Tuesday Posters

Posters

 

HCV Drug Pipeline - Telaprevir

 

1846. Viral Responses in African-Americans, Latinos and Caucasians in the US Phase 2 Study (PROVE1) of Telaprevir with Peginterferon Alfa-2a and Ribavirin in Treatment-Naďve Genotype 1-infected Subjects with Hepatitis C.

A. J. Muir; E. J. Lawitz; J. G. McHutchison; S. C. Gordon; I. M. Jacobson; B. S. Adiwijaya; L. Bengtsson; L. McNair; M. Rodriguez-Torres

 

Background:

African Americans and Latinos have lower sustained virologic response (SVR) rates to current treatment for chronic hepatitis C virus (HCV) compared to Caucasians. The addition of telaprevir to the current regimen led to increased SVR rates in the PROVE1 trial. Here we describe results of a sub-analysis of African Americans, Latinos and Caucasians.

 

Methods:

PROVE1 was a randomized, placebo-controlled phase 2 study of telaprevir (T) 750 mg q8h with peginterferon alfa 2a (P)180 mcg/week and ribavirin (R) 1000-1200 mg/day, in naive subjects with genotype 1 HCV infection. Subjects were randomized into 4 arms.

·        The control arm (number=75) received 48 weeks of peginterferon alfa 2a.

·        The 3 other arms all received telaprevir  for 12 wks in combination with 12, 24 or 48 wks of PR (telaprevir/peginterferon alfa 2a  arm, number=175).

 

This analysis focuses on the viral responses and pharmacokinetics of African Americans, Latinos and Caucasians subjects in these arms. Race and ethnicity were determined by subject self-reporting.

 

Results:

Enrollment of Caucasians (73.8%, number=192) was greater than African Americans (10.4%, number=27) and Latinos (8.8%, number=23). In the peginterferon alfa 2a arm, the difference in viral decline at week 1 is significantly different between the Caucasians and African Americans subgroups (p=0.04); in the telaprevir/peginterferon alfa 2a  groups, there is no significant difference between these subgroups (p=-0.36) [P values could not be calculated for Latino group because of small number].

 

SVR rates among subjects receiving telaprevir appear increased compared to the peginterferon alfa 2a arm in:

·        Caucasians (83/133, 62% vs. 25/59, 41%),

·        African Americans (8/18, 44% vs. 1/9, 11%) and,

·        Latinos (11/17, 65% vs. 2/6, 33%) subjects.

 

In the overall study population, the most common adverse events (AEs) reported more frequently than placebo were gastrointestinal events, skin events (rash, pruritus) and anemia. Treatment discontinuations through week 12 due to skin/rash AEs were 7% in the T/peginterferon alfa 2a  arms and 1% in the peginterferon alfa 2a  arm.

 

Conclusions:

This sub-analysis suggests that telaprevir-based regimens enhance early viral responses and subsequently lead to improved viral responses in African Americans, Latinos and Caucasians. Given the burden of disease among African Americans and Latinos, it is imperative these results be confirmed in larger phase 3 clinical trials.

 

 

Wk1 HCV RNA log10 decline

% with RVR

% with SVR

 

PR

T/PR

PR

T/PR

PR

T/PR

Caucasians

-1.3

-4.7

12

80

41

62

African Americans

-0.6

-4.4

11

72

11

44

Latinos

-0.6

-4.3

0

65

33

65

 


HCV Drug Pipeline – ITMN-191(R7227)

 

1847. Treatment of Chronic Hepatitis C Virus (HCV) Genotype 1 Patients with the NS3/4A Protease Inhibitor ITMN-191 Leads to Rapid Reductions in Plasma HCV RNA: Results of a Phase 1b Multiple Ascending Dose (MAD) Study.

N. Forestier; D. G. Larrey; D. Guyader; P. Marcellin; R. Rouzier; A. A. Patat; W. Z. Bradford; S. Porter; S. Zeuzem

 

Background:

ITMN-191 is an oral, highly potent, selective inhibitor of the HCV NS3/4A serine protease. Emerging evidence suggests combination regimens including direct inhibitors of viral enzymes will improve virologic response rates relative to the current standard of care. In order to identify doses for subsequent studies of ITMN-191-based combination regimens, we evaluated the safety, pharmacokinetics, and effects on plasma HCV RNA of multiple ascending doses of ITMN-191 in patients with chronic HCV infection.

 

Methods:

In a double-blind, randomized, placebo-controlled study, 4 cohorts of treatment-naďve HCV genotype 1 patients and one cohort of non-responders (NR) were randomized to receive ITMN-191 or matched placebo for 14 days. Cohorts consisted of 8 and 2 patients receiving ITMN-191 and placebo, respectively. Patients were sequestered in a Phase 1 unit for 16 days and completed standardized clinical and laboratory evaluations.

 

Results:

Fifty patients were randomized and all completed the study. ITMN-191 was safe and well-tolerated. Adverse events were generally mild and transient and without association to treatment group or dose level. A single serious adverse event of benign paroxysmal positional vertigo was observed in a patient with a history of similar symptoms. The event was deemed unrelated to study drug and resolved rapidly without study drug discontinuation. ITMN-191 reduced HCV RNA in a dose dependent manner with both every 8 hours (q8h) and 12 every 12 hours (q12h) schedules; reductions occurred rapidly and were typically sustained through day 14. Viral variants with reduced drug sensitivity were observed in the subset of patients that experienced virologic rebound but not in those who experienced a continual decline in HCV RNA.

 

Conclusion:

ITMN-191 was safe and well tolerated. Treatment resulted in rapid and sustained reductions in HCV RNA, with a median reduction at day 14 of 3.8 log10 in patients receiving 200 mg every 8 hours. Treatment response was lower in the NR cohort; this observation will inform regimen selection in future studies in this population. Based on these findings, a Phase 1b study to assess the safety and efficacy of ITMN-191 in combination with peginterferon α-2a plus ribavirin is currently underway.

 

Change from baseline in Log10 (IU/mL) HCV RNA

Cohort

Dose

N

Median Change
HCV RNA Log10 (IU/mL)
Day 14

P (naďve)

Placebo

8

0.0

P (NR)

Placebo

2

0.0

1 (naďve)

100 mg q12h

8

-0.7

2 (naďve)

100 mg q8h

8

-1.7

3 (naďve)

200 mg q12h

5

-3.1

4 (naďve)

200 mg q8h

8

-3.8

5 (NR)

300 mg q12h

8

-2.5

 


HCV Drug Pipeline - Nitazoxanide

 

1848. Evaluation of a 4 Week Lead-In Phase with Nitazoxanide (NTZ) Prior To Peginterferon (PegIFN) Plus NTZ for Treatment of Chronic Hepatitis C: Final Report.

J. Rossignol; A. Elfert; E. B. Keeffe

 

Background and aim.

In a randomized controlled trial (STEALTH C-1) in patients with chronic hepatitis C genotype 4, patients treated with nitazoxanide for 12 weeks followed by Peginterferon alfa (PegIFN) plus nitazoxanide (NTZ)or PegIFN+ribavirin (RBV) plus nitazoxanide for 36 weeks responded more rapidly than patients treated with PegIFNplus RBV and experienced higher sustained virologic response (SVR) rates. We evaluated the effect of reducing the duration of nitazoxanide lead-in therapy to 4 weeks.

 

Methods.

44 treatment-naďve patients with chronic hepatitis C were enrolled at the University of Tanta in Egypt. Patients received nitazoxanide 500 mg twice daily for 4 weeks followed by PegIFN (180 µg/wk) plus  nitazoxanide for 36 weeks. Physical examination, hematologic and chemistry tests and HCV RNA or viral load (RT-PCR, Abbott m2000™) were performed every 4 weeks during treatment. The study was designed to use data from the STEALTH C-1 trial as a historical control. Primary endpoint was sustained virological response (SVR--HCV RNA <10 IU/mL at 24 weeks following end of treatment). Secondary endpoints included HCV RNA <10 IU/mL after 4 weeks (RVR) and 12 weeks (cEVR) of combination therapy, and at end of treatment (ETR). Analysis was intent to treat.

 

Results

Baseline HCV RNA, Body Mass Index (BMI), fibrosis, age, sex and other demographic and disease-related characteristics of the 44 patients were similar to patients enrolled in the STEALTH C-1 trial.

·        40 patients were infected with HCV genotype 4,

·        3 with genotype 1, and

·        1 with genotype 2.

 

RVR, cEVR, ETR and SVR rates are presented in the table. Each of the genotype 1 and 2 patients had cEVR, ETR and SVR, and 2 of 3 genotype 1 patients had RVR. Adverse events were similar to those observed in the STEALTH C-1 trial.

 

Conclusions.

The nitazoxanide lead-in phase used in the STEALTH C-1 trial can be reduced from 12 weeks to 4 weeks without compromising RVR, cEVR, ETR and SVR rates. Results support the need for further studies of the efficacy of dual therapy with PegIFN plus nitazoxanide without RBV and suggest similar efficacy of PegIFN plus nitazoxanide in patients with genotypes other than genotype 4.

 

Virologic Response Rates by Treatment Group

 

No.

RVR

cEVR

ETR

SVR

4 wk lead-in, PegIFN+NTZ 36wk

44

26 (59%)

36 (82%)

38 (86%)

35 (80%)

12 wk lead-in, PegIFN+NTZ 36wk

28

15 (54%)

19 (68%)

20 (71%)

17 (61%)

12 wk lead-in, PegIFN+RBV+NTZ 36wk

28

18 (64%)

24 (86%)

23 (82%)

22 (79%)

PegIFN+RBV 48wk

40

15 (38%)

28 (70%)

30 (75%)

20 (50%)

 


HCV Drug Pipeline – General

 

1849. Safety and antiviral activity of BI201335, a new HCV NS3 protease inhibitor, in treatment-naive patients with chronic hepatitis C genotype-1 infection given as monotherapy and in combination with Peginterferon alfa 2a (P) and Ribavirin (R). 

M. P. Manns; M. Bourliere; Y. Benhamou; S. Pol; M. Bonacini; T. Berg; C. Trepo; D. Wright; G. Steinmann; D. B. Huang; J. Mikl; G. Kukolj; J. O. Stern

 

Background:

BI201335 is a HCV NS3 protease inhibitor (EC50 of 3-6 nM). A multiple rising dose study evaluated safety and antiviral activity in treatment-naive patients (pts) with chronic HCV genotype-1 infection as monotherapy for 14 days followed by triple combination therapy with pegylated interferon plus ribavirin (P+R) for an additional 14 days.

 

Methods:

34 patients (France, Germany, Spain, USA) with a Metavir fibrosis score of 0-3 and no prior therapy with any interferon (IFN) or ribavirin (R) were randomized (2 placebo:6 active) to 4 dose groups of once-daily (qd) BI201335: 20 mg (n=8), 48 mg (n=9), 120 mg (n=9), or 240 mg (n=8).

 

BI201335 was given as monotherapy for 14 days. Patients with <1 log10 decrease in Day 10 viral load (VL) had BI201335 discontinued after Day 14. Patients with a ≥1 log10 decrease in Day 10 viral load continued BI201335 on Day 15 and added pegylated interferon (P)(180ug/week) plus ribavirin (weight based) for triple combination therapy through Day 28. The primary endpoint was ≥2 log10 viral load reduction at any time to Day 14. Plasma HCV-RNA levels were measured with Roche COBAS TaqMan (LLOQ 25 IU/mL).

 

Results:

33 patients were white, 1 was Asian, 27 were male, mean age = 48.9±11.1 years, mean body weight 79.1±17.5 kg, and median (range) baseline viral load was 6.8 (4.7-7.7) log10. There were no significant demographic differences between dose groups. BI201335 was well tolerated. No patients discontinued treatment during monotherapy due to adverse events (AEs). AEs observed were typical for pegylated interferon plus ribavirin.  One serious AE, asthenia, occurred in the 20 mg dose cohort 6 days after initiating pegylated interferon plus ribavirin. Rapid decline of viral load was observed in all patients with maximal decline 2-4 days after starting BI201335. With the exception of 1 patient in the 20 mg cohort, all patients on BI201335 achieved > 2 log10 viral load decline during the monotherapy period. Median (range) maximal reductions in viral load during 14 day monotherapy for the 20 mg, 48 mg, 120 mg, and 240 mg groups were 3.0 (1.5-3.9), 3.6 (3.1-3.8), 3.7 (3.3-4.1), and 4.2 (3.6-4.8) log10, respectively.

 

No significant change in viral load was observed with placebo. Viral load rebound during treatment was seen in the first 14 days of monotherapy in a majority of patients from all dose groups. Population sequencing of the NS3/4A protease at baseline and rebound during treatment revealed selection of variants that confer in vitro resistance to BI201335.

