All-Oral Therapy With Sofosbuvir and GS-0938 for 14 Days in Treatment-Naive Geno 1 Hepatitis C (NUCLEAR)

Journal of Viral Hepatitis

All-Oral Therapy With Nucleotide Inhibitors Sofosbuvir and GS-0938 for 14 Days in Treatment-Naive Genotype 1 Hepatitis C (NUCLEAR)

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
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).

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 (C_max), time to maximum plasma concentration (T_max), concentration at the end of dosing C_tau, area under the plasma concentration–time curve from 0 h to end of dosing (AUC_0-tau) and elimination half-life (t_1/2).

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.

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 (Table 2 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 (Table 2). 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).
 

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

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 T_max) 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 T_max) and a longer plasma circulating half-life of 9.4 h (median t₁/₂).

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 (AUC_0-tau and C_max) 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 AUC_0-tau and C_max 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 see below). 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.
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.

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

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 see below). 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).

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.

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.

Abstract and Introduction

Experimental Procedures

Results 

Discussion

References

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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.

AASLD - Genes Associated With Unhealthy Liver Function

Genes Associated With Unhealthy Liver Function

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 Translational Genomics Research Institute

Hepatitis C - Danoprevir yielded high rates of sustained virologic response

Infectious Diseases

Novel HCV therapy leads to rapid response 

 

By: DENISE NAPOLI, Family Practice News Digital Network 

 

Combination therapy with the second-generation protease inhibitor danoprevir yielded high rates of sustained virologic response in hepatitis C.

Moreover, a large portion of patients also demonstrated an extended rapid virologic response up to 20 weeks, reported Dr. Patrick Marcellin and his colleagues in the October issue of Gastroenterology.

Dr. Marcellin, of the Hôpital Beaujon in Clichy, France, and his coinvestigators looked at 225 treatment-naive adults with hepatitis C virus (HCV) genotype 1 infection, including those who had a serum RNA level of 50,000 IU/mL or more. 

Exclusion criteria included advanced fibrosis or cirrhosis, anemia, poorly controlled diabetes, or body mass index less than 18 kg/m² or greater than 36 kg/m². 

The goal of this phase II, randomized, placebo-controlled study (ATLAS) was to evaluate the efficacy of treatment with danoprevir plus peginterferon alfa-2a/ribavirin for 12 weeks, compared with peginterferon alfa-2a/ribavirin alone. 

Patients were randomized to one of three doses of oral danoprevir or placebo: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours. 

All doses and placebo were given with standard combination HCV therapy, including subcutaneous peginterferon alfa-2a 180 mg/week plus oral ribavirin (1,000 mg/day for patients with a body weight less than 75 kg or 1,200 mg/day for patients weighing 75 kg or more). 

At week 12, treatment with danoprevir or placebo was stopped, and peginterferon alfa-2a/ribavirin was continued for a total duration of 24 or 48 weeks, according to patient response. 

Dr. Marcellin found that by week 1, mean decreases in HCV RNA ranged from 3.95 to 4.28 log₁₀ IU/mL in the danoprevir groups, compared with 0.77 log₁₀ IU/mL in the placebo group.

By week 2, according to the investigators, more than half of the danoprevir patients and none of the placebo recipients had achieved undetectable HCV RNA levels. 

Indeed, broken down by dose, the researchers calculated that 74% of the danoprevir 300-mg group achieved a rapid virologic response (undetectable serum HCV RNA at week 4), with 65% maintaining an extended rapid virologic response (eRVR), defined as an undetectable HCV RNA that lasted from weeks 4 through 20. 

Among the patients taking 600-mg doses, 88% achieved an RVR, with 79% maintaining an eRVR at week 20. 

Finally, 86% of patients in the 900-mg treatment group achieved an RVR, although only 18% reached an eRVR. 

Patients with an eRVR stopped all treatment at 24 weeks.

"Relapse occurred in 18%, 8%, and 11% of patients treated with danoprevir 300 mg, 600 mg, and 900 mg, respectively, versus 38% in the placebo group," the authors wrote. 

Looking at the side-effect profile, Dr. Marcellin reported that fatigue, headache, nausea, insomnia, myalgia, and chills were the most common adverse events for both the treatment and placebo groups.

