Tuesday
Posters
Posters
HCV Drug Pipeline - Telaprevir
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 (
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].
·
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 |
|||
|
|
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 –
1847.
Treatment of Chronic Hepatitis C Virus (HCV) Genotype 1 Patients with the
NS3/4A Protease Inhibitor
N. Forestier; D. G. Larrey;
D. Guyader; P. Marcellin; R. Rouzier; A. A. Patat; W. Z. Bradford; S. Porter;
S. Zeuzem
Background:
Methods:
In a double-blind, randomized, placebo-controlled study, 4
cohorts of treatment-naïve HCV genotype 1 patients and one cohort of
non-responders (NR) were randomized to receive
Results:
Fifty patients were randomized and all completed the study.
Conclusion:
Change from baseline in Log10 (IU/mL) HCV RNA
|
Cohort |
Dose |
N |
Median Change |
|
P (naïve) |
Placebo |
8 |
0.0 |
|
P (NR) |
Placebo |
2 |
0.0 |
|
1 (naïve) |
100 mg q12h |
8 |
-0.7 |
|
2 (naïve) |
100 mg q8h |
8 |
-1.7 |
|
3 (naïve) |
200 mg q12h |
5 |
-3.1 |
|
4 (naïve) |
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 (
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 (
Methods.
44 treatment-naïve patients with chronic hepatitis C were
enrolled at the
Results
Baseline HCV RNA, Body Mass Index (
·
40
patients were infected with HCV genotype 4,
·
3
with genotype 1, and
·
1
with genotype 2.
RVR, cEVR,
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,
Virologic Response Rates by Treatment Group
|
|
No. |
RVR |
cEVR |
|
|
|
4 wk lead-in, PegIFN+ |
44 |
26 (59%) |
36 (82%) |
38 (86%) |
35 (80%) |
|
12 wk lead-in, PegIFN+ |
28 |
15 (54%) |
19 (68%) |
20 (71%) |
17 (61%) |
|
12 wk lead-in, PegIFN+ |
28 |
18 (64%) |
24 (86%) |
23 (82%) |
22 (79%) |
|
PegIFN+ |
40 |
15 (38%) |
28 (70%) |
30 (75%) |
20 (50%) |
HCV Drug Pipeline – General
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-naïve HCV patients.
HCV Drug Pipeline – Telaprevir
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
(
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;
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
|
Prior PR responses in PROVE studies |
HCV RNA |
HCV RNA <10 IU/mL on T12/PR24 |
||
|
Wk 4 |
Wk 8 |
Wk 12 |
||
|
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
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
|
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
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-
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
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
Aim:
Demonstrate that a correlation exists between response and
anemia with equivalent TBV exposure in ViSER1 and the phase 2b trial for naïve
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
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
Table 1
|
ViSER1(N) |
Anemia1 |
RVR %2 |
cEVR %3 |
pEVR %4 |
|
|
RR % |
|
TBV 20-25mg |
9.4 |
13.2 |
47.2 |
22.6 |
56.6 |
47.2 |
16.6 |
|
|
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 |
9.0 |
16.4 |
41.8 |
22.4 |
|
|
|
|
TBV |
7.1 |
14.3 |
41.4 |
15.7 |
|
|
|
|
|
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
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
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 (
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 (
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
No (serious) adverse events related to escitalopram were
observed. Compliance with
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
Number of events of the primary and secondary outcome measures in the esitalopram arm and placebo arm
|
Outcome measures |
Escitalopram: |
Placebo: |
p-value |
|
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
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 (
Methods:
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
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
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).
Results:
The overall
In total, 43% (46/107) had a HCV RNA <15 IU/mL at week 12,
of whom 93% (43/46) achieved an
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
HCV Drug Pipeline –
1861.
Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships for
C. Rubino; W. Z.
Bradford; A. Forrest; S. Porter; L. M. Blatt; S. Seiwert; S. Zeuzem
Introduction:
Methods:
Four cohorts of 10 naïve patients were randomized (8:2) to
receive oral
Results:
Conclusion:
Observed Data and Fitted PK-PD
relationship for
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
The percentage of patients with an ISHAK modified
In Latinos and non-Latinos, baseline ISHAK modified
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 |
Non-Latino |
||
|
Virologic status |
Improved % |
Worsened % |
Improved % |
Worsened % |
|
Overall |
25 |
22 |
42 |
18 |
|
|
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
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 (
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
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
Conclusion:
Intravenous
HCV Treatment – Pegasys
1864.
Pharmacokinetics (PK) of ribavirin (
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
Methods:
Patients with
Patients received peginterferon alfa-2a 180µg/week (Groups A,
B, D) or 135µg/week (Group C) plus
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
Conclusion:
Cl/F of
|
Group (impairment) |
A (Moderate) |
B (Severe) |
C (ESRD) |
D (None) |
|
Median |
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
S. J. Mills; R. J.
Naus; K. Barstow; S. Harrison
Background:
Insulin resistance (IR) is associated with
Methods:
Thirty-four IR, GT 1,
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 (
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
HCV Drug Pipeline –
1871. A Phase
1 Study of the Safety, Tolerability, and Pharmacokinetics (PK) of Single
Ascending Oral Doses of the NS3/4A Protease Inhibitor
W. Z. Bradford; C.
Rubino; S. Porter; A. Forrest; L. M. Blatt; A. A. Patat
Background:
Aim:
The aim of the present study was to evaluate the safety,
tolerability, and PK of single ascending doses of
Methods:
In a double-blind, placebo-controlled study, healthy adult
subjects were randomized to receive a single oral dose of
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
Conclusion:
Mean (±SD) for selected ITMN -191
PK
|
Single Dose(mg) |
N |
Cmax (ng/mL) |
AUC0-∞ |
|
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. Brandão-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 (
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
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
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
·
When
the significantly higher
·
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)/
|
|
72 weeks |
48 weeks |
|
On-treatment AEs*, n |
4047 |
3814 |
|
Treatment years |
499 |
378 |
|
|
74 (16) |
38 (8) |
|
Treatment years per |
6.7 |
10.0 |
*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
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 (
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
HCV Drug Pipeline – Nitazoxanide
1881.
Nitazoxanide (
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 (
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
Results:
Nitazoxanide was found to increase the intracellular levels
of phosphorylated eIF2alpha, a key mediator of host cell antiviral defenses.
Furthermore IFN augmented the
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 –
1885. Combination of the NS3/4A
Protease Inhibitor
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:
Methods:
In the HCV clearance assay, cells harboring an HCV genotype
1b replicon were treated for 2 weeks with
Results:
In the HCV clearance assay, 18 nM
Conclusions:
The combination of
HCV Drug Pipeline – Telaprevir
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
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
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
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
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 (
Aim:
To evaluate the effect of treatment
with TZDs or metformin on IR and viral load prior to IFN +
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+
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-naïve to IFN+
Conclusion:
The use of a TZD or metformin improved insulin sensitivity
prior to treatment with IFN +
HCV Drug Pipeline – General
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
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
Results:
50 patients were actively treated with an
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
G. A. van 't Klooster;
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 t½: 11.4 h.
A dose escalating Phase IIa trial in treatment-naïve genotype
1 HCV-infected individuals is ongoing in
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/
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,
HCV Drug Pipeline – General
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-
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
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
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
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
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 (
Methods:
The current trial is designed to evaluate R7128 with 180µg
peginterferon alfa-2a (
·
25
patients (20 active /5 placebo) in Cohort 1 received R7128 500mg
·
25
patients (20 active /5 placebo) in Cohort 2 received
R7128 1500mg
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,
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%
In patients randomized to receive standard of care (
In Cohort 1 (R7128 500mg
In Cohort 2 (R7128 1500mg
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,
Conclusions:
R7128 administered in combination with
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) |
|
|
+0.30 (2) |
-3.53 (5) |
-3.38 (1) |
-3.04 (2) |
|
500mg |
-3.08 (3) |
-4.25 (11) |
-3.70 (4) |
-3.70 (1) |
|
1500mg |
-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
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.