 

Conclusion:

BI 201335 as monotherapy for 14 days followed by combination with pegylated interferon plus ribavirin for additional 14 days was well tolerated, and induced a strong and rapid antiviral response. The results support further study of BI201335 as a once-daily potent antiviral for treatment-naďve HCV patients.

 


HCV Drug Pipeline – Telaprevir

 

1852. A Study of Telaprevir Combined with Peginterferon-Alfa-2a and Ribavirin in Subjects with Well-Documented Non-Response or Relapse after Previous Peginterferon-Alfa-2a and Ribavirin Treatment: Interim Analysis. 

M. L. Shiffman; T. Berg; F. Poordad; J. Bronowicki; A. J. Muir; S. C. Gordon; S. George; N. Adda; J. G. McHutchison

 

Background:

Patients who have not achieved sustained virological response (SVR) with prior treatment represent a large unmet medical need in hepatitis C virus (HCV) management. This is an ongoing open-label study of telaprevir (telaprevir,T), a potent and selective inhibitor of HCV NS3-4A protease, combined with peginterferon-alfa-2a (Peg-IFN, P) and ribavirin (RBV, R) in patients with HCV genotype 1 infection who did not achieve SVR in PR control arms of the Phase 2 PROVE studies. The study aims to determine antiviral responsiveness to T/PR in well-characterized null and partial responders and relapsers to pegylated interferon/ribavirin , and assess the correlation between the response to T/pegylated interferon/ribavirin  treatment with the original response to pegylated interferon/ribavirin .

 

Methods:

Null responders (<1-log10 decrease in HCV RNA at wk 4 or <2-log10 decrease at wk 12), partial responders (≥2-log10 decrease at wk 12, detectable HCV RNA at wk 24) and relapsers (end-of-treatment response but relapsed following 48 weeks of pegylated interferon/ribavirin) from the pegylated interferon/ribavirin  arms of the PROVE studies were eligible. Pts received telaprevir 750 mg q8h + pegylated interferon/ribavirin at standard doses for 12 wks, then pegylated interferon/ribavirin for 12 wks (relapsers or partial responders) or 36 wks (null responders) based on prior response to pegylated interferon/ribavirin and on-treatment response. Treatment was discontinued if HCV RNA was >25 IU/mL (LOQ 25 IU/mL; LOD 10 IU/mL) at wk 4 or wk 12.

 

Results:

72 patients received ≥1 dose of study drugs; 60, 36 and 16 patients have completed treatment through wks 4, 8 and 12, respectively. Baseline characteristics (n=59) were: 46 male; median age 52 yrs; 52 Caucasians, 6 Blacks and 1 Hispanic; median baseline HCV RNA 6.8 log10 IU/mL. Virologic responses are shown (table).

 

Two patients had viral breakthrough (>1-log10 increase above HCV RNA nadir or >100 IU/mL HCV RNA) at wk 2; both were wk 4 null responders to prior pegylated interferon/ribavirin. Reported adverse events (AEs) were as expected for pegylated interferon/ribavirin, and consistent with telaprevir -based regimens in the PROVE studies. Two patients discontinued treatment due to adverse events.

 

Conclusions:

These preliminary findings suggest that patients with genotype 1 HCV infection who fail to respond to Peg-IFN-alfa-2a and RBV (including well-documented null responders) can achieve and maintain on-treatment response with a telaprevir -based regimen. Follow-up treatment of these patients is ongoing to evaluate the clinical significance of these interim findings in this difficult-to-treat population.

 

Prior PR responses in PROVE studies

HCV RNA
<25 IU/mL
at Wk 4
n/N (%)

HCV RNA <10 IU/mL on T12/PR24

Wk 4
n/N (%)

Wk 8
n/N (%)

Wk 12
n/N (%)

Wk 4 null responders

18/24 (75)

8/24 (33)

10/15 (67)

8/9 (89)

Wk 12 null responders

7/10 (70)

5/10 (50)

5/5 (100)

3/3 (100)

Partial responders

18/19 (95)

15/19 (79)

9/9 (100)

1/1 (100)

Relapsers

5/5 (100)

4/5 (80)

6/6 (100)

2/2 (100)

N=total number of patients with assessment at the respective visit

 


HCV Drug Pipeline – Telaprevir

 

1854. Phase 2 Study of Telaprevir Administered q8h or q12h with Peginterferon-Alfa-2a or -Alfa-2b and Ribavirin in Treatment-Naďve Subjects with Genotype 1 Hepatitis C: Week 4 Interim Results.  

X. Forns; P. Marcellin; T. Goeser; P. Ferenci; F. Nevens; G. Carosi; J. P. Drenth; K. De Backer; R. van Heeswijk; T. J. Vangeneugden; G. Picchio; M. Beumont-Mauviel

 

Background:

Study C208 is an ongoing open-label, randomized Phase 2 study of telaprevir (telaprevir) that is testing the feasibility of a dosing schedule for telaprevir of every 12 hours (q12h)—twice a day dosing.  The study will compare the twice a day dosing to the current dosing of telaprevir every 8 hours (q8h)—three times a day—that is currently in clinical development. 

 

The study medication includes a triple combination therapy of peginterferon-alfa-2a (Pegasys) or Peg-IFN-alfa-2b (PegIntron) with standard doses of ribavirin and different doses of telaprevir (based on dosing schedule).  The 4 week interim analysis was released at AASLD conference.  

 

Methods:

161 subjects were randomized into 4 arms (table). Subjects in all arms received telaprevir/pegylated interferon/ribavirin treatment for 12 weeks, and will subsequently receive either 12 or 36 additional weeks of pegylated interferon/ribavirin based on rapid virologic response (RVR) criterion. Subjects who met the definition of viral breakthrough (≥1-log increase in HCV RNA above nadir) discontinued telaprevir dosing and will complete 48 weeks of pegylated interferon/ribavirin. An intent-to-treat analysis was performed when all treated subjects had completed week 4 of treatment or had discontinued earlier than week 4. The analysis also assessed all treatment or telaprevir dosing discontinuations including subjects who discontinued beyond week 4, up to the time of data cut-off. The proportion of subjects with HCV RNA below the limit of detection (TaqMan assay LOD 10 IU/mL) at week 4 (RVR) is reported.

 

Group

N

Peg-IFN

telaprevir 

Ribavirin

A

40

alfa-2a (180 μg/wk)

750 mg q8h

1000–1200 mg/d

B

42

alfa-2b (1.5 μg/kg/wk)

750 mg q8h

800–1200 mg/d

C

40

alfa-2a (180 μg/wk)

1125 mg q12h

1000–1200 mg/d

C

39

alfa-2b (1.5 μg/kg/wk)

1125 mg q12h

800–1200 mg/d

 

Results:

Baseline characteristics were balanced across arms. Although differences did not reach statistical significance, a higher rate of HCV RNA clearance was observed at week 4 in arms A and C compared with arms B and D.

 

Week 4 HCV RNA negative (<10 IU/mL) with telaprevir /ribavirin (daily) and pegylated interferon (weekly):

·        Group A – 80.0% (32 out of 40 patients) – every 8 hours

·        Group B—69.0% (29 out of 42 patients) –every 8 hours

·        Group C—82.5% (33 out of 40 patients)—every 12 hours

·        Group D – 66.7% (26 out of 39 patients)—every 12 hours

 

Up to week 4, the number of subjects with viral breakthrough was 0 and 2 in arms A and C, respectively; and 2 and 1 in arms B and D, respectively. The overall proportion of telaprevir discontinuations for any reason was 15% (n=24). Similar discontinuation rates were observed in each of the arms.

 

Conclusions:

In the context of the two currently available standard-of-care regimens, telaprevir 750 mg q8h or 1125 mg q12h in combination with pegylated interferon/ribavirin  yielded high rates of virological response and low viral breakthrough at week 4. Differences in the proportion of subjects with undetectable HCV RNA were observed between arms receiving different pegylated interferon/ribavirin regimens.

 

Future results from a week 12 interim analysis will further assess the therapeutic potential of telaprevir q12h dosing, as well as potential differences in efficacy related to the combination of telaprevir with either Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and ribavirin.

 


HCV Drug pipeline – Telaprevir

 

1856. No Compensatory Fitness Mutations Selected in NS3/4A Protease Cleavage Sites During Treatment with Telaprevir, Peg-IFN-Alfa-2a, and Ribavirin in Phase II Studies of Treatment-Naďve HCV Genotype 1-Infected Patients. 

E. Z. Zhang; D. J. Bartels; J. Sullivan; M. Marcial; J. Dorrian; A. Tigges; A. D. Kwong; T. L. Kieffer

 

Background:

Emergence of viral variants with decreased sensitivity to direct-acting antivirals has been observed for viral infections including HIV, HBV, and HCV. These variants typically have decreased fitness compared to wild-type (WT) virus, and can therefore be replaced quickly by WT virus in the absence of drug selective pressure. However, the selection of compensatory mutations can help overcome this fitness impairment and allow resistant variants to persist after treatment. One known mechanism for improving the fitness of HIV protease inhibitor-resistant variants is the development of mutations in the cleavage sites recognized by the protease. Telaprevir (telaprevir), an HCV NS3/4A protease inhibitor in Phase 3 clinical trials, is being studied in combination with Peg-IFN-alfa-2a (P) and ribavirin (R) for genotype 1 hepatitis C. Previously described telaprevir-resistant variants have been shown to have a decreased fitness compared to WT. For the first time, we investigate whether the selection of these variants is accompanied by sequence co-evolution in any of the 4 NS3/4A protease cleavage sites during or after treatment with telaprevir /P±R in PROVE1 and PROVE2 clinical studies.

 

Methods:

Plasma samples for population sequencing were taken before and at multiple times during and after treatment with telaprevir /P±R or PR. The non-structural HCV RNA region was amplified by nested RT-PCR and sequenced in samples with HCV RNA > 1,000 IU/mL. Prospectively defined criteria for identifying telaprevir -selected mutations were applied using a Poisson distribution.

 

Results:

Analysis of all subjects (n=569) prior to treatment showed that cleavage sites were highly conserved: NS3-NS4A (99.7%), NS4A-NS4B (93.6%), NS4B-NS5A (92.3%) and NS5A-B (90.1%).

 

In subjects who failed telaprevir /P±R treatment due to viral breakthrough or relapse (n=106), sequence analysis of the 4 NS3/4A cleavage sites did not identify any telaprevir -selected amino acid changes. Thus, protease cleavages sites remained conserved during telaprevir /P±R treatment (mean duration of telaprevir dosing = 81 days; range = 16-85 days).

 

Conclusions:

In subjects treated with telaprevir /P±R who had viral breakthrough or relapse, no compensatory fitness mutations were observed in any of the 4 cleavage sites recognized by the NS3/4A protease, suggesting that this potential mechanism for improving fitness of viral variants did not occur after up to 12 weeks of treatment with a telaprevir /P±R regimen. Further evaluation of other genome regions is required to determine whether other mechanisms for improving fitness occur that would allow variants to persist or eventually be replaced by WT virus upon telaprevir discontinuation.

 


HCV Drug Pipeline – General

 

1857. Taribavirin Exposure Analysis from a Previous Phase 3 Trial Correlates with Phase 2b Weight Based Dosing Interim Results. 

P. Pockros; I. M. Jacobson; B. R. Bacon; N. H. Afdhal; F. Poordad; E. Chun; J. Hammond

 

Background:

The phase 3 study (ViSER1) compared a fixed dose of taribavirin (TBV, 600mg BID), an oral prodrug of ribavirin (RBV), vs. standard weight-based dose (WBD) RBV (1-1.2 g/day), both in combination with pegylated interferon α- 2b (PEG) demonstrated significantly lower rates of anemia, but TBV failed to demonstrate non-inferior efficacy compared to RBV. Post- hoc analysis demonstrated higher dose exposure correlated with increases in SVR. An ongoing phase 2b randomized, active control trial using WBD of TBV plus PEG in chronic hepatitis C naďve genotype 1 (G1) patients is being conducted to assess whether with WBD, the efficacy of TBV can be improved while retaining the anemia advantage.

 

Aim:

Demonstrate that a correlation exists between response and anemia with equivalent TBV exposure in ViSER1 and the phase 2b trial for naďve G1 patients.

 

Methods:

ViSER1 database was retrospectively reviewed for G1 patients with TBV exposure of 20-25 mg/kg/day based on body weight. Response rates were calculated in these patients for weeks 4, 12, 48, and 72 as well as relapse and anemia. Equivalent clinical data available for the Phase 2b 20 and 25mg/kg/day dosing arms are reported through week 12. (Table 1)

 

Results:

Fifty three (53) patients from ViSER1 on TBV 20-25mg/kg/day and 226 WBD RBV patients were identified; 137 equivalently dosed TBV patients and 70 WBD RBV patients in the phase 2b study were identified.

