October 1, 2013

J Hepatol. 2013 Oct;59(4):667-74. doi: 10.1016/j.jhep.2013.05.017. Epub 2013 May 23.

Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J; Kyushu University Liver Disease Study (KULDS) Group.

Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.

Abstract

BACKGROUND & AIMS: Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.

METHODS: This prospective, multicenter study consisted of 292 patients (median age: 62years) infected with HCV genotype 1. All received 12weeks of TVR in combination with 24weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85g/L.

RESULTS: 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135g/L (Hazard ratio [HR], 2.53; p=0.0013), estimated glomerular filtration rate <80ml/min/1.73m(2) (HR, 1.83; p=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p=0.0281).

CONCLUSIONS: Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: AUROC, Anemia, CI, HCV, HR, Hb, Hepatitis C virus, ITPA, Inosine triphosohatase, PegIFN, Pegylated interferon, RBV, RVR, Ribavirin, SNP, SVR, TVR, Telaprevir, area under the receiver operating characteristic curve, confidence interval, eGFR, estimated glomerular filtration rate, hazard ratio, hemoglobin, hepatitis C virus, inosine triphosphatase, pegylated interferon, rapid virological response, ribavirin, single nucleotide polymorphism, sustained virological response, telaprevir

PMID: 23707372 [PubMed - in process]

Source

Eur J Gastroenterol Hepatol. 2013 Nov;25(11):1300-7. doi: 10.1097/MEG.0b013e32836140bb.

Brunner N, Senn O, Rosemann T, Falcato L, Bruggmann P.

aDepartment of Research, Institute of General Practice and Health Services, University of Zurich bDepartment of Internal Medicine, ARUD, Centres for Addiction Medicine, Zurich, Switzerland.

Abstract

OBJECTIVES/BACKGROUND: The population of people who use drugs (PWUD) has the highest prevalence of hepatitis C virus (HCV) infections in Europe. PWUD are multimorbid patients who are difficult to integrate into existing healthcare systems. In our study, we evaluated the feasibility of providing HCV treatment within opioid maintenance treatment (OMT) programmes offering integrated primary care-based health services under one roof.

METHODS: We evaluated 66 charts of patients in four outpatient clinics (OMT) with HCV treatment (between 2002 and 2010). Fourteen of the patients were treated with heroin and nine patients had an HIV coinfection. Data on the socioeconomic characteristics and quality of life were assessed. We counted the number of consultations in the clinic to assess how much supportive care the patients needed.

RESULTS: Overall, 62% of all patients (41 out of 66) achieved a sustained virological response (SVR). A total of 84% of patients with genotype 3 achieved an SVR. Sixty-four percent of patients treated with heroin achieved an SVR. The majority of patients (71%) used illicit drugs during HCV treatment and over 80% were diagnosed with psychiatric comorbidities. Comparisons of patient characteristics according to SVR or non-SVR showed that a longer duration of OMT, more consultations per week during HCV treatment and poor self-reported physical condition were associated with non-SVR.

CONCLUSION: We conclude that offering HCV treatment in an integrated primary care-based setting with OMT and individualized use of different supporting strategies allows for treatment success rates in the population of PWUD that is comparable to the ones in the population of patients without drug use. Heroin maintenance treatment programmes offer a feasible and safe setting for providing HCV treatment.

PMID: 23571610 [PubMed - in process]

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PRESS RELEASE

Oct. 1, 2013, 4:05 p.m. EDT

Data Support Strong Statistical Association of PBC Biochemical Endpoint with Clinical Outcomes

NEW YORK, Oct. 1, 2013 /PRNewswire via COMTEX/ -- Intercept Pharmaceuticals, Inc. /quotes/zigman/12230574/quotes/nls/icpt ICPT -3.47% (Intercept), a clinical stage biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat chronic liver diseases such as primary biliary cirrhosis, today announced that two analyses by the Global Primary Biliary Cirrhosis (PBC) Study Group (also known as the PBC Supergroup) have been accepted for oral presentation at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place November 1 - 5 in Washington, D.C.

Data from over 3,895 PBC patients collected and pooled by an independent group of 15 academic medical centers across eight countries have been analyzed by the Global PBC Study Group. These analyses are expected to further confirm that the surrogate biochemical endpoint used by Intercept in its ongoing Phase 3 POISE trial (i.e., alkaline phosphatase (ALP) < 1.67x upper limit of normal and normal bilirubin) is strongly predictive of adverse clinical outcomes in PBC patients.

"This international collaboration has assembled data from the largest group of PBC patients to have ever been evaluated since PBC was first described over 150 years ago," commented Dr. Henk van Buuren, one of the principal investigators at Erasmus University Medical Centre. "The data show that abnormal biochemical values predict a higher risk of adverse clinical outcomes. We believe that our results will facilitate the development of new drugs by clearly establishing meaningful biochemical goals for therapy and enable physicians to determine if a given treatment is effective. PBC is a rare disease and we are very grateful to our colleagues at the many participating institutions around the world for sharing their data."

The two abstracts from the Global PBC Study Group can be accessed through the AASLD website, www.aasld.org.  

Primary Biliary Cirrhosis and the Global PBC Study Group PBC is an autoimmune chronic liver disease that typically affects women. The disease progresses in those patients who have an inadequate response to therapy and may require a liver transplant or die. Biochemical assessments of liver function, particularly by measuring plasma levels of ALP and bilirubin, are typically used by physicians to diagnose and manage PBC patients. There is a log-linear relationship between ALP levels and transplant-free survival; higher levels are associated with a worse prognosis. Accordingly, the relationship between these biochemical assessments of liver function and adverse clinical outcomes is highly important in the selection of appropriate endpoints in therapeutic clinical trials.

Data from the Global PBC Study Group are being analyzed under the direction of Dr. Bettina Hansen, Dr. Henk van Buuren and colleagues at Erasmus University Medical Centre in Rotterdam, The Netherlands. Intercept is sponsoring this independent academic research program but is not involved in the data collection and analysis. In April 2013, the Global PBC Study Group presented an analysis of data from over 2,100 patients at the annual meeting of the European Association for the Study of the Liver (EASL). These preliminary data demonstrated that the primary endpoint being used in Intercept's Phase 3 POISE trial is highly statistically predictive of liver transplant-free survival in PBC patients.

About Intercept Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat orphan and more prevalent liver diseases utilizing its expertise in bile acid chemistry. The company's lead product candidate, obeticholic acid (OCA), is a bile acid analog and first-in-class agonist of the farnesoid X receptor (FXR). OCA is initially being developed for the second line treatment of primary biliary cirrhosis (PBC) in patients with an inadequate response to, or who are unable to tolerate, ursodiol, the only approved therapy for this indication. OCA has received orphan drug designation in both the United States and Europe for the treatment of PBC. Intercept owns worldwide rights to OCA outside of Japan and China, where it has out-licensed the product candidate to Dainippon Sumitomo Pharma. For more information about Intercept, please visit the Company's website at: www.interceptpharma.com.