They also observed reversible, grade 4 elevations in alanine aminotransferase (ALT) levels between weeks 6 and 12 in 2% of danoprevir-treated patients, including three in the 900-mg cohort and one in the 600-mg cohort. 

Treatment was discontinued, and serum ALT levels returned to within 1.5 times the upper limit of normal within a month for all four patients, the authors added. 

"Notwithstanding the low incidence of reversible ALT elevations observed with high-dose danoprevir in this trial, danoprevir also appears to have a better tolerability profile than either boceprevir or telaprevir, as evidenced by the lower incidence of rash and anemia among danoprevir-treated patients compared with placebo recipients," concluded the investigators. 

Indeed, they pointed to other studies showing that coadministration of low-dose ritonavir, another protease inhibitor, "significantly inhibits danoprevir reactive metabolite formation, proposed to be associated with ALT elevations." 

"Studies to further evaluate the efficacy and safety of danoprevir in different patient groups are ongoing," the researchers said. 

Dr. Marcellin and his fellow investigators reported financial relationships with numerous pharmaceutical companies, including Roche, the maker of danoprevir, which also funded this study.

View on the News

Danoprevir's role still unclear
Second-generation protease inhibitors (PIs) currently in development are generally thought to have less drug-drug interactions, improved dosing schedules, as well as less frequent and less severe side effects. Many of the second-generation PIs are macrocyclic molecules, which have been shown to generally be more potent and, depending on the location of the macrocycle, able to retain activity against resistant variants. Common wild-type and drug-resistant variants of the NS3 protein include Q80K, R155K, V36M/R155K, A156T, and D168A (ACS Chem. Biol. 2013;8:1469-78). They have also shown increased efficacy against genotype 1, though they still have limited efficacy against other genotypes (Curr. Gastroenterol. Rep. 2013;15:303 [doi: 10.1007/s11894-012-0303-3]).

This report on danoprevir clearly shows it is a potent, pan-genotypic, macrocyclic second-generation PI that meets all of these criteria. However, the grade 4 elevations in alanine aminotransferase (ALT) levels seen in 2% of danoprevir-treated patients (including three in the 900-mg cohort and one in the 600-mg cohort) that were seen in this study became a major roadblock to the phase III development of the compound. Instead, the coadministration of low-dose ritonavir, another protease inhibitor, which significantly inhibits danoprevir reactive metabolite formation, has allowed the compound to move forward into advanced studies without the hepatotoxicity concern [J. Hepatol. 2012;56(Suppl 2):S467; Hepatology 2012;56(Suppl 1):552A; Hepatology 2012;56(Suppl 1):231A; J. Hepatol. 2012;56(Suppl 2):S555].

The role for a ritonavir-boosted PI in all-oral interferon-free regimens remains to be defined over the coming years. This is not the only PI that requires boosting (ABT450); however, the field is quickly becoming crowded with PIs that do not require ritonavir (asunaprevir, faldaprevir, simeprevir, and vaniprevir). The role for danoprevir in the United States is therefore still unclear.

Dr. Paul J. Pockros is director of the Liver Disease Center of the division of gastroenterology/hepatology at the Scripps Clinic, director of the Scripps Clinic Liver Research Consortium, and director of clinical research at the Scripps Translational Science Institute, La Jolla, Calif. He is a researcher, speaker, and advisory board member for Roche/Genentech.

AASLD- Bristol-Myers Daclatasvir + Sunaprevir Data In Hepatitis C Patients to be Presented

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 SVR ₂₄ 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

Bristol-Myers Squibb Company (NYS: 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 BARACLUDEis 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 WARNINGSclick 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

 

AASLD - Boehringer Ingelheim Faldaprevir Data in Hepatitis C Patients to be Presented

 Pivotal Phase 3 Data from Boehringer Ingelheim Hepatitis C Portfolio to be Presented at 64th Annual AASLD Meeting

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SOURCE Boehringer Ingelheim

RIDGEFIELD, Conn., Oct. 1, 2013 /PRNewswire/ -- New data from Boehringer Ingelheim's hepatitis C virus (HCV) clinical development program have been accepted for presentation at the 64^th 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-naive 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-naive 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-naive 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-naive, 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.