 

Conclusions:

Responses from ViSER1 correlate with interim data from this phase 2b study and may be predictive of ultimate patient outcome. TBV doses of 20-25mg/kg may achieve SVR comparable to RBV with a lower incidence of anemia compared to standard doses of RBV.

 

Table 1

ViSER1(N)

Anemia1
% Overall

RVR %2

cEVR %3

pEVR %4

EOT %

SVR %

RR %

TBV 20-25mg
(53)

9.4

13.2

47.2

22.6

56.6

47.2

16.6

RBV
(226)

25.7

20.4

50.9

23.0

52.7

41.6

21.1

TBV Phase 2b (N)

Anemia1 % Wk 12

RVR %2

cEVR 3 %

pEVR %4

 

 

 

TBV
20 mg
(67)

9.0

16.4

41.8

22.4

 

 

 

TBV
25 mg
(70)

7.1

14.3

41.4

15.7

 

 

 

RBV
(70)

24.3

11.4

31.4

20.0

 

 

 

1Hg level <10 g/dl; 2Wk 4 viral negative; 3Complete EVR-viral negative at wk 12; 4Partial EVR-2 log decline at wk 12 and viral positive

 


HCV Drug Pipeline – Adjunct Therapies – General

 

1858. A double blind, placebo-controlled trial with escitalopram to prevent psychiatric adverse events during treatment with pegylated interferon-alpha and ribavirin for chronic hepatitis C: The “Prevention Of Psychiatric Side effects (POPS)-study.”

G. Bezemer; A. R. Van Gool; J. P. Drenth; B. E. Hansen; H. A. Droogleever Fortuyn; C. J. Weegink; M. W. Hengeveld; H. L. Janssen; R. J. de Knegt

 

Background/Aim:

Treatment with PEG-interferon (PEG-IFN) for chronic hepatitis C (HCV) is associated with psychiatric side effects, most notably depression and increased irritability, which frequently necessitate dose reduction or cessation of therapy.

 

Methods:

We completed an investigator-initiated, randomized, double-blind, controlled trial, in chronic HCV patients, investigating the efficacy of prophylactic escitalopram (lexapro) (10 mg; number=40) versus placebo (number=39) on psychiatric side effects in patients treated with PEG-IFN α-2a and ribavirin (RBV).

 

Primary outcome measures were an increase of at least two points on reported sadness, inner tension, impaired concentration of the Montgomery-Asberg Depression Rating Scale (MADRS) or on irritability of the Brief Anxiety Scale (BAS). Secondary outcome measure was depression as diagnosed by the Mini International Neuropsychiatric Interview.

 

Psychometric measurements were performed at baseline, week 4, 12 and 24, together with the completion of self-rating scales (Beck Depression Inventory (BDI) and Symptom Check List-90 (SCL-90)). In case of major psychopathology, study code was broken and open-label escitalopram was started.

 

Results:

We observed significantly less psychiatric side effects for patients treated with escitalopram as compared to those treated with placebo for all primary and secondary outcome measures, except for impaired concentration (Table 1).

 

Regarding the other psychometric measurements, patients treated with escitalopram scored significantly better than those treated with placebo on sum scores and all subscales of the BDI and SCL-90 at all different evaluation points (p ≤ 0.04), except for SCL-90 somatic complaints at week 4 and 12.

 

No (serious) adverse events related to escitalopram were observed. Compliance with PEG-IFN and RBV was similar probably due to the possibility of open-label treatment.

 

Conclusion:

Prophylactic treatment with escitalopram (lexapro) is effective in the prevention of psychiatric side effects during antiviral therapy of hepatitis C and should be considered for all chronic HCV patients who are treated with PEG-IFN based regimens.

 

Number of events of the primary and secondary outcome measures in the esitalopram arm and placebo arm

Outcome measures

Escitalopram:
Events (%) n=40

Placebo:
Events (%) n=39

p-value
(χ2)

Reported sadness 1

11 (27.5)

19 (48.7)

0.050

Inner tension 1

7 (17.5)

15 (38.5)

0.025

Impaired concentration 1

22 (55)

26 (66.7)

0.277

Irritability 2

9 (22.5)

17 (43.6)

0.045

Depression 3

5 (12.5)

14 (35.9)

0.012

 

1 items Montgomery-Asberg Depression Rating Scale 2 item Brief Anxiety Scale 3 Mini International Neuropsychiatric Interview

 


HCV Drug Pipeline – General

 

1859. Double-blind, randomized, placebo-controlled, multi-center, Phase II dose-ranging study to assess the antifibrotic activity of farglitazar in chronic hepatitis C infection.

J. G. McHutchison; Z. D. Goodman; H. R. Makhlouf; M. Rodriguez-Torres; M. L. Shiffman; D. C. Rockey; P. Husa; W. Chuang; D. Theodore; R. A. Brigandi; A. Webster; M. Schultz; H. A. Watson; B. Stancil; S. L. Fox; M. J. Gartland; S. D. Gardner

 

Background:

Hepatic stellate cells (HSC) are key effectors of fibrogenesis in response to liver injury, during which they become activated and transform into myofibroblast-like cells. Activated HSCs express α-smooth muscle actin (α-SMA) and produce extracellular matrix proteins. Peroxisome proliferator-activated receptor gamma (PPARγ) ligands suppress several markers of HSC activation, including α-SMA. Farglitazar, an insulin-sensitizing agent, selectively binds and activates PPARγ and inhibits stellate cell activation. Thus, it was evaluated as a potential antifibrotic agent in patients with chronic hepatitis C (CHC) and hepatic fibrosis.

 

Methods:

CHC subjects with compensated liver disease were eligible if they were non-responders to prior anti-viral treatment and had a screening liver biopsy with Ishak fibrosis stage 2-4. They were randomized to 1 of 2 doses of farglitazar (0.5mg or 1.0mg daily) or placebo for 52 weeks after which a repeat liver biopsy was obtained. Tissue α-SMA and collagen were quantified by morphometric image analysis. Safety of farglitazar was also assessed.

 

Results:

585 subjects had a screening biopsy and 265 were randomized to 1 of 3 treatments. Of these, 227 subjects had both a pre- and post-treatment biopsy of which 209 pairs were adequate for analysis. Subjects were well matched across the groups by demographics and histological characteristics. Pre-treatment Ishak fibrosis stages 2, 3, and 4 were 37%, 46% and 15%, respectively.

 

Week 52 showed no overall treatment difference for α-SMA (p=0.58) and collagen (p=0.99) with pre-treatment values as a covariate in the model. For α-SMA, median % change showed an increase of 49% in placebo, 58% in 0.5 mg and 52% in 1.0 mg. Collagen increased by a median of 27% in placebo and 31% in both 0.5 and 1.0 mg. There were no significant differences across treatment groups in Ishak or Metavir scores or by ranked assessment of inflammation and fibrosis. Overall in the study, α-SMA and collagen increased by a median % change of 56% and 31%, respectively. Adverse events were similar across all treatment groups.

 

Conclusions:

In these CHC subjects with moderate fibrosis, 52 weeks of treatment with farglitazar showed no effect on α-SMA, collagen, or ranked assessment of paired biopsies.

 

Changes in αSMA and Collagen After 52 Weeks of Treatment

 

Placebo

Farglitazar

0.5 mg

1.0 mg

Pre

Post

Pre

Post

Pre

Post

αSMA, n

64

65

71

72

72

72

Mean±SD*

0.06±0.05

0.08±0.05

0.06±0.04

0.08±0.05

0.05±0.04

0.08±0.05

Collagen, n

65

66

71

71

72

72

Mean±SD*

0.08±0.06

0.11±0.07

0.08±0.07

0.11±0.09

0.08±0.08

0.11±0.07

 


HCV Treatment – Pegasys

 

1860. High sustained virologic response rates in HCV genotype 1 relapser patients retreated with peginterferon alfa-2a (40KD) plus ribavirin for 72 weeks. 

S. Kaiser; B. Lutze; H. G. Hass; C. R. Werner

 

Background:

Combination therapy with pegylated interferon plus ribavirin for 48 weeks is the current standard of care for treatment-naive hepatitis C genotype 1 patients. This treatment regimen results in relapse rates between 20-30% with the highest rates being seen in partial or slow responders to therapy (HCV RNA >15 IU/mL at weeks 4 and 12 but at least a 2 log10 drop at week 12). Strategies for treating the growing pool of patients who have relapsed to a previous course of pegylated interferon plus ribavirin are needed.

 

Methods:

This study evaluated the efficacy of peginterferon alfa-2a (40KD) in 107 hepatitis C patients who had demonstrated prior relapse to 48 weeks of treatment with peginterferon alfa-2a or peginterferon alfa-2b both plus ribavirin.

 

These patients were predominantly genotype 1 (81.3%), male (74%) with an average weight of 81±7kg and 22 patients where classified as having advanced fibrosis/cirrhosis (Ishak 5/6). Patients were treated with peginterferon alfa-2a 180 µg/wk plus ribavirin 1000/1200 mg/day for 72 weeks. Virologic responses were assessed at week 4 (RVR, HCV RNA <15 IU/mL), week 12 (HCV RNA >15 IU/mL at week 4, <15 IU/mL at week 12; HCV RNA >15 IU/mL at weeks 4 and 12 but at least a 2 log10 drop at week 12), week 24 (HCV RNA <15 IU/mL) and at week 72 (end of treatment response, HCV RNA <15 IU/mL). SVR was measured at week 96 and defined as an HCV RNA <15 IU/mL.

 

Results:

The overall SVR rate was 51% (54/107). Overall, 27% (29/107) of patients achieved an RVR of whom 28 (97%) went on to achieve an SVR.

 

In total, 43% (46/107) had a HCV RNA <15 IU/mL at week 12, of whom 93% (43/46) achieved an SVR. In addition, 79% (85/107) patients achieved an end of treatment response. Breakthrough occurred in 4 patients and 9 patients discontinued treatment.

 

During the trial, 17 (16%) and 23 (21%) patients required a dose reduction of peginterferon alfa-2a and ribavirin, respectively.

 

Conclusion:

A treatment duration of 72 weeks with peginterferon alfa-2a plus ribavirin in patients that had relapsed to previous therapy resulted in high SVR rate, particularly in those who were negative at weeks 4 and 12. Therefore, with 72 weeks of re-treatment sustained virological response can be achieved in approximately half of patients that previously relapsed with 48 weeks of treatment.

 


HCV Drug Pipeline – ITMN-191 (R7227)

 

1861. Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships for ITMN-191 in a Phase 1 Multiple Ascending Dose Trial in Patients with Genotype 1 Chronic Hepatitis C (CHC)Infection. 

C. Rubino; W. Z. Bradford; A. Forrest; S. Porter; L. M. Blatt; S. Seiwert; S. Zeuzem

 

 

Introduction:

ITMN-191 is a highly potent, slowly dissociating NS3/4A protease inhibitor designed to achieve high liver concentrations with only modest plasma exposure. This study examines PK-PD relationships for ITMN-191 in chronic hepatitis C (CHC) patients.

 

Methods:

Four cohorts of 10 naďve patients were randomized (8:2) to receive oral ITMN-191 (100 mg every 12 hours (q12h), 100 mg every 8 hours (q8h), 200 mg q12h, or 200 mg q8h) or placebo for 14 days. PK parameters and PK-PD relationships were assessed using non-compartmental methods and non-linear models, respectively.

 

Results:

ITMN-191 showed potent antiviral activity with relatively low plasma concentrations. At 200 mg q8h, the mean AUC0-24, Cmax, and Cmin values were 500 ng×h/mL, 91 ng/mL and 2.78 ng/mL, respectively, and the mean max. decline in HCV RNA was 3.9 log10.The dose-exposure relationship was not uniformly proportional.Predicted Cmin values for 2, 3, and 4 log10 HCV RNA declines were 0.07, 0.19, and 2.7 ng/mL, respectively. In an inhibitory Emax model, the strongest relationship was between Day 1 Cmin and max change in HCV RNA (figure); fitted Eo, Emax and EC50 values were -0.33 log10, 3.6 log10 and 0.08 ng/mL, respectively.

 

Conclusion:

ITMN-191 achieves significant antiviral effects with substantially lower plasma exposures than reported for other NS3 inhibitors. This is consistent with the high liver: plasma concentration ratios seen in animals and likely contributes to the favorable safety and antiviral activity in patients. These data, plus in vitro evidence of synergy with peginterferon, provide a strong rationale for the ongoing triple combination study to further evaluate the PK-PD and antiviral effect of an ITMN-191.