Safe Harbor Statement This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the analyses of the Global PBC Study Group data and the results thereof, the relationship between ALP and bilirubin and adverse clinical outcomes, the clinical utility of the POISE trial selected endpoints and any potential consensus relating thereto, clinical, preclinical and regulatory developments for our product candidates, the anticipated results of our clinical and preclinical trials and other development activities, and our strategic directives under the caption "About Intercept." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the initiation, cost, timing, progress and results of Intercept's development activities, preclinical studies and clinical trials; the timing of and Intercept's ability to obtain and maintain regulatory approval of OCA and any other product candidates it may develop, and any related restrictions, limitations, and/or warnings in the label of any approved product candidates; Intercept's plans to research, develop and commercialize future product candidates; the election by Intercept's collaborators to pursue research, development and commercialization activities; Intercept's ability to attract collaborators with development, regulatory and commercialization expertise; Intercept's ability to obtain and maintain intellectual property protection for its product candidates; Intercept's ability to successfully commercialize its product candidates; the size and growth of the markets for Intercept's product candidates and its ability to serve those markets; the rate and degree of market acceptance of any future products; the success of competing drugs that are or become available; regulatory developments in the United States and other countries; the performance of third-party suppliers and manufacturers; Intercept's ability to obtain additional financing; Intercept's use of the proceeds from its recently completed initial public offering; the accuracy of Intercept's estimates regarding expenses, future revenues, capital requirements and the need for additional financing; the loss of key scientific or management personnel; and other factors discussed under the heading "Risk Factors" contained in Intercept's annual report on Form 10-K for the year ended 2012, as well as any updates to these risk factors filed from time to time in Intercept's other filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Intercept undertakes no duty to update this information unless required by law.

For more information about Intercept, please contact Barbara Duncan or Senthil Sundaram, both of Intercept Pharmaceuticals, at 1-646-747-1000.

SOURCE Intercept Pharmaceuticals

Copyright (C) 2013 PR Newswire. All rights reserved

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Public release date: 1-Oct-2013

Contact: Steve Yozwiak
syozwiak@tgen.org
602-343-8704
The Translational Genomics Research Institute

Study with Geisinger Health System tests nearly 2,300 extremely obese diabetes patients

PHOENIX, Ariz. — Oct. 1, 2013 — A groundbreaking study of nearly 2,300 extremely obese diabetes patients, led by the Translational Genomics Research Institute (TGen), has identified genes associated with unhealthy liver function.

This is believed to be the nation's first large-scale genome-wide association study in overweight patients with diabetes.

Results of the study, done in conjunction with the Geisinger Health System, will be presented at the 64th annual meeting of the American Association for the Study of Liver Diseases Nov. 1-5 at the Walter E. Washington Convention Center in Washington, D.C.

The study — Genome-wide analysis identifies loci associated with total bilirubin levels, steatosis, and mild fibrosis in nonalcoholic fatty liver disease — looked at how genomic factors affect the development of non-alcoholic fatty liver disease. It was selected for presentation from among a record 3,139 submittals from around the world proposed for what also is known as The Liver Meeting 2013.

"These genetic factors could help us identify patients who are most at risk of developing non-alcoholic forms of fatty-liver disease (NAFLD), and which patients may be more likely to progress to severe forms of NAFLD, such as steatohepatitis (NASH)," said Dr. Johanna DiStefano, the study's principal investigator and lead author. Dr. DiStefano is Director of TGen's Diabetes, Cardiovascular and Metabolic Diseases Division.

NAFLD is the build up of extra fat in liver cells, not caused by alcohol. It is one of the most common causes of chronic liver disease. NASH is liver inflammation and damage caused by a buildup of fat in the liver, not caused by alcohol.

"Our results showed evidence for new genetic loci that may play a role in the biological mechanisms of NAFLD and NASH," said Dr. Glenn S. Gerhard, a faculty member of the Geisinger Obesity Institute and a co-investigator of the study.

"We discovered genes that may help identify those patients most at risk for the types of liver disease so severe that they could require transplants," said Dr. Gerhard, Administrative Director for the Institute for Personalized Medicine at Penn State University-Hershey.

Patients included in this study were those with extreme obesity enrolled in a bariatric surgery program.

The study identified evidence for association with markers in the neurocan gene (NCAN) on chromosome 19p12, and rs2501843 on chromosome 1.

###

The American Association for the Study of Liver Diseases (AASLD) is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists to bring together those who had contributed to the field of hepatology.

AASLD has grown to an international society responsible for all aspects of hepatology. Its annual meeting, The Liver Meeting, has grown in attendance from 12 to more than 9,500 physicians, surgeons, researchers, and allied health professionals from around the world.

About Geisinger Health System

Geisinger Health System is an integrated health services organization widely recognized for its innovative use of the electronic health record, and the development of innovative care models such as ProvenHealth Navigator® and ProvenCare®. As the nation's largest rural health services organization, Geisinger serves more than 2.6 million residents throughout 44 counties in central and northeastern Pennsylvania. The physician-led system is comprised of more than 19,500 employees, including a 1,000-member multi-specialty group practice, six hospital campuses, two research centers and a 448,000-member health plan, all of which leverage an estimated $6.1 billion positive impact on the Pennsylvania economy. The health system and the health plan have repeatedly garnered national accolades for integration, quality and service. In addition to fulfilling its patient care mission, Geisinger has a long-standing commitment to medical education, research and community service. For more information, visit http://www.geisinger.org, or follow the latest Geisinger news and more on Twitter and Facebook.

Press Contact:

Wendy Wilson
Media Team Director
Geisinger Health System
570-969-7807
wkwilson@geisinger.edu

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: http://www.tgen.org.

Press Contact:

Steve Yozwiak
TGen Senior Science Writer
602-343-8704
syozwiak@tgen.org

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(Thomson Reuters ONE via COMTEX) --New York, NY - October 1, 2013 - Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on oncology, announced today that the U.S. Food & Drug Administration (FDA) has granted the Company orphan drug designation for melphalan in the treatment of patients with hepatocellular carcinoma (HCC, or primary liver cancer).

Orphan-drug designation is granted by the FDA Office of Orphan Products Development to novel drugs or biologics that treat a rare disease or condition affecting fewer than 200,000 patients in the U.S. The designation provides the drug developer with a seven-year period of U.S. marketing exclusivity if the drug is the first of its type approved for the specified indication or if it demonstrates superior safety, efficacy, or a major contribution to patient care versus another drug of its type previously granted the designation for the same indication. It also provides tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance and waiver of Prescription Drug User Fee Act (PDUFA) filing fees.

Melphalan for use with the Delcath Hepatic Delivery System is not currently approved in the United States for the treatment of patients with HCC.

About Delcath Systems

Delcath Systems, Inc. is a specialty pharmaceutical and medical device company focused on oncology. Our proprietary drug/device combination product, the Delcath Hepatic Delivery System, is designed to administer high dose chemotherapy and other therapeutic agents to the liver, while controlling the systemic exposure of those agents. The Company's initial focus is on the treatment of primary and metastatic liver cancers. Outside of the United States, our proprietary product to deliver and filter melphalan hydrochloride is marketed under the trade name Delcath Hepatic CHEMOSAT® Delivery System for melphalan hydrochloride. The Company obtained authorization to affix a CE Mark for the Generation Two CHEMOSAT Delivery System for Melphalan in April 2012. The right to affix the CE mark allows the Company to market and sell the CHEMOSAT Delivery System for Melphalan in Europe. In addition, the Company has initiated plans to investigate the Melphalan Hydrochloride for Injection for use with the Delcath Hepatic Delivery System for primary liver cancer. For more information, please visit the Company's website at www.delcath.com.

Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by the Company or on its behalf. This news release contains forward-looking statements, which are subject to certain risks and uncertainties that can cause actual results to differ materially from those described. Factors that may cause such differences include, but are not limited to, uncertainties relating to: the timing and results of the Company's future clinical trials including without limitation the HCC trials, FDA approval of the melphalan Delcath Hepatic Delivery System for the treatment of HCC,, the Company's ability to benefit from the orphan drug designation for melphalan for the treatment of HCC, the Company's ability to satisfy the requirements of the FDA's Complete Response Letter and provide the same in a timely manner, clinical adoption, use and resulting sales, if any, for the CHEMOSAT system to deliver and filter melphalan in Europe, our ability to successfully commercialize the chemosaturation system and the potential of the chemosaturation system as a treatment for patients with primary and metastatic disease in the liver, our ability to obtain reimbursement for the CHEMOSAT system in various markets, approval of the current or future chemosaturation system for delivery and filtration of melphalan, doxorubicin or other chemotherapeutic agents for various indications in the US and/or in foreign markets, actions by the FDA or other foreign regulatory agencies, our ability to successfully enter into strategic partnership and distribution arrangements in foreign markets including Australia and key Asian markets and timing and revenue, if any, of the same, uncertainties relating to the timing and results of research and development projects,, and uncertainties regarding our ability to obtain financial and other resources for any research, development, clinical trials and commercialization activities. These factors, and others, are discussed from time to time in our filings with the Securities and Exchange Commission. You should not place undue reliance on these forward-looking statements, which speak only as of the date they are made. We undertake no obligation to publicly update or revise these forward-looking statements to reflect events or circumstances after the date they are made.

This announcement is distributed by Thomson Reuters on behalf of Thomson Reuters clients.

The owner of this announcement warrants that:

(i) the releases contained herein are protected by copyright and other applicable laws; and

(ii) they are solely responsible for the content, accuracy and originality of the

information contained therein.

Source: Delcath Systems, Inc via Thomson Reuters ONE

HUG#1732945

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Journal of Viral Hepatitis

E. J. Lawitz, M. Rodriguez-Torres, J. Denning, A. Mathias, H. Mo, B. Gao, M. T. Cornpropst, M. M. Berrey, W. T. Symonds

J Viral Hepat. 2013;20(10):699-707.

Abstract and Introduction

Abstract

Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of −4.50 (−4.66, −4.24) in Cohort 1, −4.55 (−4.97, −4.13) in Cohort 2, −4.65 (−4.78, −4.17) in Cohort 3 and −4.43 (−4.81, −4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log10 IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1–4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938—alone and in combination—were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.

Introduction

Adding the protease inhibitors telaprevir or boceprevir to peginterferon and ribavirin has improved rates of sustained virologic response in patients with genotype 1 chronic hepatitis C virus (HCV) by as much as 30% over those seen with peginterferon and ribavirin alone.[1,2] However, these regimens can be challenging for patients to adhere to and tolerate.[3] Peginterferon in particular is associated with a number of onerous side effects, including flulike symptoms, anaemia and depression.[4] Telaprevir, boceprevir and many other direct-acting antivirals cannot be used as monotherapies because of the potential for viral resistance. To minimize the development of resistance, many experimental all-oral regimens involve combination therapy. Recently, it was reported that an all-oral combination therapy with an NS5A replication complex inhibitor and an NS3 protease inhibitor can lead to sustained virologic response in HCV genotype 1 patients who were prior nonresponders to peginterferon and ribavirin,[5,6] suggesting that interferon-free regimens may be a viable treatment strategy.

Sofosbuvir (GS-7977) is a pyrimidine nucleotide analogue inhibitor of the HCV NS5B polymerase. GS-0938 is a purine nucleotide analogue inhibitor of the NS5B polymerase. They both employ unique prodrug components that deliver the monophosphorylated forms of the respective nucleosides. Like other nucleoside or nucleotide analogues, sofosbuvir and GS-0938 appear to have equal antiviral activity against various HCV subtypes as well as high barriers to genetic resistance.[7–10] Phenotypic evaluation of mutations from an in vitro resistance selection experiment with GS-0938 indicated that single amino acid changes were not sufficient to significantly reduce the activity of GS-0938. Among these, the highest fold-shift in EC50 was 3.7 ± 1.4 attributed to C223H.[8] Combinations of three and four amino acid changes were required to confer 17-fold and 20-fold reduced susceptibility to GS-0938. A resistance selection experiment performed with sofosbuvir identified NS5B S282T and M289L as resistance-associated mutations.[9] In vitro, the combination of sofosbuvir and GS-0938 results in additive to synergistic antiviral activity.[11] In patients with HCV genotype 1 infection, 7 days of monotherapy with GS-0938 resulted in HCV RNA reductions of up to 5.35 log10 IU/mL.[12] Before this trial, sofosbuvir had not been administered as monotherapy, but was studied as one of the two diasteromers of the compound GS-9851 (PSI-7851). In a dose-ranging monotherapy study, patients receiving 400 mg of GS-9851 for 3 days experienced a mean maximal reduction in HCV RNA of 1.95 log10 IU/mL.[13] When sofosbuvir was administered to HCV genotype 1 patients in combination with peginterferon and ribavirin for 28 days, the combination resulted in mean HCV RNA reductions of up to 5.3 log10 IU/mL.[14]

Sofosbuvir and GS-0938 have a number of structural differences; they employ different prodrug cleavage pathways, have largely independent phosphorylation pathways, compete with separate endogenous nucleotide pools (purine/pyrimidine) and have complementary resistance profiles.[15–17] This phase 1, placebo-controlled study of sofosbuvir and GS-0938 alone and in combination for 14 days is the first proof-of-concept study of the feasibility of combining two nucleotides for the treatment of patients with genotype 1 HCV and is the first trial characterizing the activity of sofosbuvir administered as monotherapy for 7 days.

Experimental Procedures

Study Design

This was a multicentre, randomized, double-blind, placebo-controlled study of sofosbuvir, GS-0938 and the combination of sofosbuvir and GS-0938 in 4 cohorts of patients infected with HCV genotype 1. Between July 2010 and February 2011, patients were sequestered at 1 of 2 study sites (1 in Texas and 1 in Puerto Rico) the day prior to dosing initiation and stayed for 17 days. Dosing occurred in the mornings on Days 1–14, as follows: GS-0938 300 mg once daily (QD) for all 14 days (Cohort 1); GS-0938 300 mg QD on Days 1–7 followed by GS-0938 300 mg QD and sofosbuvir 400 mg QD on Days 8–14 (Cohort 2); sofosbuvir 400 mg QD on Days 1–7 followed by GS-0938 300 mg QD and sofosbuvir 400 mg QD on Days 8–14 (Cohort 3); and GS-0938 300 mg QD and sofosbuvir 400 mg QD for all 14 days (Cohort 4). Two patients from each arm were randomized to receive placebo (Cohort 5) (Fig. 1).

811157-fig1

Figure 1. Study design.

Patients fasted 10 h prior to receiving study drug and 4 h postdose on Day 1 in Cohort 4, on Day 7 in Cohorts 2 and 3 and on Day 14 in all cohorts. In all cohorts and on all other study days, patients received the first meal of the morning 2 h after dosing. Each cohort had 10 patients, who were randomly assigned to active drug and placebo in a ratio of 4:1 with a block size of 5. Random allocation sequence was generated by PharStat (Durham, NC, USA). Patients remained in the clinic until Day 17 and then returned on Day 21 for follow-up assessments.

This study was blinded to both investigators and patients through Day 14. Study medication was prepared from bulk supply by an unblinded pharmacist or pharmacist designee and administered by a qualified site staff member who was not otherwise directly involved in this study.

Treatment group sizes were chosen empirically; no formal power or sample size calculations were made. The efficacy endpoint was the change from baseline in plasma HCV RNA, assessed as continuous change from baseline (log10 IU/mL) and as categorical reduction [i.e. <1, ≥1, ≥2, ≥3 log10 IU/mL, or below the lower limit of detection (<15 IU/mL)].