Contact:
Boehringer Ingelheim Pharmaceuticals, Inc.
Name: Susanne Granold
Public Relations
Phone: 203-791-5851
Email: Susanne.Granold@boehringer-ingelheim.com

AASLD- AbbVie To Present Data From Phase II Hepatitis C Program

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

PHASE III TOP-LINE RESULTS EXPECTED BEGINNING LATER IN 2013

NORTH CHICAGO, Ill., Oct. 1, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced that new data from its phase II hepatitis C clinical development program will be presented at The Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C., November 1-5, 2013. In total, eight abstracts will be presented, four of which include additional analyses from the phase IIb AVIATOR study. The data examine sustained virologic response (SVR) concordance, patient adherence to the regimen, patient reported outcomes and the impact of ribavirin dose reduction.

The Liver Meeting will precede AbbVie's reporting of initial results from the pivotal phase III clinical trials of the safety and efficacy of AbbVie's investigational triple direct-acting antiviral (DAA) regimen for the treatment of hepatitis C. Reporting of those results is expected to begin later this year.

"At AbbVie, we are committed to researching new therapies that maximize sustained virologic response with the hope of providing much needed new options for people with hepatitis C," said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "We are very encouraged as we await top-line results from our phase III program, which we will share later this year."

Additionally, the oral presentation at AASLD will provide results from the PEARL-I study evaluating an interferon- and ribavirin-free, two-DAA investigational regimen in genotype 1b treatment-naïve patients and prior null responders. AbbVie is also investigating drug combinations for additional genotypes and next generations of DAAs as part of their ongoing commitment to the HCV community.

A brief summary of AbbVie's abstract titles is presented below.

About AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge by investigating an interferon-free, all-oral DAA regimen with the goal of producing high SVR rates in as many patients as possible, including those typically most difficult to cure. The large, multinational HCV program includes more than 2,200 patients from 30 countries.

AbbVie's hepatitis C portfolio includes investigational medicines with three different mechanisms of action targeting areas of the viral replication process including boosted protease inhibitor (ABT-450), polymerase (ABT-333) inhibitor and NS5A (ABT-267) inhibitor, currently being studied in clinical trials. ABT-450/r is co-formulated with ABT-267.

Details of AbbVie's phase III clinical programs are as follows:

 
   Study          Patients (n)         Treatment Regimen    Treatment Duration 
------------  ---------------------  ---------------------  ------------------ 
SAPPHIRE I    GT1,                   -- ABT450/r +ABT267**  12 weeks 
              treatment-naïve    -- ABT333 
              (600*)                  -- Ribavirin 
------------  ---------------------  ---------------------  ------------------ 
SAPPHIRE II   GT1,                   -- ABT450/r +ABT267**  12 weeks 
              treatment-experienced   -- ABT333 
              (400*)                  -- Ribavirin 
------------  ---------------------  ---------------------  ------------------ 
PEARL II      GT1b,                  -- ABT450/r +ABT267**  12 weeks 
              treatment-experienced   -- ABT333 
              (210*)                  -- Ribavirin 
------------  ---------------------  ---------------------  ------------------ 
                                     --ABT450/r +ABT267**   12 weeks 
                                      ABT333 
------------  ---------------------  ---------------------  ------------------ 
PEARL III     GT1b,                  -- ABT450/r +ABT267**  12 weeks 
              treatment-naïve    -- ABT333 
              (400*)                  -- Ribavirin 
------------  ---------------------  ---------------------  ------------------ 
                                     -- ABT450/r +ABT267**  12 weeks 
                                      -- ABT333 
------------  ---------------------  ---------------------  ------------------ 
PEARL IV      GT1a, treatment-naive  -- ABT450/r +ABT267**  12 weeks 
               (300*)                 -- ABT333 
                                      -- Ribavirin 
------------  ---------------------  ---------------------  ------------------ 
                                     -- ABT450/r +ABT267**  12 weeks 
                                      -- ABT333 
------------  ---------------------  ---------------------  ------------------ 
TURQUOISE II  GT1,                   -- ABT450/r +ABT267**  12 weeks 
              treatment-naïve    -- ABT333 
              and                     -- Ribavirin 
              treatment-experienced 
              (with compensated 
              cirrhosis) (300*) 
------------  ---------------------  ---------------------  ------------------ 
                                     -- ABT450/r +ABT267**  24 weeks 
                                      -- ABT333 
                                      -- Ribavirin 
------------  ---------------------  ---------------------  ------------------ 
 

*projected study population
**ABT-267 is co-formulated with ABT-450/r

In May of 2013, AbbVie's investigational DAA regimen with and without ribavirin for HCV genotype 1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA). This designation is intended to help expedite the development of drugs for serious or life-threatening conditions and is based in part on preliminary clinical evidence demonstrating a drug or regimen may have substantial improvement on at least one clinically significant endpoint compared to available therapy.