 

Observed Data and Fitted PK-PD relationship for ITMN-191


HCV Treatment – Pegasys

 

1862. Histologic Response to Peginterferon Alfa-2a Plus Ribavirin in Treatment-Naive Latino and Non-Latino White Patients Infected With HCV Genotype 1: The LATINO Study. 

L. A. Balart; F. M. Hamzeh; M. Rodriguez-Torres

 

Aim

To determine the effect of peginterferon alfa-2a/ribavirin on hepatic histology in treatment-naive Latino and non-Latino whites infected with HCV genotype 1.

 

Methods

This prospective, open-label, multicenter study enrolled 269 Latinos and 300 non-Latinos. Cirrhotic patients were to be balanced between groups. Patients received peginterferon alfa-2a 180 µg/wk and ribavirin 1000/1200 mg/day for 48 wks and were followed to week 72. Liver biopsies were obtained within 18 months of baseline and at week 72. Improved or worsened fibrosis status was defined as an increase or decrease of ≥1 grading category from baseline to week 72. Baseline factors predictive of improvements in histology were assessed using multiple linear regression; a P-value of ≤.2 identified significant factors.

 

Results

Paired biopsy data were available for 157 Latinos and 201 non-Latinos. At baseline, the extent of liver impairment was similar between the 2 groups, although a higher percentage of Latinos had ALT >3× upper limit of normal (25% vs 17%) and cirrhosis (13% vs 10%).

 

The percentage of patients with an ISHAK modified HAI response at Wk 72 was higher in non-Latinos than Latinos (59% vs 47%; P=.03). The percentage of patients with improved fibrosis score was higher in patients with a SVR than in those who relapsed or did not respond (Table).

 

In Latinos and non-Latinos, baseline ISHAK modified HAI score (P<.0001 for both) and age (P=.002 and P=.13, respectively) were positive predictors of ISHAK modified HAI response. In addition, BMI (P=.07), ALT quotient (P=.03), and fibrosis score (P=.02) were predictors for Latinos. Various factors predicted response based on ISHAK modified HAI fibrosis score for both ethnic groups, which differed between groups.

 

Improved fat scale scores were seen in 32% of Latinos and non-Latinos. Sinusoidal fibrosis improved in 13% of Latinos and 21% of non-Latinos, and percentage of Mallory bodies remained stable in both groups. Hepatocyte ballooning worsened in 12% of Latinos vs 6% of non-Latinos.

 

Conclusion

The magnitude of histologic response to peginterferon alfa-2a/ribavirin appeared to be lower in Latinos than non-Latinos regardless of virologic response. Predictors of change in histologic response were different for the 2 groups.

 

 

Latino
Fibrosis score

Non-Latino
Fibrosis score

Virologic status

Improved %

Worsened %

Improved %

Worsened %

Overall

25

22

42

18

SVR

37

14

55

15

Relapse*

17

29

26

24

Non-responder†

14

30

15

22

*Detectable HCV RNA at Wk 72 after undetectable at Wk 48, or missing data at Wk 72 †Included patients with breakthrough

 


HCV Drug Pipeline – General

 

1863. Intravenous silibinin for treatment of nonresponders to peginterferon/ribavirin therapy in chronic hepatitis C. 

P. Ferenci; T. Scherzer; H. Kerschner; K. Rutter; S. Beinhardt; H. Hofer; M. Schöniger-Hekele; H. Holzmann; P. E. Steindl-Munda

 

Background:

By chance we observed that IV silibinin (SIL) had marked antiviral properties in patients with chronic hepatitis C, confirming in vitro findings that SIL inhibited viral replication. The aim of this investigation was a dose finding study and the assessment of safety.

 

Methods:

20 nonresponders (17 male, 3 female; age: 52.7±12.8 years, 17 genotype 1; 2=1; 4=2; F3/4: n=7, F1/2: n=10; n.a.:3) to full dose of peginterferon/ ribavirin (PR) combination therapy were included. Nonresponse was defined by the lack of a > 2log drop of viral load after 12 weeks of full dose PR therapy and/or by not achieving an end of treatment response. Patients first received daily 5, 10 or 15 mg/kg 20mg/kg SIL (Rottapharm-Madaus, Köln, Germany) infused over 4 hrs for 14 consecutive days. On day 8 treatment with 180µg/wk PegIFNα-2a and 1-1.2 g/d ribavirin was started. After day 14 patients received 280 mg silymarin (Rottapharm-Madaus, Köln) TID per os. Viral load was determined daily preinfusion by the TaqMan PCR assay (Cobas Ampliprep/ Cobas TaqMan HCV Test; limit of detection, 15 IU/mL, Roche Diagnostics).

 

Results:

After 7 days of silibinin monotherapy the 5mg/kg dose was marginally effective (n=3, log drop 0.55±0.5), whereas the 10 mg/kg (n=3, log drop 1.41±0.59), 15 mg/kg (n=5, log drop 2.11±1.15) and 20 mg/day doses (n=9, 3.02±1.01) led to a significant decrease in viral load (p<0.001). After 1 week of combined silibinin and PR therapy viral load decreased further (log drop: 5 mg/kg: 1.63±0.78; 10 mg/kg: 4.16±1.28; 15 mg/kg 3.69±1.29; 20 mg/kg 4.8± 0.89; all p<0.0001 vs. baseline). Two of the 5 and 4 of the 9 patients in the 15 mg/kg and 20 mg/kg groups, respectively had HCV-RNA<15 IU/mL at day 15. Further 4 had a HCV-RNA < 50 IU/mL. 7 of these patients had a rapid virologic response (week 5 = after 4 weeks of PR combination therapy), and 8 (57%) had HCV-RNA <15 IU/mL at week 13, one relapsed at week 9. HCV-RNA increased in all patients with HCV-RNA > 50 IU/mL at the end of the infusion period. HCV-RNA became undetectable in 3 of them after a second cycle of SIL infusions given after week 13. All responders are still on PR therapy. SIL treatment was well tolerated.

 

Conclusion:

Intravenous SIL is a potent antiviral agent and may be a treatment option for treatment of PR nonresponders.

 


HCV Treatment – Pegasys

 

1864. Pharmacokinetics (PK) of ribavirin (RBV) in patients with renal impairment or end-stage renal disease (ESRD) and chronic hepatitis C (CHC) during treatment with peginterferon alfa-2a (40KD) (PEGASYS®) and RBV (COPEGUS®). 

K. Wang; A. A. Lawal; M. Majchrowicz; P. N. Morcos; S. Moreira; S. A. Draibe; R. H. Ghalib; A. Zaman; J. S. Crippin; V. Joshi; P. Martin; J. Grippo

 

Background:

Ribavirin RBV is an essential component of pegIFN-based regimens for treatment of chronic hepatitis C (CHC). Ribavirin (RBV) is eliminated in part by renal excretion; thus, patients with renal impairment are at risk of RBV toxicity and dosage reductions are mandatory. Our objective was to characterize the PK of RBV in patients with varying degrees of renal impairment including those with end-stage renal disease (ESRD) compared to patients with normal renal function.

 

Methods:

Patients with CHC and moderate (Group A: Clcr >30 to <50mL/min, n=17) or severe (Group B: Clcr <30 mL/min, n=14) renal impairment or ESRD on dialysis (Group C, n=19) were enrolled. Group D comprised a control group (Clcr >80mL/min; n=13).

 

Patients received peginterferon alfa-2a 180µg/week (Groups A, B, D) or 135µg/week (Group C) plus RBV 600 (Group A), 400 (Group B), 200 (Group C), or 800–1200mg/day (Group D). Blood samples for RBV PK were collected pre-dose and up to 12 hours post-dose on day 1 (single dose) and after 12 weeks’ treatment (multiple dose). In Group C, samples (arterial, venous, and dialysate) were collected 15 minutes after the start of dialysis, mid-dialysis and before the end of dialysis.

 

Results:

Relative to Group D, the ratio of the geometric least square means (LSM) value and 90% CI for Groups A, B, and C, respectively, were 0.69 (0.49–0.97), 0.89 (0.69–1.15), and 0.81 (0.67–0.99) for single-dose AUC and 1.31 (1.0–1.7), 1.17 (0.87–1.57) and 0.81 (0.68–0.97) for multiple-dose AUC. Relative to Group D, the LSM for apparent clearance (Cl/F) for Groups A, B, and C were 0.34 (0.13–0.55), 0.28 (0.07–0.49) and 0.26 (0.04–0.49). The mean RBV extraction coefficient during dialysis ranged from 0.48 to 0.54. RBV dose modifications were required by 9, 10, 4, and 3 patients in Groups A, B, C, and D, respectively, and serious adverse events were reported, by 2, 3, 3, and 1 patient respectively.

 

Conclusion:

Cl/F of RBV was 26–34% lower in patients with renal impairment compared to the control group. Most of the patients with moderate/severe renal impairment had frequent dose reduction/discontinuation during the first 12 weeks with dose reductions continuing after week 12. The median dose of RBV after week 12 was approximately 200mg/day for groups A–C, suggesting that this dose may be tolerated among patients with varying degrees of renal impairment.

Group (impairment)

A (Moderate)

B (Severe)

C (ESRD)

D (None)

Median RBV dose to/after wk 12 (mg/day)

464/287

319/190

200/196

1088/980

Single dose Cmax (ng/mL)

399.6

572.6

473.2

716.4

Single dose AUC0-12 (ng●h/mL)

2471.6

3190.7

2924.2

3595.8

Multiple dose Cmax (ng/mL)

3879.6

3241.1

2309

2814

Multiple dose AUC0-12 (ng●h/mL)

35561.9

31805.1

22053.6

27247.6

Mean Cl/F (L/h)

6

6

5

20

Cmax and AUC values are geometric LSM 

 


HCV Drug Pipeline – General

 

1870. Viral Kinetic Response to 12 Week Treatment with Rosiglitazone in Chronic Hepatitis C, Genotype 1 Patients Who Are Previous Relapsers or Nonresponders to Pegylated Interferon and Ribavirin. 

S. J. Mills; R. J. Naus; K. Barstow; S. Harrison

 

Background:

Insulin resistance (IR) is associated with CHC GT 1 virus. IR is associated with decreased SVR. The aim of this trial was to evaluate the effects rosiglitazone (Avantia) (rosi) on insulin sensitivity in a group of chronic hepatitis C (CHC), genotype (GT) 1, patients who are prior nonresponders or relapsers to peg-interferon and ribavirin (RBV) and assess viral kinetic (VK) response to interferon-alfacon-1 given before and 12 weeks after rosiglitazone was initiated.

 

Methods:

Thirty-four IR, GT 1, CHC patients, nonresponders (n=23), relapsers (n=11)to peg-interferon and RBV enrolled. Patients randomized to rosiglitazone 8mg daily and diet/exercise routines vs. diet/exercise routines alone. Baseline VK obtained at time point zero, 8, 16, 24 hours, day 3, 5 and 7 after giving a 15mcg single dose of interferon-alfacon-1. Repeat VK were obtained 12 weeks later after a second dose of 15mcg of interferon-alfacon-1 was given.

 

Results:

33 of 34 eligible patients completed the 12-week study and obtained repeat VK. Mean age: 49.6 years (range 23 - 66), 45.5% female, 48.5% Caucasian (Cauc), 36% African American (AA). Mean body mass index (BMI): 29.8, 36.4% were F3/4 (fibrosis score), mean QUICKI:0.32, logarithmic (log) mean viral load:13.29.

 

Eighteen patients received rosiglitazone.  No difference was observed between the two groups at baseline. Mean QUICKI improved from 0.32 to 0.33 in the rosiglitazone group and 0.31 to 0.32 in the diet/exercise group. Mean log value at baseline for the rosiglitazone group was 13.68, and decreased to 12.47 by the end of the first 24-hour period. A similar decline was noted with the second injection given at 12 weeks. No significant difference compared with the diet/exercise group.

 

Patients (in either group) who improved QUICKI had a moderate correlation (r=.34) with improvement in 24 hr VK. Glucose at week 12 correlated (r =-.44, p < .05) with viral load. Mean adiponectin improved from 20250.3 to 33761.5 in patients who improved their IR and adiponectin at day 97 was significantly and inversely correlated with day 97 glucose, at r =-.74, p<.05). The mean improvement for resistance was 17914.3 to 15266.8 and the resistance and insulin relationship was moderately correlated (r = .39).

 

Within the rosiglitazone group, the mean change in insulin (-4.2) from baseline correlated with an improvement in VK response by a mean of 1.3 log (p<0.001, r=0.60). Using linear regression and the 3 variables adiponectin, QUICKI and fasting insulin, r2=0.56, suggesting a high in sample proportion of variability on outcome measures (improvement in VK).