The study protocol was approved by each institution's review board prior to study initiation and was performed in accordance with Good Clinical Practice guidelines outlined by the International Conference on Harmonization. On Day 14 of the study, all patients were offered a full course of standard of care therapy with pegylated interferon and ribavirin. Please see clinical trial protocol, available in the supplementary materials; Appendix S1.

Patients

Eligible patients were men and women between the ages of 18–65 years, chronically infected with HCV genotype 1 (plasma HCV RNA ≥50 000 IU/mL at screening) and had received no prior treatment for HCV infection. Patients had a body mass index of 18–36 kg/m2 inclusive, and were noncirrhotic, as judged by liver biopsy within the prior 3 years. Patients with any of the following were excluded: a chronic liver disease besides hepatitis C; hepatic decompensation; QTc value ≥450 msec; coinfection with HIV or hepatitis A or B virus; creatinine ≥1.5 × ULN; alanine aminotransferase (ALT), aspartate aminotransferase or alkaline phosphatase levels ≥5 × ULN; total bilirubin ≥2 × ULN; haemoglobin <11 g/dL in females and <12 g/dL in males; albumin ≤3 g/dL; serum lipase ≥1.5 × ULN; potassium or magnesium <LLN; creatinine clearance <60 mL/min; or absolute neutrophil count <1500 cells/mm3. Concomitant prescription medications were prohibited during the study unless approved by the investigator and sponsor. Females were required to be surgically sterile or postmenopausal for at least 12 months confirmed by FSH value >35 IU/mL at screening. Where allowed by local regulations, females of child-bearing potential were enrolled provided they used two methods of acceptable contraception. All patients provided written informed consent before undertaking any study-related procedures.

Efficacy Assessments

HCV RNA Blood samples for determining plasma HCV RNA levels were collected at screening; on Days 1–4, 6, 8–11 and 13 prior to study drug dosing; and on Days 15, 17 and 21. Plasma HCV RNA was analysed by Cenetron Central Laboratories (Austin, TX, USA) using the Roche COBAS AmpliPrep/COBAS HCV TaqMan assay (Roche Molecular Systems, Inc., Branchburg, NJ, USA), Research Use Only version, which has a lower limit of quantification of 43 IU/mL and a lower limit of detection of 15 IU/mL.

Resistance Monitoring Serum samples for NS5B genotypic and phenotypic monitoring were collected on Days 1, 4, 8, 11, 15 and 17 in the morning (before dose on dosing days) and at follow-up on Day 21.

Population sequencing of the HCV NS5B-encoding region of the polymerase of all baseline and end-of-treatment viral samples was performed by the DDL Diagnostic Laboratory (Rijswijk, Netherlands) using standard sequencing technology. Amino acid substitutions in samples taken after baseline were compared with baseline.

Pharmacokinetic Assessments

The pharmacokinetic profiles of sofosbuvir and GS-0938 administered alone and in combination were examined on Days 7 (Cohorts 2 and 3) and 14 (Cohorts 1–4), respectively. Blood samples were drawn at selected time points over the dosing interval. Pharmacokinetic parameters estimated (nonlinear curve-fitting; Phoenix WinNonlin version 6.3; Pharsight Corporation, Mountain View, CA, USA) for sofosbuvir, GS-0938 and GS-331007 (the predominant circulating nucleoside metabolite of sofosbuvir) included maximum observed plasma concentration (Cmax), time to maximum plasma concentration (Tmax), concentration at the end of dosing Ctau, area under the plasma concentration–time curve from 0 h to end of dosing (AUC0-tau) and elimination half-life (t1/2).

Safety Assessments

From baseline through the Day 21 follow-up visit, safety was evaluated on the basis of reported adverse events, physical examinations, clinical laboratory tests, vital signs and ECG recordings. Concomitant medication intake was also recorded. Treatment-emergent adverse events were summarized by treatment, system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA®), version 14.0. The intensity of an adverse event was graded based on the DAIDS Therapeutic Research Program's 'Table for Grading Severity of Adult Adverse Experiences, August 2009'.

Results

Study Population

Forty patients were randomized and received study drug. Median (Q1, Q3) baseline HCV RNA levels were similar between cohorts and ranged from 5.9 (5.2, 6.7) log10 IU/mL in the placebo group to 7.0 (6.2, 7.5) in the group receiving GS-0938 monotherapy. Between 75% and 100% of patients in each treatment group were infected with genotype 1a HCV. The distribution of IL28B genotypes was uneven across treatment arms; for example, 63% of patients in the GS-0938 monotherapy arm harboured the CC genotype, as compared to no patients in the group that received sofosbuvir plus GS-0938 for 14 days (Table 1). All patients completed treatment and participated in the study through follow-up.

Table 1.  Patient demographics and baseline characteristics

Baseline Characteristics GS-0938 × 14days (n = 8) GS-0938 × 7 days, GS-0938 + SOF × 7 days (n = 8) SOF × 7 days, GS-0938 + SOF × 7 days (n = 8) GS-0938 + SOF × 14 days (n = 8) Placebo (n = 8)
Median (range) age at baseline, years 49.5 (24–58) 44.0 (28–59) 33.5 (24–58) 47.5 (35–58) 41.5 (27–53)
Male, n (%) 5 (62.5) 7 (87.5) 7 (87.5) 6 (75.0) 7 (87.5)
Race, n (%)
   White 6 (75.0) 5 (62.5) 5 (62.5) 5 (62.5) 6 (75.0)
   Black 1 (12.5) 3 (37.5) 3 (37.5) 3 (37.5) 2 (25.0)
Mean (SD) body mass index, kg/m2 28.5 (2.2) 27.1 (2.4) 29.4 (4.5) 27.5 (3.6) 27.3 (4.7)
Median (Q1, Q3) HCV RNA, log10 IU/mL 7.0 (6.2, 7.5) 6.3 (5.8, 6.7) 6.2 (5.7, 6.8) 6.3 (5.9, 6.6) 5.9 (5.2, 6.7)
Mean (SD) ALT, IU/L 90.5 (61.8) 99.0 (116.0) 56.0 (16.9) 36.3 (13.4) 44.5 (29.1)
Ishak liver biopsy score, n (%)
   0 3 (37.5) 5 (62.5) 7 (87.5) 5 (62.5) 5 (62.5)
   1 3 (37.5) 2 (25.0) 1 (12.5) 3 (37.5) 3 (37.5)
   3 2 (25.0) 0 0 0 0
   4 0 1 (12.5) 0 0 0
IL28B status, n (%)
   CC 5 (62.5) 3 (37.5) 4 (50.0) 0 1 (12.5)
   CT 2 (25.0) 2 (25.0) 3 (37.5) 5 (62.5) 4 (50.0)
   TT 1 (12.5) 3 (37.5) 1 (12.5) 3 (37.5) 3 (37.5)
HCV genotype, n (%)
   1a 6 (75.0) 7 (87.5) 8 (100.0) 7 (87.5) 6 (75.0)
   1b 2 (25.0) 1 (12.5) 0 1 (12.5) 0
   Indeterminant* 0 0 0 0 2 (25.0)

ALT, alanine aminotransferase; HCV, hepatitis C virus. *HCV genotype was originally reported as 'Indeterminant'; however, NS5b sequencing was conducted later to identify them as genotype '1a'.