AbbVie Hepatitis C Data at AASLD 2013

   -- Trends in Liver-Related Healthcare Resource Utilization for HCV-Infected 
      Individuals in the US: 2002-2010Poster #367November 2nd, 2:00PM ET; 
      Poster HallThis study analyzed years 2002-2010 of the National Inpatient 
      Sample (NIS) data set of hospital admissions from the Healthcare Cost and 
      Utilization Project (HCUP) to determine the number of adult (age 20+ 
      years) liver-related hospital admissions occurring in HCV-infected 
      patients (identified by ICD-9 codes). 
   -- Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV 
      Genotype 1b-infected Treatment-Naïve Patients and Prior Null 
      RespondersOral Presentation: Parallel Session 75November 3rd, 5:15PM ET; 
      Hall EThis oral presentation includes data from the phase IIb PEARL-I 
      study, which examines an interferon-free, ribavirin-free investigational 
      regimen of ABT-450/r plus ABT-267 in 82 patients with HCV genotype 1b. 
   -- 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 StudyPoster 
      #1089November 3rd, 8:00AM ET; Poster HallThis study evaluated the 
      concordance of SVR24 with rapid virologic response (RVR), SVR4 and SVR12 
      in treatment groups from the phase IIb AVIATOR study in 247 patients. 
   -- High Medication Adherence in HCV-Infected Patients Taking a Triple-DAA 
      Regimen for 12 WeeksPoster #1096November 3rd, 8:00AM ET; Poster HallThis 
      study presents medication adherence data based on electronic compilation 
      of drug dosing history among 327 patients receiving the investigational 
      triple-DAA regimen plus ribavirin for 8, 12 or 24 weeks. 
   -- 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 
      StudyPoster #1113November 3rd, 8:00AM ET; Poster HallThis intent-to-treat 
      analysis from the phase IIb AVIATOR study includes patient reported 
      outcomes (PRO) in patients receiving 12-week, ribavirin-containing 
      investigational triple-DAA regimen. 
   -- 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 ReductionsPoster #1118November 3rd, 8:00AM 
      ET; Poster HallThis study examined the safety of a ribavirin-containing, 
      investigational triple-DAA, interferon-free regimen and the effects of 
      ribavirin dose reductions on treatment response. 
   -- HCV RNA "Target Detected" after "Target Not Detected" During IFN-Free 
      Treatment: Time to Worry or Not?Poster #1125November 3rd, 8:00AM ET; 
      Poster HallThis study examined the frequency of TDANs (Target Detected 
      After Not Detected) and the likelihood of subsequent virologic failure in 
      subjects from the phase IIb AVIATOR study treated with ABT- 450/r plus 
      ABT-267 plus ABT-333 plus ribavirin for 12 or 24 weeks in treatment 
      naïve and null responders. 
   -- Adherence to Interferon-containing Therapy Among Veteran Affairs 
      Hepatitis C PatientsPoster #1909November 5th, 8:00AM ET; Poster HallData 
      from the United States Veterans Health Administration (VHA) Medical SAS 
      Dataset (years 2008 to 2011) were used in this analysis. 

The list of accepted abstracts for The Liver Meeting can be accessed on www.aasld.org .
ABT-450 was discovered during the course of the ongoing collaboration between AbbVie and Enanta Pharmaceuticals for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

About the Hepatitis C Virus
Across the world, about 160 million people are chronically infected with hepatitis C.[1] Hepatitis C is an inflammation of the liver caused by an infection with the hepatitis C virus (HCV).[2] HCV is transmitted when an infected person's blood enters the bloodstream of another person.[3]

For the hepatitis C virus, there are six major HCV genotypes (GT1-6).([4]) Presently, there is no vaccine for the hepatitis C virus (HCV) infection.(3) Decision to treat is dependent on a number of factors such as the amount of liver damage present, other conditions the patient may have, amount of virus in the body, and viral genotype.(4) If treatment is needed, a hepatitis C infection is typically treated with a combination of antivirals.(3)
About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. With its 125-year history, the company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com.

Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

   1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol 
      Infect. 2011; 17(2):107-15. 
 
   2. World Health Organization. Global Alert and Response (GAR): Hepatitis C. 
      2003. 
      http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index1.html. 
      Accessed April 9, 2013. 
 
   3. World Health Organization. Hepatitis C Fact Sheet 2012. 
      http://www.who.int/mediacentre/factsheets/fs164/en/ Accessed April 9, 
      2013. 
 
   4. European Association for the Study of the Liver. Clinical Practice 
      Guidelines: Management of hepatitis C virus infection. Journal of 
      Hepatology. 2011; 55: 245--264. 

OURCE AbbVie Inc.

/CONTACT: Media: Elizabeth Hoff, +1 (847) 935-4236; Javier Boix, +1 (847) 937-6113; Or Investor Relations: Elizabeth Shea, +1 (847) 935-2211

/Web site: http://www.abbvie.com 

AASLD-Merck data for MK-5172 and MK-8742 in Hepatitis C Patients to be Presented

Merck & Co., Inc. : Data from Merck's Investigational Hepatitis C Treatment Portfolio to be Presented at the 64th American Association for the Study of Liver Diseases Annual Meeting


Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of data from studies evaluating the company's investigational oral chronic hepatitis C virus (HCV) treatments MK-5172 and MK-8742 at the 64^th American Association for the Study of Liver Diseases Annual Meeting (AASLD). The meeting is scheduled to take place in Washington, D.C., Nov. 1-5, 2013.

"Merck is committed to developing HCV therapies that have the potential to offer new options for a broad range of patient types," said Dr. Eliav Barr, vice president, Infectious Diseases, Merck Research Laboratories. "We continue to build upon our strong legacy in HCV and look forward to sharing the latest clinical data for our investigational HCV therapies, MK-5172 and MK-8742."
MK-5172 is an investigational, once-daily, oral HCV NS3/4A protease inhibitor currently in Phase IIB development. MK-8742 is an investigational, once-daily, oral HCV NS5A replication complex inhibitor currently in Phase IIB development. Both candidates are being evaluated in broad clinical programs that include investigations in various HCV segments, multiple HCV genotypes and patients who have previously failed prior therapy.

Selected presentations of clinical data for MK-5172 and MK-8742
 

• High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172/MK-8742 +/- RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study. Lawitz, E., et al. Oral Presentation #76: Sunday, Nov. 3, 2013, 5:30-5:45 p.m.
• Kinetic Analyses of Antiviral Suppression by NS5A Inhibitors Reveal Early and Potent Inhibition of Viral Assembly and Release. McGivern, D.R., et al. Oral Presentation #78: Sunday, Nov. 3, 2013, 6:00-6:15 p.m.
• High Efficacy at Lower Doses of MK-5172 25mg and 50mg Daily for 12 weeks in HCV Genotype (G) 1 Treatment-Naïve Non-Cirrhotic Patients. Vierling, J., N et al. Poster #1123. Sunday, Nov. 3, 2013, 8:00 a.m. to 5:30 p.m.
• Efficacy and Safety of an Interferon-Free Regimen of MK-5172 + Ribavirin for 12 Weeks or 24 Weeks in Treatment-Naïve, Non-Cirrhotic Subjects with HCV GT1 Infection: The C-SPIRIT Study. Gane, E.J., et al., Poster #1110. Sunday, Nov. 3, 2013, 8:00 a.m. to 5:30 p.m.
• MK-8742, a HCV NS5A Inhibitor with a Broad Spectrum of HCV Genotypic Activity, Demonstrates Potent Antiviral Activity in Genotype-1 and -3 HCV-Infected Patients. Yeh, W. W., et al. Poster #479. Saturday, Nov. 2, 2013, 2:00-7:30 p.m.