 

Discussion:

Rosiglitazone given over 12 weeks is associated with improvement in IR and adiponectin levels in CHC, GT 1 patients. Among the patients who received rosiglitazone and improved their fasting insulin levels, there was a significant improvement in 24 hour VK response to interferon-alfacon-1 therapy.

 


HCV Drug Pipeline – ITMN-191 (R7227)

 

1871. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics (PK) of Single Ascending Oral Doses of the NS3/4A Protease Inhibitor ITMN 191 in Healthy Subjects.  

W. Z. Bradford; C. Rubino; S. Porter; A. Forrest; L. M. Blatt; A. A. Patat

 

Background:

ITMN-191 is a highly potent and selective inhibitor of the HCV NS3/4A serine protease that was specifically designed to achieve high liver concentrations with modest systemic exposure. Preclinical studies demonstrate a potency of 1.8 nM in an HCV genotype 1 replicon, and liver: plasma concentration ratios of 10:1 and 120:1 in rats and primates, respectively.

 

Aim:

The aim of the present study was to evaluate the safety, tolerability, and PK of single ascending doses of ITMN-191 in healthy adults.

 

Methods:

In a double-blind, placebo-controlled study, healthy adult subjects were randomized to receive a single oral dose of ITMN-191 or matched placebo in a Phase 1 research facility. Study drug was administered orally in doses ranging from 2-1600 mg. In each of 4 cohorts, 8 and 2 subjects received ITMN-191 or placebo, respectively. In order to assess the effect of food on ITMN-191 PK, an additional 2 cohorts of 12 subjects each received ITMN-191 or placebo (10:2) in both the fed and fasted states, separated by a 5-day washout period.

 

Results:

A total of 64 subjects were randomized and all completed the study. There were no serious adverse events (AE) or clinically significant laboratory or ECG (cardiac) abnormalities. AE’s were similar between groups, with the exception of a higher frequency of mild and transient diarrhea and abdominal pain in the ITMN-191 group at the highest tested dose (1600 mg). The PK of ITMN-191 was linear over a dose range of 100 – 800 mg; the relationship between dose and exposure was more than proportional at the 1600 mg dose. Co-administration with food increased the expected trough (based on q8h and q12h dosing intervals), and increased the AUC by 40-50%.

 

Conclusion:

ITMN-191 was safe and well tolerated over the range of studied doses. AE’s were generally mild and transient, with no evidence of clinically significant laboratory abnormalities or ECG changes. These findings are consistent with the target PK profile that informed the molecular design of ITMN-191 and, given the predicted liver concentrations, suggest that doses in the lower range of those studied are likely to result in significant antiviral activity with modest systemic exposure.

 

Mean (±SD) for selected ITMN-191 PK parameters

Single Dose(mg)

N

Cmax (ng/mL)

AUC0-∞
(ng×h/mL)

2

8

0.20 (0.05)

0.28 (0.06)

100

8

25.4 (20.1)

24.8 (12.1)

200

8

44.4 (37.2)

36.4 (14.8)

400(Fasted)

10

69.4 (30.2)

88.6 (41.9)

400(Fed)

10

75.2 (61.6)

122 (48.1)

800

8

318 (286)

240 (136)

1600(Fasted)

10

622 (309)

693 (172)

1600(Fed)

10

528 (392)

1070 (380)

 


HCV Treatment – Pegasys

 

1873. A 72-week treatment duration with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) has a favorable risk:benefit ratio in non-responders to pegylated interferon alfa-2b (12KD) plus ribavirin: findings of the multinational REPEAT study. 

P. Marcellin; A. Craxi; C. E. Brandăo-Mello; A. M. Di Bisceglie; P. Andreone; B. Freilich; K. Reddy; A. Olveira; G. Teuber; D. Messinger; G. Hooper; J. A. Thommes; D. M. Jensen

 

Introduction:

In REPEAT, 72 weeks of treatment was more effective than 48 weeks with peginterferon alfa-2a (40KD) plus ribavirin (RBV) in 942 non-responders to peginterferon alfa-2b (12KD) plus RBV. Sustained virological response (SVR) rates were 16% and 8% in those randomized to 72 and 48 weeks of therapy, respectively (odds ratio 2.22; 95% CI: 1.40–3.52, p=0.0006).

 

Aim:

Here we examine the risk: benefit ratio for treating non-responders for 72 vs. 48 weeks by comparing adverse event (AE) rates and outcomes for the two treatment durations.

 

Methods:

Patients were randomized to peginterferon alfa-2a 360 μg/week for 12 weeks then 180 μg/week to complete 72 (Arm A) or 48 weeks (Arm B), or 180 μg/week for 72 (Arm C) or 48 weeks (Arm D). All received RBV 1000/1200 mg/day. Rates and duration of AEs were documented. The risk:benefit ratio of treatment was assessed by calculating AE incidence per SVR and by calculating the number of treatment days and the treatment days with AEs per SVR.

 

Results (Table):

The total number of on-treatment adverse events (AEs) and cumulative treatment days with AEs (or serious AEs) were slightly higher in patients randomized to 72 weeks than in patients randomized to 48 weeks. However, the incidence per treatment year was lower for patients with 72 weeks of treatment (8.1 vs. 10.1 AEs). This difference becomes more favorable for 72 weeks of treatment if the cumulative treatment duration required to achieve an SVR (6.7 vs. 10.0 years) or AE burden per SVR (55 vs. 100 AEs) is taken into consideration.

 

Conclusion:

·        A treatment duration of 72 weeks compared with 48 weeks of peginterferon alfa-2a (40KD) plus ribavirin did not impose a large additional adverse event burden on patients who were previous non-responders to peginterferon alfa-2b (12KD) plus RBV undergoing retreatment with peginterferon alfa-2a (40KD) plus ribavirin in REPEAT.

·        When the significantly higher SVR rate is considered, extended treatment has a favorable risk: benefit ratio.

·        These data demonstrate that a 72-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is the preferred treatment duration for non-responders to previous peginterferon alfa-2b (12KD)/RBV therapy.

 

 

72 weeks
(Arm A+C)
n=473

48 weeks
(Arm B+D)
n=469

On-treatment AEs*, n

4047

3814

Treatment years
AEs per treatment year
Cumulated treatment days with AEs (years)
Cumulated treatment days with serious AEs(years)

499
8.1
435
6.6

378
10.1
331
5.7

SVR, n (%)

74 (16)

38 (8)

Treatment years per SVR achieved
On-treatment AEs per
SVR achieved
On-treatment AE years per
SVR achieved
On-treatment serious AE years per
SVR achieved

6.7
55
5.9
0.09

10.0
100
8.7
0.15

*Multiple occurences of the same AE in one patients were counted only once, AE's with an onset up to 7 days post-treatment were counted for the number of on-treatment AEs.

 


HCV Drug Pipeline – Adjunct Therapy – eltrombopag

 

1874. Population PK/PD modeling of eltrombopag concentration-platelet response and dose simulations for patients with chronic hepatitis C virus (HCV)-infection. 

J. Zhang; D. Theodore; K. H. Moore; F. M. Campbell; D. Williams

 

Introduction:

Eltrombopag is a thrombopoietin receptor agonist being developed for the treatment of thrombocytopenia (low platelets).

 

Aim:

The main objectives of the analysis were to:

1.     construct a population PK/PD model to characterize the effect of eltrombopag on platelet counts in HCV patients with and without interferon (IFN; peginterferon alfa-2a and peginterferon alfa-2b) treatment;

2.     identify covariates that influence eltrombopag PK and PD; and,

3.     predict the proportion of HCV patients at various doses achieving target platelet responses in the presence of IFN.

 

Methods

PK/PD data from 3 studies were combined and included healthy subjects, subjects with mild to severe hepatic impairment, and compensated cirrhotic HCV patients. The structural PK model was a 2-compartment model with sequential zero-order and bolus input followed by first-order absorption. Influential covariates were subsequently identified and included in the model. The final model was evaluated using visual predictive check and bootstrapping.

 

The typical oral clearance (CL/F) and volume of distribution (Vc/F) of eltrombopag were 0.71 L/hr and 8.67 L, respectively, for healthy subjects. Age, aspartate aminotransferase (AST), and Child Pugh Score (CPS) significantly impacted eltrombopag PK. Overall, CL/F was 65% and 17% lower in HCV patients and subjects with hepatic impairment, respectively, when compared to healthy subjects. Concomitant IFN had no effect on eltrombopag PK. A population PD model was developed using the individual post-hoc PK parameters in HCV patients with and without IFN. The relationship between plasma eltrombopag concentration and platelet response was well captured by a catenary cell production and loss model, with an estimated maximum stimulation (Smax) of 6.4 fold increase in platelet production and 50% of maximum stimulation achieved at 17.2 µg/mL (SC50). The model also characterized the inhibitory effect of IFN on platelet counts using a linear function of IFN dose.

 

Results

Platelet response (>50, >75, >90, >200 Gi/L) at eltrombopag doses of 12.5, 25, 50, 75 and 100 mg with and without IFN were simulated for the HCV patient population using the final PK/PD model. Results showed that more than 75% of patients who receive a dose of 50 mg QD should achieve >75 Gi/L platelet count after 2 weeks of eltrombopag alone, of whom ≥85% would maintain platelet count >90 Gi/L following a further 2 weeks of combination therapy with IFN.

 

Conclusion

Information obtained from PK/PD simulations enabled selection of optimal dosing strategies which have now been implemented into Phase III studies for the treatment of thrombocytopenia in HCV patients to achieve adequate platelet counts in order to initiate and maintain IFN therapy.

 


HCV Drug Pipeline – Nitazoxanide

 

1881. Nitazoxanide (NTZ) is an inducer eIF2a and PKR phosphorylation.

M. Elazar; M. Liu; S. McKenna; P. Liu; E. A. Gehrig; A. Elfert; J. Puglisi; J. Rossignol; J. S. Glenn

 

Purpose:

Hepatitis C virus (HCV) is an important cause of liver disease world wide, for which current therapies are inadequate for many patients. Nitazoxanide (NTZ) has recently been shown to have an unanticipated activity against hepatitis C virus (HCV) replication in vitro. A pilot study in patients chronically-infected with HCV suggested that Nitazoxanide can increase the antiviral efficacy of interferon (IFN), prompting us to search for a molecular basis for this effect. We hypothesized that Nitazoxanide might potentiate known host antiviral response pathways that are induced by IFN.

 

Methods:

We used Huh7 cells harboring genotype 1 HCV subgenomic or full-length replicons, or Huh7.5 cells infected with the genotype 2a J6/JFH virus. Cells were treated with various combinations of Nitazoxanide, with and without interferon, and the levels of phosphorylated eIF2alpha and its dsRNA activated protein kinase (PKR) were determined by western blot analysis. In addition, the effect of NTZ in in vitro PKR and eIF2alpha phosphorylation assays was determined.

 

Results:

Nitazoxanide was found to increase the intracellular levels of phosphorylated eIF2alpha, a key mediator of host cell antiviral defenses. Furthermore IFN augmented the NTZ-induced elevation of phosphorylated eIF2alpha in cells co-treated with both drugs, providing an experimental correlation with the clinical observations. Both in cells and in the in vitro assays, Nitazoxanide also increased the phosphorylation of PKR, a key step in the activation of PKR’s kinase activity towards eIF2alpha.  Nitazoxanide-induced phosphorylation of PKR in vitro and in cells was more pronounced in the presence of double-stranded or replicating viral RNA, respectively. Experiments with specific inhibitors of PKR phosphorylation are in progress.

 

Conclusions:

Taken together, these results suggest that an important mechanism of action for Nitazoxanide involves modulation of a key innate antiviral pathway, and offer an attractive explanation for nitazoxanide’s clinical antiviral effect. Moreover, Nitazoxanide represents a new class of small molecules with potential for recapitulating some of the important antiviral effects of IFN.

 


HCV Drug Pipeline – General

 

1882. Safety and antiviral activity of BI201335, a new HCV NS3 protease inhibitor, in combination therapy with Peginterferon alfa 2a (P) and Ribavirin (R) for 28 days in P+R treatment-experienced patients with chronic hepatitis C genotype-1 infection. 

M. P. Manns; M. Bourliere; Y. Benhamou; M. Schuchmann; D. Haussinger; S. Pol; M. Bonacini; J. L. Calleja; G. Steinmann; D. B. Huang; J. Mikl; G. Kukolj; J. O. Stern

 

Background:

BI201335 is a HCV NS3 protease inhibitor (EC50 of 3-6 nM). A multiple rising dose study evaluated the safety and antiviral activity in pegylated interferon alfa 2a plus ribavirin (P+R) treatment-experienced patients (patients) with chronic hepatitis C genotype-1 infection for 28 days as combination therapy with pegylated interferon alfa 2a plus ribavirin.