Efficacy Assessments

Antiviral response Substantial on-treatment reductions in HCV RNA were experienced by patients in all 4 active-therapy cohorts in the first days of treatment ( and Figs 2 and 3). The initial rapid reductions in HCV RNA were followed by more gradual virologic declines, which continued through the end of dosing on Day 14. After 7 days of dosing, patients receiving active therapy had median HCV RNA declines ranging from −4.43 to −4.65 IU/mL; after 14 days of dosing, declines ranged from −4.99 to −5.21 IU/mL (). The proportion of patients with HCV RNA <15 IU/mL ranged from 13% to 50% (overall 28%) at Day 7 and 50–100% (overall 75%) at Day 14. Dual therapy with sofosbuvir and GS-0938 did not appear to produce greater median on-treatment reductions in HCV RNA than monotherapy with GS-0938. However, a greater proportion of patients on combination therapy achieved HCV RNA <15 IU/mL by the end of treatment (50% on GS-0938 monotherapy vs 63–100% on combination therapy). All patients with undetectable HCV RNA at the end of dosing still had undetectable HCV RNA 7 days after the end of study treatment (it should be noted that most of these patients elected to continue treatment with peginterferon and ribavirin at the conclusion of the 14 days of study treatment).

Table 2.  Summary of antiviral response after 4, 8 and 15 days of treatment

  GS-0938 × 14 days (n = 8) GS-0938 × 7 days, GS-0938 + SOF × 7 days (n = 8) SOF × 7 days, GS-0938 + SOF × 7 days (n = 8) GS-0938 + SOF × 14 days (n = 8) Placebo (n = 8)
Day 4
   Median HCV RNA (Q1, Q3) −3.93 (−4.03, −3.50) −3.89 (−4.18, −3.32) −3.69 (−4.05, −3.37) −3.65 (−4.16, −3.56) −0.12 (−0.33, 0.23)
   <15 IU/mL, n (%) 1 (13) 1 (13) 1 (13) 0 0
Day 8
   Median HCV RNA (Q1, Q3) −4.50 (−4.66, −4.24) −4.55 (−4.97, −4.13) −4.65 (−4.78, −4.17) −4.43 (−4.81, −4.13) 0.07 (−0.16, 0.19)
   <15 IU/mL, n (%) 0 3 (38) 5 (63) 0 0
Day 15
   Median HCV RNA (Q1, Q3) −5.21 (−5.76, −4.71) −5.15 (−5.54, −4.61) −5.02 (−5.37, −4.49) −4.99 (−5.37, −4.66) −0.04 (−0.55, 0.28)
   <15 IU/mL, n (%) 4 (50) 8 (100) 7 (88) 5 (63) 0

Measurements on Days 4, 8, and 15 are predosing and reflect 3, 7, and 14 days of dosing.

811157-fig2

Figure 2. Median hepatitis C virus (HCV) RNA changes from baseline.

811157-fig3

Figure 3. Individual patient changes in hepatitis C virus (HCV) RNA from baseline.

Resistance Monitoring

The NS5B mutations associated with resistance to either GS-0938 (S15G, R222Q, C223Y, C223H, L320I and V321I) or SOF (S282T and M289L) were not detected in any of these patients at baseline.

No on-treatment viral breakthrough was detected in any patient among the 32 subjects who received active drugs. HCV RNA levels for all patients following a 14-day dosing period were generally very low: <1000 IU/mL at end of treatment Day 15 (HCV RNA levels were below the level of detection in the majority of subjects). With the exception of two subjects who received GS-0938 monotherapy, all subjects had HCV RNA <1000 IU/mL at Day 21 (7 days after the last dose), which precluded them from NS5B population sequencing. Population sequence results were available from one of the two subjects with sufficient HCV RNA for sequencing. At the 21-day follow-up visit, substitutions at NS5B associated with reduced susceptibilities to GS-0938 (S15G, R222Q, C223Y, C223H, L320I and V321I) were not detected in this patient.

Pharmacokinetic Assessments

Plasma pharmacokinetic parameters for sofosbuvir and GS-331007 following administration of sofosbuvir alone are summarized in Table 3. As seen in previous clinical studies, sofosbuvir exhibits low and transient exposure with maximum concentrations achieved within 0.75 h postdose (median Tmax) and a terminal half-life of 0.48 h (median t1/2). The majority of systemic exposure is accounted for by GS-331007, which exhibits a maximum concentration achieved within 2 h postdose (median Tmax) and a longer plasma circulating half-life of 9.4 h (median t1/2).

Table 3.  Plasma pharmacokinetic parameters of sofosbuvir and GS-331007 following administration of sofosbuvir alone (Day 7)

Parameter Sofosbuvir GS-331007
Mean AUC0-tau, h ng/mL (SD) 538.12 (38.97) 9638.94 (18.72)
Mean Cmax, ng/mL (SD) 602.59 (47.15) 1378.33 (19.16)
Mean Ctau, ng/mL (SD) 0.00* 98.15 (23.44)
Median Tmax, h (Q1, Q3) 0.50 (0.50, 0.77) 2.00 (1.75, 3.00)
Median t1/2, h (Q1, Q3) 0.48 (0.44, 0.52) 9.42 (8.84, 12.24)

*All Ctau measurements were below the limit of quantitation.

A direct assessment of drug–drug interactions between GS-0938 and sofosbuvir was made in patients receiving sofosbuvir and GS-0938 combination therapy vs sofosbuvir alone or GS-0938 alone. The data indicate that GS-0938 and sofosbuvir were involved in a modest pharmacokinetic drug interaction upon coadministration that is not considered clinically significant. A modest increase in GS-0938 Cmax (24% increase), but no relevant change in the GS-0938 AUC, was observed on coadministration of the combination. Exposure (AUC0-tau and Cmax) of sofosbuvir was modestly elevated (<60%) by GS-0938, with no effect of GS-0938 on the exposure of GS-331007 (the GLSM ratios and associated 90% CIs of GS-331007 AUC0-tau and Cmax were contained within the equivalence bounds of 70–143%). For sofosbuvir, the increase in exposure observed on coadministration with GS-0938 was within the range of sofosbuvir exposures observed in other clinical trials and does not warrant any dose adjustment.

Safety Assessments

Sofosbuvir and GS-0938 both had favourable safety profiles. No serious adverse events were reported, and no patients interrupted or discontinued dosing because of an adverse event (Table 4). Headache was the most commonly reported adverse event among patients receiving either active therapy or placebo: headache was reported in 4 of 32 patients receiving nucleotides (13%) and in 2 of 8 patients receiving placebo (25%). No Grade 3 or 4 adverse events were reported, and there were no clinically relevant changes in vital signs, ECG or physical examination assessments. Among all cohorts, one treatment-emergent Grade 1 elevation in ALT occurred in a patient receiving placebo.