The abstracts were published today and can be accessed on the AASLD website. For program information, please visit: http://www.aasld.org/livermeeting/program/Pages/default.aspx

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2012 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Merck
Media:
Sarra Herzog, 908-423-6154
or
Investor:
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Justin Holko, 908-423-5088

© Business Wire 2013

AASLD-Simeprevir Data in Hepatitis C Patients to be Presented

Simeprevir Data in Hepatitis C Patients to be Presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)

CORK, Ireland, Oct. 1, 2013 /PRNewswire/ -- Janssen R&D Ireland (Janssen) announced that data will be presented on the investigational protease inhibitor simeprevir (TMC435) for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease at the upcoming Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which will take place November 1 to 5 in Washington, D.C.

"Simeprevir's clinical profile has been characterized through a robust clinical development program including more than 3,700 patients," said Gaston Picchio, Disease Area Leader Hepatitis, Janssen. "The study results that will be presented at the AASLD Annual Meeting support the potential utility of simeprevir in a number of different hepatitis C patient populations."

Simeprevir was approved in Japan in September 2013 for the treatment of genotype 1 hepatitis C. In the U.S., the New Drug Application (NDA) filed by Janssen for simeprevir administered once daily in combination with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients was granted Priority Review designation by the Food and Drug Administration (FDA) in May. Simeprevir is also being studied in several interferon-free regimens using selected combinations of direct-acting antiviral agents with different mechanisms of action.

The data to be presented at the 2013 AASLD Annual Meeting include:

Poster Presentations: HCV Therapeutics: New Agents, Poster Hall, November 3, 8:00 a.m. - 5:30 p.m. (EST)

Simeprevir (TMC435) with peg-interferon alpha-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: Efficacy and safety in patient sub-populations in the PROMISE Phase III trial
Lead Author: Xavier Forns, Hospital Clinic, Barcelona, Spain

Adding simeprevir to peginterferon/ribavirin for HCV shortens time with patient-reported symptoms and impairment in quality of life: Results from the simeprevir Phase III QUEST 1, QUEST 2, and PROMISE studies
Lead Author: Jane A. Scott, Janssen

Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: Efficacy in difficult-to-treat patient sub-populations in the QUEST-1 and 2 Phase III trials
Lead Author: Ira M. Jacobson, Weill Cornell Medical College, New York, USA

Resistance analyses of HCV isolates from patients treated with simeprevir in Phase 2b/3 studies
Lead Author: Oliver Lenz, Janssen

The relative efficacy and safety of simeprevir-based triple therapy compared to boceprevir and telaprevir in treatment naive patients chronically infected with genotype-1 hepatitis C virus: Bayesian network meta-analyses
Lead Author: Peter A. Bryden, Oxford Outcomes

Full session details and data presentation listings for the 2013 AASLD Annual Meeting can be found at http://www.aasld.org/livermeeting.

About Simeprevir
Simeprevir is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells.

Janssen is responsible for the global clinical development of simeprevir and has acquired exclusive, worldwide marketing rights, except for in the Nordic countries. Medivir will retain marketing rights for simeprevir in these countries. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

Additionally, simeprevir is being studied in combination with several direct-acting antiviral agents (DAAs) with different mechanisms of action, with and without ribavirin, as part of interferon-free regimens.

These include:
The Phase 2 COSMOS study of simeprevir and Gilead's nucleotide polymerase inhibitor sofosbuvir (GS-7977) in treatment-naive and previous null-responder genotype 1 HCV patients, including patients with cirrhosis;

A Phase 2 study of simeprevir and Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir in treatment-naive and previous null-responder genotype 1 HCV patients;

The Phase 2 HELIX-1 study of simeprevir and Idenix's once-daily pan-genotypic NS5A inhibitor samatasvir (IDX719) in treatment-naive genotype 1b and genotype 4 HCV patients.

For additional information about simeprevir, please visit www.clinicaltrials.gov.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide – including approximately 3.2 million people in the United States – and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Janssen R&D Ireland
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen R&D Ireland is part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssenrnd.com for more information.

Media Contact: Daniel De Schryver
Mobile: +49 173 76 89 149

Media Contact: Craig Stoltz
Mobile: +1 (215) 325-3612

Investor Contact: Stan Panasewicz
Office: +1 (732) 524-2524

Investor Contact: Louise Mehrotra
Office: +1 (732) 524-6491

SOURCE Janssen R&D Ireland

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