 

Methods:

19 patients (France, Germany, Spain, USA) with a Metavir fibrosis score of 0-3, who experienced previous virologic failure with pegylated interferon alfa 2a plus ribavirin combination therapy, were assigned to receive BI201335 once-daily (qd) doses of 48 mg (n=6), 120 mg (n=7), or 240 mg (n=6) in combination with P (180ug/wk)+R (weight based) for 28 days.

 

All patients were monitored for safety and tolerability of study drugs. The primary endpoint was a ≥2 log10 reduction in HCV viral load (VL) from baseline at any time up to Day 28. Plasma HCV-RNA levels were measured using the Roche COBAS TaqMan assay (LLOQ 25 IU/mL).

 

Results:

19 patients were white, 11 were male, mean age was 48±9 years, mean body weight was 81±15 kg, and median (range) baseline VL was 6.9 (5.9-7.4) log10. There were no significant demographic differences between dose groups. BI201335 was well tolerated and no serious or severe adverse events (AEs) were observed among patients in this study. AEs were typical for pegylated interferon alfa 2a plus ribavirin therapy. 1 subject discontinued treatment due to an AE (anxiety). A rapid, dose-related decline of VL was observed in all patients. All patients treated with BI201335 plus pegylated interferon alfa 2a plus ribavirin achieved > 2 log10 VL decline with triple combination therapy. Median (range) maximal decline in VL during 28 day combination therapy for 48 mg, 120 mg, and 240 mg dose cohorts was 4.8 (3.4-5.9), 5.2 (3.9-6.0), and 5.3 (4.8-6.1) log10, respectively. Virologic rebound during treatment was observed during the first 28 days of BI201335 plus pegylated interferon alfa 2a plus ribavirin dosing in 2/6 patients in the 48 mg and in 1/7 patients in the 120 mg dose groups. In these patients, population sequencing of the NS3/4A protease at baseline and at viral rebound during treatment revealed selection of variants in the NS3 protease domain shown to confer in vitro resistance to BI 201335.

 

No rebound during treatment was seen in the 240 mg qd dose cohort: 5/6 patients had VL < 25 IU/mL at Day 28. The sixth pt had a 4.7 log decline in VL from baseline on Day 28 and VL was < 25 IU/ml at next visit, Day 42.

 

Conclusion:

BI201335 given once-daily in combination therapy with pegylated interferon alfa 2a plus ribavirin for 28 days was well tolerated, and induced a strong and rapid antiviral response. The results support further study of BI201335 as a potent protease inhibitor for pegylated interferon alfa 2a plus ribavirin treatment-experienced HCV patients.

 


HCV Drug Pipeline – ITMN-191 (R7227)

 

1885. Combination of the NS3/4A Protease Inhibitor ITMN-191 (R7227) with the Active Moiety of the NS5B Inhibitors R1626 or R7128 Enhances Replicon Clearance and Reduces the Emergence of Drug Resistant Variants. 

H. Tan; S. Rajyaguru; T. Wu; M. McCown; S. Ali; W. Jiang; M. J. Otto; P. A. Furman; I. Najera; K. Klumpp; J. Symons; N. Cammack; L. M. Blatt; S. Seiwert

 

Background:

ITMN-191 is an inhibitor of HCV NS3/4A protease activity, and R1626 and R7128 are nucleoside inhibitors of the polymerase activity of HCV NS5B. All three compounds promote multi-log10 reductions in circulating HCV RNA in chronic HCV patients when administered for short durations as monotherapy. Here, to support future clinical studies that would combine ITMN-191 with R1626 or R7128, we investigated the combined antiviral effect of these compounds.

 

Methods:

In the HCV clearance assay, cells harboring an HCV genotype 1b replicon were treated for 2 weeks with ITMN-191, the active moiety of R1626 (R1479), the active moiety of R7128 (PSI 6130), or a combination of inhibitors in the absence of G418 selection for replicon retention. Cells were counted and aliquots harvested for RT-PCR-based quantification of replicon RNA levels under G418 selection over 4 subsequent weeks. In the colony formation assay, cells were treated with either one or two compounds at 1X, 10X, or 15X their respective EC50. After 3 weeks in culture with G418, cells were fixed and stained with crystal violet or total cellular RNA extracted. For drug-drug interaction studies, HCV replicon cells were treated for 3 days with a pair of inhibitors in checkerboard dilution and percent reductions of reporter gene activity obtained.

 

Results:

In the HCV clearance assay, 18 nM ITMN-191 and low μM concentrations of the active moiety of R1626 and R7128 (18 μM & 27 μM, respectively) eliminated HCV replicon in the absence of G418 selective pressure for replicon retention. Addition of the lowest tested concentration of ITMN-191 (6 nM) to the lowest tested concentration of the active moiety of R1626 or R7128 (0.3 μM & 0.45 μM, respectively) resulted in replicon clearance, demonstrating significant combined antiviral effect. In the colony formation assay in the presence of G418 selective pressure for replicon retention, NS5B inhibitors at 10X or 15X EC50 supported replicon clearance and did not result in drug resistant colonies. Similar treatment with ITMN-191 selected resistant colonies, but these were suppressed by an NS5B inhibitor at 1X EC50. Drug-drug interaction studies over a 3 day incubation period demonstrated additive to slightly synergistic interactions between the two inhibitor classes.

 

Conclusions:

The combination of ITMN-191 with the active moeity of either R1626 or R7128 results in enhanced antiviral activity and suppression of ITMN-191 resistant variants. These findings suggest that the combination of ITMN-191 with R1626 or R7128 may confer significantly greater antiviral activity than has been observed with these agents in previous monotherapy trials.

 


HCV Drug Pipeline – Telaprevir

 

1887. Characterization of a new amino acid substitution (V36C) associated with telaprevir (VX-950) resistance in a patient treated with telaprevir, peginterferon alpha-2a and ribavirin. 

L. Barbotte; A. Ahmed-Belkacem; S. Chevaliez; A. Soulier; C. Hezode; J. Pawlotsky

 

Introduction:

Telaprevir (VX-950, Vertex Pharmaceuticals) is a novel, highly selective inhibitor of HCV NS3 protease, with potent antiviral activity in vitro and in vivo. Recent phase II trials have suggested that up to 65 to 68% of patients could achieve a sustained virologic response when telaprevir is used in combination with peginterferon alpha and ribavirin. Resistance to telaprevir is principally related to amino acid substitutions at four positions: V36A/M/L/G, T54A, R155K/T/M/I/G and A156T/V. We describe here a novel amino acid substitution conferring telaprevir resistance.

 

Methods:  

A patient with chronic HCV-1b hepatitis C has been treated with a combination of telaprevir, 750 mg q8h, peginterferon alpha-2a, 180 microg qw and ribavirin 1200 mg/d for 43 days before withdrawing consent. HCV RNA was below 10 IU/ml during the treatment period, and a virologic breakthrough occurred after treatment cessation. To characterize the dynamics of HCV viral populations, an extensive quasispecies analysis has been performed at several time points before, during and after therapy. The level of resistance conferred by the observed substitutions was tested in a cell-free FRET-based HCV NS3 protease assay and in a genotype 1b replicon model in Huh7 cells.

 

Results:  

A new amino acid substitution (valine to cysteine) was present at position 36, a known telaprevir resistance position, in 100% of quasispecies variants circulating 7 weeks after treatment cessation. It was associated with an L14F substitution, a position unlikely to modify telaprevir-protease interaction. We tested in vitro the ability of telaprevir to inhibit the NS3 protease function of 3 variants with amino acid substitutions at position 36 (V36M and V36L, known telaprevir resistance substitutions, and the newly identified V36C) relative to wild-type protease. The enzymatic inhibitory concentrations 50% (IC50s) were increased by 6-fold, 5-fold and 5-fold, respectively. V36C also conferred reduced susceptibility to telaprevir in the replicon system in Huh7 cells. Docking studies of V36 substitutions in the 3D models of NS3 protease are under way.

 

Conclusion:  

We have identified a new substitution at position 36 that confers resistance to telaprevir. The level of resistance is comparable to other substitutions at the same position. V36C can be selected in vivo by telaprevir in the presence of peginterferon alpha. The fact that the V36C substitution needs two nucleotide substitutions instead of one to occur in genotype 1b (and 1a) sequences could explain its lower prevalence than other substitutions at position V36.

 


HCV Drug Pipeline – General

 

1888. A Novel Sustained Release Interferon-Alpha-2b (IFN-Alpha-2bXL) With Optimized Pharmacokinetics/Pharmacodynamics Relationship vs. Pegylated Interferon-Alpha-2b (Peg-IFN-Alpha-2b): A Phase Ib Trial In HCV Patients. 

C. Trepo; M. Guest; J. Grassot; R. Meyrueix; R. Rouzier; C. Raffanel; H. Belhadj-Tahar; M. Maynard-Muet; P. Berthillon; F. Nicolas; Y. Donazzolo; R. Kravtzoff

 

Background and aims

To date improvement of interferons (IFNs) alpha therapy for hepatitis C (HCV) therapy relied on structural modifications such as pegylation or albumin fusion which improve half-life but decrease specific activity. Consequently, efficacy of PEG-IFNα-2b may relate to AUC, but is associated with dose-dependent adverse events, mainly dependent on Cmax. In contrast, Flamel Technologies has developed a novel formulation of IFN based on nano-coating by its Medusa® technology (IFNα-2b XL), aiming to a sustain release pharmacokinetic profile of fully active protein with consequently improved safety profile and efficacy. The present trial aimed to investigate the pharmacokinetics/pharmacodynamics relationship of IFNα-2b XL, and to confirm its safety, as compared with reference Peg-IFNα-2b.

 

Methods

A phase Ib, randomized, parallel groups study was conducted in HCV patients allocated to either IFNα-2b XL 18MIU (n=11), IFNα-2b XL 27MIU (n=12), or Peg-IFNα-2b 1.5 µg/Kg (n=14). The pharmacokinetics and pharmacodynamics following two sequential administrations, at one week interval, of each treatment were monitored during the two post-dosing periods, i.e. up to day 14.

 

Results

The sustained release was confirmed with a Tmax that occurred approximately at the same time in the three treatment groups (18 to 24 hours) and a long apparent terminal half-life (23 to 33 hours). There was a significant decrease in AUC and Cmax by 7 to 17 folds as compared with Peg-IFNα-2b.

 

Remarkably, both administrations of IFNα-2b XL led to a comparable increase of neopterin from 24 to 72 hours post dose up to 120 hours post dose, and a marked and prolonged increase of 2’,5’-OAS and β2-microglobulin from 72 hours post-dose.

 

Most importantly the antiviral activity of IFNα-2b XL 27MIU was similar to that of Peg-IFN following the first dosing in genotype 1 patients (n=9 in both groups), but resulted in a significantly greater antiviral activity following the second dosing (-0.61 vs. -0.21 log, p<0.05).

 

Finally IFNα-2b XL 27MIU was associated with a remarkably reduced mean number of treatment-related AEs/patient (IFNα-2b XL 27MIU 5.3 vs. Peg-IFNα-2b 7.6 AEs/patient), including less systemic treatment-related AEs (i.e. fever and WBC abnormalities) and a 53% decrease in injection site reactions. No serious AEs occurred in any group.

 

Conclusions

These results demonstrate that the antiviral activity of IFNα-2b XL is at least as good as that of Peg-IFNα-2b, while resulting in an improved safety profile. This superior efficacy/safety profile appears to be related to PK profile with strong reduction in Cmax and long release of fully active IFNα-2b.

 


HCV Drug Pipeline – General

 

1890. Cyclosporine in HCV-non responders: a cytoprotective effect without antireplicative action. A phase II study. 

P. Lebray; J. Moussalli; D. Thabut; V. Ratziu; T. Poynard; Y. Benhamou

 

Background:

Few studies suggested that cyclosporine during chronic hepatitis C treatment had a synergistic effect. In vitro, cyclosporine induces a reduction of viral replication by inhibition of cyclophilin A. However, in vivo studies have not been performed yet due to potential nephrotoxicity and immunosuppressive effect.

 

Aim:

To evaluate the impact of short-term low dose monotherapy of cyclosporine in patients with monoinfected chronic hepatitis C and non responders to peg interferon and ribavirin.

 

Patients and Method:

Patients who received a biotherapy with peg interferon + ribavirin and had a PCR HCV positive at 6 months of treatment were prospectively included after a wash-out period of one month. Exclusion criteria were: decompensated cirrhosis, carcinoma (hepatocellular or not), renal insufficiency, uncontrolled arterial hypertension or diabetes. Patients were treated with cyclosporine (Neoral®) at 0,25 mg/kg/bid for 2 weeks adjusted to obtain C0< 200µg/l. Clinical data, biological and virological blood tests were collected twice a week until week 3. Side effects were classified according to NCI Bethesda scale.