Table 4.  Treatment-emergent adverse events

  GS-0938 × 14 days (n = 8) GS-0938 × 7 days, GS-0938 + SOF × 7 days (n = 8) SOF × 7 days, GS-0938 + SOF × 7 days (n = 8) GS-0938 + SOF × 14 days (n = 8) Placebo (n = 8)
Patients with ≥1 adverse event, n (%) 2 (25) 3 (37.5) 3 (37.5) 4 (50) 4 (50)
Grade 3 or 4 adverse events, n 0 0 0 0 0
Adverse event leading to discontinuation, n 0 0 0 0 0
Adverse events, n (%)
   Eye pruritus 0 1 (12.5) 0 0 0
   Constipation 0 0 0 1 (12.5) 0
   Diarrhoea 0 0 0 1 (12.5) 0
   Nausea 0 0 1 (12.5) 0 0
   Vomiting 0 0 1 (12.5) 0 0
   Chills 1 (12.5) 1 (12.5) 0 0 1 (12.5)
   Fatigue 0 0 0 1 (12.5) 0
   Irritability 0 0 0 0 1 (12.5)
   Noncardiac chest pain 0 0 1 (12.5) 0 0
   Pyrexia 0 1 (12.5) 0 0 0
   Arthralgia 0 1 (12.5) 0 0 0
   Back pain 1 (12.5) 0 0 0 0
   Myalgia 1 (12.5) 0 1 (12.5) 0 1 (12.5)
   Dizziness 0 1 (12.5) 0 0 0
   Headache 1 (12.5) 0 0 3 (37.5) 2 (25)
   Nasal congestion 0 1 (12.5) 0 0 0
   Increased perspiration 0 1 (12.5) 0 0 0
   Skin pruritus 0 0 0 1 (12.5) 1 (12.5)
   Skin rash 0 0 0 1 (12.5) 0
   Conjunctival hyperaemia 0 1 (12.5) 0 0 0
Serious adverse events, n (%) 0 0 0 0 0

In the nucleotide-treated groups, all 8 patients who had Grade 1 or higher elevations of ALT at baseline had normalized ALT levels by Day 8, and through Day 14, no patient on active treatment experienced a treatment-emergent elevation in ALT greater than normal. One patient in the placebo group had a Grade 1 or higher elevation in ALT at baseline, and by Day 14, ALT was still abnormally high.

Discussion

In this 14-day phase 1 study, treatment with the nucleotide inhibitors sofosbuvir and GS-0938 alone and in combination resulted in rapid and substantial declines in serum HCV RNA in patients infected with genotype 1 HCV. These reductions in HCV RNA were greater than or comparable with those seen after administration of other direct-acting antiviral agents currently under investigation. After 14 days of monotherapy with the protease inhibitor danoprevir 300 mg to 600 mg, median decreases in HCV RNA of −1.7 to −3.8 (range −0.9 to −5.0) were observed.[18] The combination of the NS3 protease inhibitor asunaprevir and the NS5A replication complex inhibitor daclatasvir provided a median reduction in HCV RNA of 5.1 log10 IU/mL.[5] Patients receiving the macrocyclic protease inhibitor IDX320 200 mg twice daily for 3 days experienced a decline of 3.8 log10 IU/mL.[19] Patients receiving the NS3/4A protease inhibitor TMC435 experienced a median reduction of 3.46 log10 IU/mL in HCV RNA levels after three days of treatment.[20] Data were presented earlier this year on the protease inhibitor ABT-450 in combination with low-dose ritonavir (ABT-450/r). After 3 days of treatment with 3 different doses of ABT-450/r, the mean maximum decreases from baseline in HCV RNA were 3.91–4.11 log10 IU/mL.[21]

Of note, this was the first characterization of the antiviral potency of sofosbuvir given as monotherapy, rather than in the form of GS-9851, of which sofosbuvir is one of the diasteromers. Compared to the earlier results with GS-9851 over 3 days, sofosbuvir produced significantly greater reductions in HCV RNA with 3.69 log10 IU/mL at Day 3 compared with 1.95 log10 IU/mL at Day 3 in the earlier GS-9851 study. Thus, development of sofosbuvir rather than the mixture of diasteromers has resulted in approximately double the antiviral potency at the same mg dose level.

Combining sofosbuvir and GS-0938 did not appear to cause greater on-treatment viral suppression than either agent alone. While both agents show additive to synergistic activity in vitro,[11] no obvious additive activity was observed in this study although a greater proportion of patients on combination therapy achieved undetectable HCV RNA at Day 14 (Table 2). This, however, may have been attributable simply to the higher HCV RNA values at baseline, particularly in the 4 subjects who failed to achieve undetectable HCV RNA in the GS-0938 monotherapy arm (i.e. 6.97–7.49 log10 IU/mL). One possible explanation for the uniformity of response among the arms may be that each drug alone leads to near-maximal suppression of viral replication and adding a second drug of the same class does nothing to further suppress replication as can be measured by currently available HCV RNA assays. However, in this study, treatment lasted only 14 days, and it is possible that combination therapy with 2 nucleotides could confer additional benefits during a longer time course (i.e. prevention of breakthrough, relapse and/or resistance emergence over therapeutic treatment durations).

Sofosbuvir with its potent pan-genotypic activity is under development as the cornerstone of multiple regimens across all HCV genotypes including combination with pegylated interferon and ribavirin, ribavirin and with various DAAs with different mechanisms of action, including NS5a inhibitors, NS3 protease inhibitors and a non-nucleoside inhibitor. Sofosbuvir fulfils the major attributes of a cornerstone agent in that it (i) has a high barrier to resistance, (ii) is highly potent, (iii) provides once daily dosing and (iv) is pan-genotypic. Promising results from phase 2 studies suggest that sofosbuvir in combination with ribavirin or peginterferon and ribavirin can provide high rates of SVR in patients with genotype 1, 2, 3, 4 and 6 infections.[22–24] GS-0938 is no longer in clinical development due to safety concerns (elevated ALT levels) that arose in a subsequent phase 2 study; all treatment arms containing GS-0938 were halted.

In conclusion, treatment with the HCV nucleoside inhibitors sofosbuvir and GS-0938—alone and in combination—led to rapid and substantial reductions in viral load without any incidences of viral breakthrough. Sofosbuvir demonstrated potent HCV RNA suppression when administered alone for 7 days, an antiviral effect almost double that observed with GS-9851 at the same dose. Sofosbuvir is currently in phase 3 clinical development as a possible backbone of multiple anti-HCV regimens for chronic hepatitis C.

References

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  2. Poordad F, McCone J Jr, Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–1206.

  3. H_ezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int 2012; 32(Suppl 1): 32–38.

  4. Sulkowski MS, Cooper C, Hunyady B et al. Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C. Nat Rev Gastroenterol Hepatol 2011; 8: 212–223.

  5. Lok AS, Gardiner DF, Lawitz E et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 216–224.

  6. Chayama K, Takahashi S, Toyota J et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asuna- previr, in hepatitis C virus genotype 1b-infected null responders. Hepatology 2012; 55: 742–748.

  7. Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138: 447–462.

  8. Lam AM, Espiritu C, Bansal S et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 2012; 56: 3359–3368.

  9. Lam AM, Espiritu C, Bansal S et al. Hepatitis C virus nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA. J Virol 2011; 85: 12334–12342.

  10. Lam AM, Espiritu C, Murakami E et al. Inhibition of hepatitis C virus replicon RNA synthesis by PSI- 352938, a cyclic phosphate prodrug of b-D-2'-deoxy-2'-a-fluoro-2'-b-Cmethylguanosine. Antimicrob Agents Chemother 2011; 55: 2566–2575.

  11. Zennou V, Lam A, Keilman M et al. Combination of two complementary nucleotide analogues PSI-7977 and PSI-938 effectively clears wild type and NS5B:S282T HCV replicons - comparisons with combinations of other antiviral compounds. J Hepatol 2010; 52(Suppl 1): S400.

  12. Rodriguez-Torres M, Lawitz E, Denning J et al. PSI-352938, a novel purine nucleotide analog, exhibits potent antiviral activity and no evidence of resistance in patients with HCV genotype 1 over 7 days. J Hepatol 2011; 54(Suppl 1): S488.

  13. Lawitz E, Rodriguez-Torres M, Denning JM et al. Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection. GS-9381 Antimicrob Agents Chemother 2013; 57: 1209–1217.

  14. Lawitz E, Lalezari J, Rodriguez-Torres M et al. High rapid virologic response (RVR) with PSI-7977 QD plus PEG-IFN/RBV in a 28-day phase 2A trial. Hepatology 2010; 52 (Suppl 1): 181A.

