

Our findings suggest that simple, short sofosbuvir-based regimens are effective for patients with HCV genotypes 1, 4, and 6. Further study of this agent in phase 3 studies are warranted and ongoing.

Source