 

Results:

Nine patients were treated. At baseline, patients data were: male sex in 78%; mean age: 49,7 years ± 7; mean weight: 74 kg ± 14, median ALT 103 UI/l [38-203], median GGT 118 UI/l [40-507], normal bilirubinemia for all, Metavir score (according to fibrotest®) F01(15%), F23(70%), F4 (15%), genotype 1 in 85% and mean HCV viremia 7± 0,5 log10 UI/ml.

 

All patients completed the 2 weeks of treatment. One patient had a dose reduction at Day 10 for high C0. After 14 days of cyclosporine therapy patients had 32% (ranging from 3 to 48%), 13% and 11% of mean decrease in ALT, AST and GGT level respectively. One week after, ALT, AST and GGT increased to their baseline values. HCV viremiae were continuously stable during and after treatment for all patients.

 

Side effects were always transient with arterial hypertension de novo (n=1, grade 1) hyperbilirubinemia (n=2, grade 2), acute pancreatitis (n=2, grade 2 and 3), increase of creatininemia > 25% (n =1, grade 1) but no effect on WBC, platelets or glycaemia. Conclusion: Cyclosporine therapy may have a cytoprotective effect at low dose but no action against HCV replication. Its interest for maintenance therapy needs further studies with long term follow up.

 


HCV Drug Pipeline – General

 

1891. In Chronic Hepatitis C (HCV), Pretreatment with Thiazolidinediones (TZDs) or Metformin Decreases Insulin Resistance (IR) and HCV Viral Load and Increases Early Virologic Response (EVR). 

M. Adler; J. L. Matloff; A. S. Boxer; H. Han; M. Vachon; D. C. Carriero; D. T. Dieterich

 

Background:

Chronic HCV is associated with increased incidence of insulin resistance (IR), which leads to a lower rate of sustained virologic response (SVR) following treatment with peginterferon plus ribavirin (IFN + RBV). Romero-Gomez et al. reported an SVR rate of 32.8% in genotype 1-infected patients with IR (HOMA-IR > 2) compared to 60.5% in those without IR. In addition, IR is associated with increased liver fibrosis and is characterized by a higher viral load, two other independent risk factors for decreased response to treatment. A recent study showed 0/5 EVR in patients with IR who were given a TZD at initiation of IFN + RBV. It is unknown if therapeutic intervention to improve insulin sensitivity prior to anti-viral treatment increases response to HCV treatment.

 

Aim:

To evaluate the effect of treatment with TZDs or metformin on IR and viral load prior to IFN + RBV and the impact on EVR.

 

Methods:

IRB-approved, we retrospectively reviewed charts of patients with chronic HCV from a liver clinic in our center. We included patients with IR treated with either metformin or a TZD for at least 3 months prior to initiating IFN+RBV. We compared HOMA-IR, HCV viral load, liver enzymes and BMI at baseline, after treatment with an insulin sensitizer (IS), and at week 12 of HCV treatment.

 

Results:

17 patients met inclusion criteria. 10 were co-infected with HIV. The average age was 52.2 years, and 82% of patients were genotype 1. 11 patients were treatment-naďve to IFN+RBV. The mean stage of fibrosis was 2.7 on Metavir score in 12 patients. 11 patients received a TZD and 6 received metformin. The mean HOMA-IR decreased from 7.99 to 6.06 after treatment with an IS to 4.60 at 12 weeks of IFN + RBV. There was a significant mean decrease of 0.52 log in HCV viral load on each patient after treatment with an IS (p<0.01). An EVR was achieved in 12 patients (71%). The mean ALT value decreased from 86.2 at baseline to 72.5 (p=0.02) after treatment with an IS to 34.1 IU/L (p=0.01) after 12 weeks of IFN + RBV. BMI significantly decreased from 27.9 to 26.8 kg/m2 (p=0.02) following treatment with an IS.

 

Conclusion:

The use of a TZD or metformin improved insulin sensitivity prior to treatment with IFN + RBV. The baseline viral load, a risk factor for decreased response to treatment and until now referred to as an unmodifiable factor, was also significantly lowered. This intervention allowed a 71% rate of EVR in a population of mono and co-infected patients, the majority being genotype 1. This small pilot study suggests that targeting insulin resistance prior to treatment may enhance the chance of response to traditional treatment for chronic HCV.


HCV Drug Pipeline – General

 

1892. Niacin but not simvastatin is associated with reduced Hepatitis C RNA titers: A Cross-Sectional Analysis. 

K. A. Forde; C. Law; R. M. O'Flynn; D. E. Kaplan

 

Background:

In vitro studies suggest HCV replication depends on prenylation and that viral excretion depends on VLDL. Medications that are commonly used for dyslipidemia such as HMG-coA reductase inhibitors (statins) and other hypolipidemic agents such as niacin could exhibit antiviral effects in vivo by interfering with lipid metabolism.

 

Aim:

To identify whether an effect of various hypolipidemic agents on HCV RNA replication could be detected during routine clinical usage prior to prospective pilot investigation.

 

Methods:

We performed a retrospective analysis of HCV-infected patients who had at least one one quantitative HCV RNA PCR (Taqman®) from 3/04-9/06 at the Philadelphia VAMC. Cases who had concomitant exposure to hypolipidemic agents were identified via pharmacy records. Exclusion criteria included: HIV or HBV coinfection, acute HCV, and CKD. HCV RNA titers obtained during interferon-alpha therapy and those with fewer than 30 days of medication exposure were censored. Dyslipidemic patients (Total cholesterol > 240 mg/dl, LDL > 130mg/dl or TGL > 250mg/dl) not exposed to hypolipidemic medications were also identified. Two hypolipidemic-unexposed controls were selected randomly for each case.

 

Results:

50 patients were actively treated with an HMG-coA reductase inhibitor (42/50 simvastatin) and 12 with niacin for at least 30 days prior to HCV viral load determination. 32 hypercholesterolemic and 13 hypertriglyceridemic patients not on hypolipidemic medications with HCV RNA quantification were identified as dyslipidemic controls. Median HCV RNA titers in statin-exposed patients were 4,550,000 IU/ml vs. 4,235,000 IU/ml in hypercholesterolemic controls vs. 2,755,000 in nondyslipidemic controls (p=0.25). No differences in HCV RNA titers were observed at any dose level of simvastatin. After excluding patients on niacin and gemfibrozil, the presence of triglyceride levels greater than 250mg/dl was associated with higher median HCV RNA (6,760,000 vs. 3,130,000 IU/ml p=0.0422) and triglycerides were weakly but significantly correlated with viral titer (R2=0.023, p=0.034). Niacin-exposure was associated with lower median HCV RNA titers (3,320,000 vs. 970,000 IU/ml p=0.032). Compared to 13 patients with untreated hypertriglyceridemia (triglyceride > 250 mg/dl), niacin-exposure was associated with a 1.16-log reduction in median HCV RNA titer (p=0.009).

 

Conclusions:

There is no apparent effect of simvastatin at typical doses on HCV viral replication in this single center retrospective analysis. The possible antiviral properties of triglyceride-lowering agents such as niacin merit further prospective investigation.

 


HCV Drug Pipeline - General

 

1895. Pharmacokinetics of once-daily regimens of the novel HCV NS3/4A-protease inhibitor TMC435350, with and without pegIFN and ribavirin, in HCV-infected individuals. 

G. A. van 't Klooster; I. Vanwelkenhuysen; R. Verloes; K. Marien; P. Van Remoortere; K. Simmen

 

Introduction:

TMC435350 is a novel HCV NS3/4A-protease inhibitor, with an EC50 of 6 ng/ml (8 nM; replicon), with a good oral bioavailability and high liver to plasma ratio. The pharmacokinetics (PK) of TMC435350 supports once-daily (QD) dose regimens for efficacy evaluation at doses as low as 25mg QD (1). Mean plasma concentrations of TMC435350 were shown to increase in a dose-proportional fashion for doses up to 100mg, and more than dose-proportional for higher doses, both for single and repeated dosing (2). TMC435350 is subject to prolonged absorption with a Tmax of 6 hours. The time to steady state is determined by the characteristics and PK of the absorption rather than the elimination (1).

 

Results:

We currently present the first steady-state PK data of TMC435350, both in healthy volunteers (200 mg QD) and in HCV-infected individuals (25 and 75 mg QD, preliminary analysis in an ongoing dose ranging trial).

 

In healthy volunteers receiving TMC435350 as capsules (200 mg QD), steady state pharmacokinetics were attained within 7 days, with the following mean values: Cmin: 1030 ng/ml, Cmax: 4610 ng/ml, AUC24h: 60300 ng.h/ml and t˝: 11.4 h.

 

A dose escalating Phase IIa trial in treatment-naďve genotype 1 HCV-infected individuals is ongoing in Europe. Within each TMC435350 dose group, half of the study participants receive once-daily TMC435350 as monotherapy for 7 days, followed by 3 weeks of combination therapy with pegylated interferon-a-2a (peg-IFN) and ribavirin (RBV). The other half receive peg-IFN and RBV during 4 weeks treatment with TMC435350. All patients continue to receive peg-IFN and RBV for a total of at least 24 weeks.

 

In the fully-recruited dose groups, patients received once-daily regimens of 25 mg, 75 mg or placebo as capsules. No TMC435350-related serious adverse events or study discontinuations were reported. For both regimens, steady state conditions were attained within 3 days, with plasma concentrations essentially proportional to the dose. Steady-state Cmin values ranged from 37 to 156 ng/ml for the 25 mg QD regimen, and from 70 to 510 ng/ml for the 75 mg QD regimen, 6 to 85-fold in excess of the EC50 based on plasma concentrations, and over 200-fold when taking into account the anticipated liver distribution, extrapolated from animal studies.

 

No differences were observed in TMC435350 plasma levels with or without peg-IFN/RBV.

 

Conclusion

In conclusion, once daily regimens for 25 mg and 75 mg TMC435350 yield plasma concentrations well in excess of its EC50, and pharmacokinetic steady-state is readily attained.

(1) G. van ‘t Klooster et al., EASL, Milan, April 2008

(2) R. Verloes et al., AASLD, Boston, November 2007

 


HCV Drug Pipeline – General

 

1897. Genotypic and phenotypic analysis of Hepatitis C Virus NS5B polymerase variants to BILB 1941 inhibition. 

M. Marquis; K. Deterding; A. Erhardt; Y. Benhamou; C. Moelleken; X. Forns; S. Pol; J. Calleja; S. Ross; H. Spangenberg; C. Toro; M. Fuchs; J. Enríquez; J. Wiegand; P. Beaulieu; G. Nehmiz; J. Steffgen; J. O. Stern; G. Kukolj

 

Background:

BILB 1941 is a specific non-nucleoside inhibitor of the HCV polymerase with an EC50 of 84 and 153 nM against subtype 1b and 1a, respectively, HCV subgenomic replicons. A previously reported multiple rising dose, 5-day monotherapy study that evaluated safety and antiviral activity in patients with chronic HCV genotype-1, revealed a significant anti-viral response which was limited by GI intolerance to the investigational drug. As part of the BILB 1941 anti-viral response analysis, we report here the genotypic and phenotypic characterization of the viral NS5B polymerase segments from these clinical samples.

 

Methods:

The complete NS5B sequence from all 96 patient baseline samples was amplified by RT-PCR. The NS5B sequence was also determined at day 5 of treatment for all treatment responders. Furthermore, NS5B segments amplified from baseline samples were transferred, without cloning, to a HCV subtype-1b based luciferase reporter replicon for phenotypic analysis of the susceptibility to inhibition. In vitro transcribed RNA from these NS5B chimeric replicons were electroporated into Huh-7 cells and the susceptibility to BILB 1941, and control inhibitors, was determined by quantification of luciferase activity across a range of inhibitor concentrations.

 

Results:

The NS5B sequence analysis at day 5 of BILB 1941 treatment failed to detect the selection of any sequence changes that were consistent with known resistant mutants. However, baseline NS5B variants were found that showed either enhanced or reduced susceptibility to BILB 1941 inhibition (the changes in EC50 ranged from 0.14-to-11-fold relative to subtype reference). The two NS5Bs with the largest baseline shift in BILB1941 potency (8- and 11-fold higher EC50, respectively) were amplified from treatment non-responders and encoded amino acid substitutions, relative to their 1a and 1b reference sequence, at 18 and 42 different positions, respectively; among these, we identified pre-existing NS5B substitution of amino acids (V494I or I424V, V494A, P496A) in thumb pocket 1. P496A is a known thumb pocket 1 mutant that was previously shown to shift the replicon potency of a related inhibitor by 10-fold.