  15. Sofia MJ, Bao D, Chang W et al. Discovery of a b-d-2'-deoxy-2'-a-fluoro- 2'-b-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010; 53: 7202–7218.

  16. Lam AM, Murakami E, Espiritu C et al. PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. Antimicrob Agents Chemother 2010; 54: 3187– 3196.

  17. Reddy PG, Bao D, Chang W et al. 2'-deoxy-2'-a-fluoro-2'-b-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938. Bioorg Med Chem Lett 2010; 20: 7376–7380.

  18. Forestier N, Larrey D, Guyader D et al. Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN- 191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study. J Hepatol 2011; 54: 1130–1136.

  19. de Bruijne J, van Vliet A, Weegink CJ et al. Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor. Antivir Ther 2012; 17: 633–642.

  20. Reesink HW, Fanning GC, Farha KA et al. Rapid HCV-RNA decline with once daily TMC435: a Phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 2010; 138: 913–921.

  21. Lawitz E, Poordad F, DeJesus E et al. ABT-450/ritonavir (ABT-450/r) combined with pegylated interferon alpha-2a/ribavirin (P/R) after 3-day monotherapy in HCV Genotype 1 (GT1)-infected treatment-naive subjects: 12-week sustained virologic response (SVR12) and safety results. Presented at the 47th Annual European Association for the Study of the Liver meeting from April 18th- 22nd 2012 in Barcelona, Spain.

  22. Kowdley K, Lawitz E, Crespo I et al. ATOMIC: 97% RVY for PSI- 7977 + PEG/RBV 9 12 week regimen in HCV GT1: an end to response-guided therapy? Presented at: 47th Annual Meeting of the European Association for the Study of the Liver (EASL); 2012 April 18– 22; Barcelona, Spain. J Hepatol 2012; 56: S1.

  23. Lawitz E, Lalezari JP, Hassanein T et al. PROTON: PSI-7977 & Peg/RBV in treatment-naive patients with HCV GT1: sustained virologic response. 62nd Annual Meeting of the American Association for the Study of Liver Diseases; 2011 November 4–8; San Francisco, CA.

  24. Gane EJ, Stedman CA, Hyland RH et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. 62nd Annual Meeting of the American Association for the Study of Liver Disease 2011 November 4–8; San Francisco, CA.

Source

WATERTOWN, Mass.--(BUSINESS WIRE)--Oct. 1, 2013--

Enanta Pharmaceuticals, Inc., (NASDAQ: ENTA) a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, today announced that six abstracts reporting results of regimens containing ABT-450, Enanta’s lead protease inhibitor for hepatitis C virus (HCV), have been accepted for presentation at The Liver Meeting, the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) taking place November 1-5, 2013 in Washington, D.C. Abstracts can now be viewed at the AASLD website at www.aasld.org.

There will be an oral presentation at AASLD highlighting data from study M13-393 (PEARL-I). PEARL-I is an interferon-free and ribavirin-free 320-patient study being conducted by Abbvie to evaluate the once-daily, two-DAA regimen consisting of ABT-450/r + ABT-267 in GT-1b and GT-4 HCV patients. SVR4 rates were 100% (39/39) in GT-1b treatment-naïve patients and 87.9% (29/33) among prior null responders (observed data). SVR12 rates will be presented during an oral presentation of this data on November 3.

Abstracts reporting regimens containing ABT-450 are listed below:

Oral Presentation:

  • #75 - Interferon and Ribavirin-Free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-naïve Patients and Prior Null Responders
    Lawitz, et al., November 3, 2013, 5:15 PM ET

Poster Presentations:

  • #1089 - Low Relapse Rate Leads to High Concordance of SVR4 and SVR12 with SVR24 After Treatment with ABT-450/r, ABT-267, ABT-333 + Ribavirin in Patients with Chronic HCV Genotype 1 Infection in the AVIATOR Study
    Poordad, et al., November 3, 2013, 8:00 AM – 5:30 PM ET
  • #1096 - High Medication Adherence in HCV-Infected Patients taking a Triple-DAA Regimen for 12 Weeks
    Bourliere, et al., November 3, 2013, 8:00 AM – 5:30 PM ET
  • #1125 - HCV RNA “Target Detected” after “Target Not Detected” During IFN-Free Treatment: Time to Worry or Not?
    M King, et al., November 3, 2013, 8:00 AM – 5:30 PM ET
  • #1118 - Safety of Ribavirin-containing Regimens of ABT-450/r, ABT-333, and ABT-267 for the Treatment of HCV Genotype 1 Infection and Efficacy in Subjects with Ribavirin Dose Reductions
    Cohen, et al., November 3, 2013, 8:00 AM – 5:30 PM ET
  • #1113 - Health-Related Quality of Life (HRQoL), Health State, Function and Wellbeing of Chronic HCV Patients Treated with Interferon-Free, Oral DAA Regimens: Patient Reported Outcome (PRO) Results from the AVIATOR Study
    Baran, et al., November 3, 2013, 8:00 AM – 5:30 PM ET

Protease Inhibitor Collaboration with AbbVie (formerly the research-based pharmaceutical business of Abbott Laboratories)

In December 2006, Enanta and Abbott announced a worldwide agreement to collaborate on the discovery, development and commercialization of HCV NS3 and NS3/4A protease inhibitors and HCV protease inhibitor-containing drug combinations. ABT-450 is a protease inhibitor identified as a lead compound through the collaboration. Under the agreement, AbbVie (as the successor to Abbott) is responsible for all development and commercialization activities for ABT-450. Enanta received $57 million in connection with signing the collaboration agreement, has received $55 million in subsequent clinical milestone payments, and is eligible to receive an additional $195 million in payments for regulatory milestones, as well as double-digit royalties worldwide on any revenue allocable to the collaboration’s protease inhibitors. Also, for any additional collaborative HCV protease inhibitor product candidate developed under the agreement, Enanta holds an option to modify the U.S. portion of it rights to receive milestone payments and worldwide royalties. With this option, Enanta can fund 40 percent of U.S. development costs and U.S. commercialization efforts (sales and promotion costs) for the additional protease inhibitor in exchange for 40 percent of any U.S. profits ultimately achieved after regulatory approval instead of receiving payments for U.S. commercial regulatory approval milestones and royalties on U.S. sales of that protease inhibitor.

About Enanta

Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs in the infectious disease field. Enanta is discovering and developing novel inhibitors designed for use against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes – protease (partnered with AbbVie), NS5A (partnered with Novartis) and nucleotide polymerase – as well as a host-targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, Enanta has created a new class of antibiotics, called Bicyclolides, for the treatment of multi-drug resistant bacteria, with a focus on developing an intravenous and oral treatment for hospital and community MRSA (methicillin-resistant Staphylococcus aureus) infections.

Forward Looking Statements Disclaimer

This press release contains forward-looking statements, including with respect to clinical data, plans for announcing additional data, and the planned clinical development of ABT-450. Statements that are not historical facts are based on our management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate and our management’s beliefs and assumptions. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors that may affect actual results include final results of ongoing clinical trials, the development and marketing efforts of AbbVie (our collaborator on ABT-450), regulatory actions affecting clinical development of ABT-450 and clinical development of competitive product candidates. Enanta cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Enanta undertakes no obligation to update or revise these statements, except as may be required by law.

Source: Enanta Pharmaceuticals, Inc.

Investor Contact
Enanta Pharmaceuticals, Inc.
Carol Miceli, 617-607-0710
cmiceli@enanta.com
or
Media Contact
MacDougall Biomedical Communications
Kari Watson, 781-235-3060
kwatson@macbiocom.com

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Also See: AbbVie To Present Investigational Data From Phase II Hepatitis C Program At The Liver Meeting

logo3

October 01, 2013

For U.S. Media Only

Ridgefield, CT, October 1, 2013 New data from Boehringer Ingelheim’s hepatitis C virus (HCV) clinical development program have been accepted for presentation at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), also known as The Liver Meeting®, taking place November 1-5 in Washington, D.C.

Presentations will include data from several studies evaluating Boehringer Ingelheim’s investigational compound, faldaprevir, including final results from the STARTVerso 1, 2 and 3 pivotal trial programs (NCT01343888, NCT01297270, NCT01358864) in treatment-naïve and treatment-experienced patients. End-of-treatment results from STARTVerso 4™ (NCT01399619) evaluating HIV/HCV co-infected patients will also be presented.

Additionally, data will be presented from studies evaluating drug-drug interactions of faldaprevir with common birth control and anti-addiction medications, as well as a study evaluating faldaprevir pharmacokinetics, safety, and tolerability in patients with renal impairment. Final results from SOUND-C3 (NCT01132313), a Phase 2b study from Boehringer Ingelheim’s interferon-free development program, will also be presented.

Together these studies explore the use of Boehringer Ingelheim’s investigational HCV compounds in a broad range of patients with HCV, in addition to helping understand the potential for interactions with several commonly used medications. Also, they offer insight into the clinical profile of the compounds for researchers and healthcare professionals looking for potential new treatment options for patients with HCV.

“We are pleased to see the presentation of the final results from STARTVerso 1, 2 and 3, Boehringer Ingelheim’s pivotal Phase 3 program in our hepatitis C portfolio, as well as other important analyses evaluating various patient subgroups at this year’s AASLD meeting,” said Peter Piliero, M.D., Vice President, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “These data, combined with that of our interferon-free trial, SOUND-C3, are evidence of our commitment to researching new therapeutic options for patients infected with HCV.”

Faldaprevir and deleobuvir are investigational compounds and not approved by the FDA. Their safety and efficacy have not been established.

Boehringer Ingelheim’s abstracts can be accessed on the AASLD website today at www.aasld.org.

Poster Presentations

 

Title Lead Author Presentation Details
Effect of multiple oral doses of faldaprevir on the multiple dose pharmacokinetics of a combination oral tablet of ethinylestradiol and levonorgestrel in healthy premenopausal female volunteers J. Sabo ID# 482

Session: HCV Therapy: The Developmental Pipeline

Date: Sat, Nov. 2
Time: 2:00 PM – 7:30 PM ET
Location: Poster Hall
Mass balance, metabolic profile and the role of hepatic and bacterial enzymes in the metabolism of the HCV polymerase inhibitor, deleobuvir (BI 207127) R. Sane ID# 491

Session: HCV Therapy: The Developmental Pipeline

Date: Sat, Nov. 2
Time: 2:00 PM – 7:30 PM ET
Location: Poster Hall
Pharmacokinetics, safety, and tolerability of faldaprevir in patients with different levels of renal impairment F. Huang

ID# 466

Session: HCV Therapy: The Developmental Pipeline

 

Date: Sat, Nov. 2
Time: 2:00 PM – 7:30 PM ET
Location: Poster Hall

Effect of steady-state faldaprevir on the pharmacokinetics of steady-state methadone and buprenorphine/naloxone in subjects on stable addiction management therapy D. Joseph ID# 483

Session: HCV Therapy: The Developmental Pipeline

Date: Sat, Nov. 2
Time: 2:00 PM – 7:30 PM ET
Location: Poster Hall
A pooled analysis of two randomized, double-blind placebo-controlled Phase III trials (STARTVerso1&2) of faldaprevir plus pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C genotype-1 infection D. Jensen ID# 1088

Session: HCV Therapeutics: New Agents

Date: Sun, Nov. 3
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall
Subgroup analyses and baseline predictors of response with faldaprevir plus pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C genotype-1 infection: a pooled analysis of STARTVerso1 and 2 E.M. Yoshida

ID# 1114

 

Session: HCV Therapeutics: New Agents

 

Date: Sun, Nov. 3

Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

STARTVerso3: A randomized, double-blind, placebo-controlled Phase III trial of faldaprevir in combination with pegylated interferon alfa-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection I. Jacobson

ID# 1100

 

Session: HCV Therapeutics: New Agents

 

Date: Sun, Nov. 3
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

Interferon-Free Treatment with Faldaprevir, Deleobuvir (BI 207127) and Ribavirin in SOUND-C3: 95% SVR12 in HCV-GT1b J.F. Dufour

ID# 1102

 

Session: HCV Therapeutics: New Agents

 

Date: Sun, Nov. 3
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

STARTVerso 4 Phase III trial of faldaprevir plus peg interferon alfa-2a and ribavirin (PR) in patients with HIV and HCV genotype 1 coinfection: end of treatment response J. Rockstroh

ID# 1099

 

Session: HCV Therapeutics: New Agents

Date: Sun, Nov. 3
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

Pharmacokinetic interactions of Faldaprevir and Deleobuvir (BI 207127) and their individual and combined effect on selected cytochrome P450 (CYP) probe substrates in genotype 1 hepatitis C infected patients

C. Cooper

ID# 1083

 

Session: HCV Therapeutics: New Agents

 

Date: Sun, Nov. 3
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

About Boehringer Ingelheim in Hepatitis C Virus (HCV)
In partnership with the scientific community, our clinical trial program is rigorously designed to find answers to the challenges that HCV patients face, including those who are the most difficult to treat. Our pivotal HCV clinical trials for faldaprevir and deleobuvir are comprised of two multi-trial programs, STARTVerso and HCVerso®.

Faldaprevir, also known as BI 201335, is an investigational, oral protease inhibitor that is specifically designed to target viral replication in the liver. Boehringer Ingelheim is developing faldaprevir as a core component of both interferon-based and interferon-free hepatitis C treatment regimens. STARTVerso is a multi-study Phase 3 trial program that evaluates faldaprevir combined with PegIFN/RBV. The four trials that make up this program study the combination in treatment-naïve, treatment-experienced and HIV co-infected patients with chronic genotype-1 HCV. Deleobuvir, also known as BI 207127, is an investigational NS5B non-nucleoside polymerase inhibitor that has shown the potential to eliminate interferon from HCV treatment when combined in a regimen with faldaprevir and RBV. Phase 2 trials of this interferon-free regimen have been completed and Phase 3 HCVerso® trials investigating this regimen are now underway. As part of our long-term commitment to HCV, the company is exploring other combinations of investigational HCV compounds that work in complementary ways. The recent collaboration of Boehringer Ingelheim with Presidio Pharmaceuticals, Inc. for a Phase 2a clinical study investigating an interferon- and ribavirin-free, all-oral combination is part of the company’s continued commitment to discover and develop innovative options for the treatment of HCV.

STARTVerso and HCVerso® are registered service marks of Boehringer Ingelheim International GmbH.

The Liver Meeting® is a registered trademark of the American Association for the Study of Liver Diseases (AASLD).

Hepatitis C is a blood-born infectious disease and a leading cause of chronic liver disease, transplant and failure that affects as many as 150 million people globally. In the United States, an estimated 4.1 million Americans have been infected with HCV, of which approximately 3.2 million have chronic HCV infection. Since 1999 there has been a significant increase in deaths due to chronic HCV, which accounts for 10,000-12,000 deaths in the United States per year.

About Boehringer Ingelheim
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim’s culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

For more information please visit www.us.boehringer-ingelheim.com

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