 

Conclusion:

We have developed a replicon-based phenotypic susceptibility assay for clinically-derived NS5B segments that has successfully characterized all targeted samples. BILB 1941 has broad spectrum antiviral activity against genotype 1a and 1b isolates with susceptibility among the majority (>90%) within 3-fold of reference subtype values. Rare subtype 1a and 1b variants were detected with pre-existing amino acid substitutions that confer a modest shift in the potency of BILB 1941.

 


HCV Drug Pipeline – General

 

1898. Safety, Tolerability and Pharmacokinetics of the HCV Polymerase Inhibitor PF-00868554 Following Multiple Dose Administration in Healthy Volunteers. 

J. L. Hammond; V. S. Purohit; J. Fang; M. F. DeBruin

 

Background:

PF-00868554 is a novel, potent, non-nucleoside inhibitor of the HCV polymerase.

 

Objective:

The objectives of this study were to assess the safety, tolerability and pharmacokinetics (PK) of multiple oral doses of PF-00868554 in HCV negative, healthy volunteers.

 

Methods:

This was a randomized, placebo-controlled, sequential dose escalation study. Thirty-three subjects were randomized to receive placebo or PF-00868554 50, 100 or 300 mg BID or 300 mg TID for 14 days. All doses of study medication were administered as an oral solution. Safety and tolerability were assessed through physical examinations, electrocardiography (ECG), clinical laboratory tests and adverse event (AE) monitoring. Concentrations of PF-00868554 in plasma were determined using validated analytical methods.

 

Results:

There were no deaths, serious adverse events, or withdrawals due to AEs reported in this study. The safety profile of PF-00868554 up to 300 mg TID was similar to that observed for placebo. Most AEs were mild in severity and did not require treatment. The most frequently reported all-causality AEs were flatulence and headache. No subject discontinued the study due to an abnormal safety laboratory finding and none of the laboratory abnormalities observed in the study were clinically significant. There were no clinically significant changes in vital signs and no significant effects on QTcF or other ECG parameters were observed. PF-00868554 exposures (AUC and Cmax) increased with higher doses in a greater than dose proportional manner. Absorption of PF-00868554 was rapid with maximum plasma concentrations generally achieved by approximately 1 hour post-dose. Following attainment of Cmax, plasma concentrations exhibited a bi-exponential decline over time with a mean apparent elimination half-life ranging from 11.1 to 11.7 hours on Day 14. Steady state plasma concentrations of PF-00868554 were achieved by approximately Day 6. Doses of PF-00868554 ≥100 mg BID achieved minimum steady state plasma concentrations that are several fold greater than the median protein binding adjusted in vitro EC50 for PF-00868554 against genotype 1 strains of HCV.

 

Conclusions:

Multiple oral doses of PF-00868554 up to 300 mg TID were safe and well tolerated up to 14 days. The safety profile of PF-00868554 was similar to that observed for placebo in this study. Doses of PF-00868554 ≥100 mg BID achieve plasma concentrations that are expected to inhibit viral replication in vivo. A multiple dose study of PF-00868554 in HCV-infected subjects is currently ongoing.

 


HCV Drug Pipeline – R7128

 

1899. Potent Antiviral Response To The HCV Nucleoside Polymerase Inhibitor R7128 For 28 Days With Peg-Ifn And Ribavirin: Subanalysis by Race/Ethnicity, Weight and HCV Genotype.  

M. Rodriguez-Torres; J. Lalezari; E. J. Gane; E. DeJesus; D. R. Nelson; G. T. Everson; I. M. Jacobson; K. Reddy; J. G. McHutchison; A. Beard; S. Walker; W. Symonds; M. M. Berrey

 

Background:

R7128 is a potent nucleoside analog inhibitor of HCV polymerase. When administered for 28 days in combination with pegylated interferon and ribavirin, R7128 1500mg twice a day (BID) resulted in an 85% RVR.

 

Methods:

The current trial is designed to evaluate R7128 with 180µg peginterferon alfa-2a (PEG-IFN) and 1000-1200mg ribavirin (RBV) for 28 days in treatment-naďve, HCV+ G1 patients.

·        25 patients (20 active /5 placebo) in Cohort 1 received R7128 500mg BID/placebo with PEG-IFN+RBV;

·        25 patients (20 active /5 placebo) in Cohort 2 received R7128 1500mg BID/placebo with PEG-IFN+RBV.

 

Using an analysis of variance method, a model was fitted to look at reductions in viral load at day 29. Baseline HCV RNA, race/ethnicity, HCV genotype, weight, BMI and gender were evaluated along with randomized treatment.

 

Results:

50 subjects were randomized into the first 2 cohorts: 48% Caucasian, 24% Latino, 16% African American (AA) and 8% Other. Fifty-four percent of Caucasian subjects were >85 kg (15% BMI>30), compared to 33% Latinos (42%), 38% AA (25%) and 75% Other (25%). Least-square mean Week 4 HCV RNA change from baseline versus race/ethnicity and adjusted for baseline are displayed in the table below.

 

In patients randomized to receive standard of care (SOC), 1 (Caucasian) patient in 10 (10%) achieved RVR.

 

In Cohort 1 (R7128 500mg BID) RVR rates were 45% for the Caucasian subjects, 25% for Latinos, 0% (0 of 3) for AA, and 0% Other.

 

In Cohort 2 (R7128 1500mg BID) RVR rates were 90% for the Caucasian subjects, 86% for Latinos, 50% (1 of 2) for AA, and 100% (1 of 1) Other.

 

Two subjects were omitted from this analysis: 1 discontinued therapy on Day 24, and 1 with poor venous access resulting in no Week 4 data. HCV genotype, Weight, BMI and gender were not significant predictors of antiviral response. No serious adverse events were reported, and no differences in AEs were noted by race/ethnicity.

 

Conclusions:

R7128 administered in combination with PEG-IFN/RBV for 28 days demonstrated clinically significant antiviral potency regardless of race/ethnicity, with a numerical improvement in RVR rates in Latino patients who received R7128 1500mg BID. Further studies are planned to fully characterize the incremental benefit of R7128 over SOC with longer durations of treatment in in these sub-populations.

 

Least-square Mean Week 4 HCV RNA Change from Baseline Adjusted for Baseline HCV RNA by Race and Ethnicity

 

African-American

Caucasian

Latino

Other

Cohort

LSmean (n)

LSmean (n)

LSmean (n)

LSmean (n)

SOC

+0.30 (2)

-3.53 (5)

-3.38 (1)

-3.04 (2)

500mg BID

-3.08 (3)

-4.25 (11)

-3.70 (4)

-3.70 (1)

1500mg BID

-4.66 (2)

-5.27 (9)

-5.12 (7)

-5.27 (1)

 


HCV Drug Pipeline – General

 

1900. Effects of ACE-Inhibitors on Liver Fibrosis in HIV and Hepatitis C (HCV) Co-Infection. 

L. Reese; D. Tider; A. Stivala; D. A. Fishbein

 

Background: 

Liver fibrosis is accelerated in patients with HIV and hepatitis C virus (HCV) co-infection, mediated by the pro-fibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is) attenuate liver fibrosis in co-infection.

 

Methods:

A retrospective review of 199 co-infected subjects was conducted from 7/04-7/07 to analyze the association between ACE-Is and liver fibrosis. Previously validated noninvasive indices of liver fibrosis (APRI, FIB-4, and Forns) were used as surrogate markers for disease severity. These scores and ACE-I use were compared using chi-square and non-parametric tests of association. ACE-I use as an independent predictor of these indices was adjusted by demographics, alcohol use, body mass index, CD4, and HIV and HCV viral loads (VL) using multivariate logistic and linear regression models.

 

Results:  

Of 199 subjects, 131 (66%) were men, with a mean age of 51 ± 8 years, 74 (37%) black, 107 (54%) Hispanic,18 (9%) white. Median CD4 (cells/ml), HIV and HCV log10 viral loads were 375 (11-2193), 3.7 (1.8-5.9), and 6.6 (4.1-7.6). Sixty-one subjects (31%) were cirrhotic by clinical criteria. Forty subjects (20%) had taken ACE-Is for one year and 28 (14%) for three years. There were significant associations between the APRI (p < .001, PPV 72%, NPV 81%), FIB-4 (p < .001, PPV 64%, NPV 86%), and Forns (p < .001, PPV 62%, NPV 78%) scores and liver cirrhosis by clinical criteria. Subjects taking ACE-Is for three years were no different than those not taking ACE-Is on the APRI and FIB-4 indices (p = 0.49, p = 0.25 respectively); however, subjects on ACE-Is had higher Forns scores, indicative of more progressive cirrhosis, compared to those not on ACE-Is (p = 0.001). Independent predictors of a Forns score > 6.9, indicating significant fibrosis, were ACE-I use for three years (ORadj 8.9, CI95% 2.4-33.1), HCV log10 VL (ORadj 1.4, CI 1.0-2.0), HIV log10 VL (ORadj 0.7, CI 0.4-1.0), and black race (ORadj 0.3, CI 0.1-0.9).

 

Conclusions:  

There was not a protective association between ACE-Is and liver fibrosis in co-infection as hypothesized. Notably, noninvasive markers of fibrosis are useful for staging liver disease in this population.

 

Table 2: Comparison of mean ranks of fibrosis indices across ACE-I/ARB use over one to three years

 

No ACE-I/ARB

ACE-I/ARB for 1 year

ACE-I/ARB for 3 years

APRI (p-value)*

98.4

102.6 (0.71)

106.5 (0.49)

FIB-4 (p-value)*

97.6

103.9 (0.59)

111.1 (0.25)

FORNS (p-value)*

41.6

51.3 (0.23)

65.2 (0.001) **

* p value as compared to the control group (No ACE-I/ARB) ** statistically significant

 


HCV Drug Pipeline – General

 

1910. Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009, a Hepatitis C Virus Non-structural 3/4a Protease Inhibitor, to Healthy Male Subjects. 

D. Wright; J. L. Miller; I. Verlinden; C. Cilissen; J. Valentine; P. Sun; M. De Smet; J. de Hoon; M. Depré; L. Cavens; J. Chodakewitz; J. A. Wagner

 

Purpose:

MK-7009 is a rapidly reversible non-covalent competitive inhibitor of the non-structural 3/4A protease of the hepatitis C virus, which exhibits good inhibitory potency against genotypes 1 and 2 (replicon EC50 values = 17 and 7 nM for genotypes 1b and 2a, in the presence of 50% human serum and 10% fetal calf serum, respectively). Initial studies evaluated the safety, tolerability and pharmacokinetics following single-dose (SD) and multiple-dose (MD) administration of MK-7009 to healthy male subjects.

 

Methods:

Single dose (SD): 6 healthy males received 10 to 825 mg single doses of MK-7009 or placebo in the fasted state, with 80 mg single doses of MK-7009 or placebo also evaluated in the fed state, in an alternating panel, multiple period, dose escalation study. Higher doses of 1000 and 1300 mg single doses of MK-7009 or placebo were evaluated in the fasted state in a separate group of 16 healthy males;

 

Multiple dose (MD): 40 healthy males received 100 to 800 mg multiple doses of MK-7009 or placebo for 14 days (once daily doses on days 1 and 14, twice daily doses on days 2 - 13) in a serial-panel study. Clinical safety evaluations were performed throughout each study. Plasma and urine samples for MK-7009 pharmacokinetic data were collected.

 

Results:

There were no serious adverse experiences (AEs) reported, nor were there any discontinuations due to AEs. Additionally, there were no dose-dependent patterns with respect to the frequency or the intensity of the AEs observed after SD and MD administration of MK-7009.

 

SD: Following oral administration, AUC0- [Antibiotics Area under the concentration time-curves from time zero to infinity; which corresponds to a calculation of mean concentration levels of a therapeutic agent in the body – ed.] and Cmax values increased greater than dose proportionally. The apparent terminal half-life averaged ~ 4-5 hours. SD administration of 80 mg of MK-7009 with a high-fat meal did not have a meaningful effect on the plasma pharmacokinetics of MK-7009. Data suggest that renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.

 

MD: Accumulation occurred over the 14-day period in all subjects, as evidenced by geometric mean ratios (Day 14 / Day 1) for AUC0-12 hr (1.5-1.8), Cmax (1.4-1.9) and C12 hr (1.2-1.9). The apparent terminal half-lives stayed constant (~3.8-5.1 hours), regardless of dose, and were consistent with previously identified values collected after SD administration.

 

Conclusions:

MK-7009 is generally safe and well-tolerated, and exhibits plasma pharmacokinetics which permit twice daily dosing. This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.