October 2012 - A special report provided by EASL of the EASL-AASLD Conference - Therapy of Hepatitis C: Clinical Application and Drug Development highlights new hepatitis C drugs in development and more
Download PDF
47th European Association for the Study of the Liver EASL - 2012
The promise of all oral hepatitis C drug regimens were the highlight of the liver conference this year. For the hepatitis C patient the drug developments in Interferon-free regimes will become the long awaited revolution in HCV treatment.
The current standard of care by genotype is listed below:
• Genotype 1: a combination of pegylated interferon, ribavirin and an HCV protease
inhibitor (boceprevir or telaprevir). The standard duration of treatment is a total of 24,
36 or 48 weeks.
o Pegylated interferon is a subcutaneousinjection—once weekly.
o Ribavirin is a pill. The dose is based on body weight (1,000/1,2000mg) and divided
into two equal doses twice a day.
HCV protease inhibitor (boceprevir or telaprevir) is taken every 7 to 9 hours with
food – boceprevir can be taken with a snack or meal; telaprevir is taken with food that is
not low-fat.
• Genotypes 2 and 3: a combination of pegylated interferon and ribavirin taken for 24 weeks.
o Pegylated interferon is a subcutaneous injection—once weekly.
o Ribavirin is a pill. The dose is given 800mg daily—dose is divided into two equal doses.
Ribavirin is taken with food.
Source HCV Advocate
New Standard Therapy In Genotype 1 Patients
Enter the two new FDA approved drugs Telaprevir/INCIVEK and Boceprevir/Vicrelis, these first-generation protease inhibitors have shortened treatment duration and increased the cure rate or SVR in the most difficult to treat genotype 1 patients.
The comparison between standard therapy and the two drugs in genotype 1 patients are as follows
Telaprevir
Pegylated interferon + ribavirin alone = 44% SVR
With the addition of telaprevir = 69-75% SVR
Boceprevir
Pegylated interferon + ribavirin alone = 38% SVR
With the addition of boceprevir = 63-66% SVR
Both drugs are used in combination with peg-IFN and ribavirin which is a problem for patients with pre-existing conditions who aren’t eligible for treatment with interferon. Unfortunately the drugs are not pan-genotypic, and in genotype 1 patients not everyone clears the virus. The need for all oral,effective and better tolerated agents regardless of genotype, genetic factors, or disease stage are desperately needed. We wait.
As once a hepatitis C patient myself, who underwent standard therapy, which included ribavirin and three injections a week of Intron A, at the highest possible dose, (I was in a trial) for 48 weeks, (genotype 2), like I said - I was in a trial, reaching SVR, which I did, was nothing less then a nightmare.
Near the end of therapy my mind was completely gone, and I think my kids took full advantage of my pain and suffering, although I could never prove it. A decade later several anecdotal stories are still shared by my children around the dinner table during Christmas or Thanksgiving.
One favorite memory, for them, not me, was during Christmas when each child received numerous gift cards for things like gas, car washes, car detailing-waxing, I stayed far too long at the corner "Wash-O-Matic", video games, restaurants, clothes, books and finally a years worth of lawn care. All because their interferon crazy mother was incapable of deciding on a purchase. The downside? My ten year old couldn't drive. The upside? I didn't cut the lawn for a year.
In the future hepatitis C patients will be spared the debilitating side effects of interferon. The dream begins. Fast forward to today with online analysts predicating interferon-free regimens reaching patients by 2013 - 2015.
The EASL brought surprising results from the interferon-free drug combo including daclatasvir (formerly BMS-790052) from Bristol-Myers and Gilead's GS-7977. In the phase II trial the combo was tested in patients with genotypes 1, 2, and 3. The result was 100% SVR4 in the genotype 1 patients and 91% SVR4 in genotype 2 and 3 patients. In the other two GS-7977 clinical trials one called Electron- study of GS-7977 plus ribavirin which enrolled 25 treatment naive, genotype 1 patients resulted in 88% SVR4 and in Quantum- The results were not as encouraging, the combo of GS-7977 and ribavirin achieved 59% SVR4, however only 16% of the patients in Quantum had the 'CC' variation near the IL28B gene whereas in Electron 44% had the favorable "CC" genetic variant. With these interim results analysts are predicating that GS-7977 will be included in the first all-oral therapy to reach hepatitis C patients.
Summary Of The 47th European Association for the Study of the Liver EASL - 2012
SVR
The FDA Defines SVR As-
Sustained virologic response (SVR), defined as undetectable plasma HCV RNA at
week 24 following treatment cessation (SVR24).
**SVR12 has been highly correlated with SVR24, which is a recognized indicator of viral cure.
May 2012-Standardization of Terminology of Virological Response in the Treatment of Chronic Hepatitis C
More Ways to Treat HCV Infection and Measure Response-Could SVR4 be the new SVR24 ?
Interferon-free
June 2012 Update - Gilead Sciences decided not to collaborate on further development of GS-7977 and daclatasvir
in Phase III (trials)
Partner? Pretty Please? Gilead-GS-7977 and Bristol's -Daclatasvir
Bristol urges combo study with Gilead hepatitis drug
Bristol CEO says Gilead holding out on hep C tie-up
Daclatasvir (formerly BMS-790052) from Bristol-Myers Squibb and Gilead's GS-7977
We begin with interim data for the all-oral combination of Gilead Sciences' GS-7977 a nucleotide polymerase inhibitor and Bristol-Myers Squibb's daclatasvir known as NS5A inhibitor in Genotype 1 naïve patients.
Source: HIV and Hepatitis
Written by Liz Highleyman
Daclatasvir + GS-7977
Excerpt:
Mark Sulkowski from Johns Hopkins Medical School and colleagues tested
various oral combinations of daclatasvir plus GS-7977, with or without
ribavirin, in an open-label Phase 2a trial (AI-444040).
The study included 88 treatment-naive participants, half with
difficult-to-treat hepatitis C virus (HCV) genotype 1a or 1b and half with
genotype 2 or 3. Participants, divided by genotype (1 vs 2/3), were randomly
allocated to receive 3 regimens, for a total of 6 study arms:
400 mg once-daily GS-7977 alone for 7 days, then add 60 mg once-daily
daclatasvir through week 24;
400 mg once-daily GS-7977 plus 60 mg once-daily daclatasvir for 24
weeks;
400 mg once-daily GS-7977 plus 60 mg once-daily daclatasvir plus ribavirin
(weight-based 1000-1200 mg/day for genotype 1 or 800 mg/day fixed-dose for
genotype 2 or 3) for 24 weeks.
Across all study arms, about half of participants were men, about 80% were
white, and the median age was about 52 years. Among genotype 1 patients, 73%
had 1a and 27% had 1b; among the rest, 59% had genotype 2 and 41% had
genotype 3.
Proportions of participants with the favorable IL28B "CC" gene pattern
ranged from 27% to 57%. People with liver cirrhosis or HIV coinfection were
excluded.
Sulkowski reported interim sustained virological response
rates at 4 weeks after completion of treatment, or SVR4. The study will
continue evaluation to see how many participants maintain undetectable viral
load 12 weeks after the end of treatment (SVR12), which is considered a cure.
Safety and tolerability were assessed through week 12 of treatment.
Results
- Among genotype 1 patients, all 3 regimens produced early viral load
decreases. - Rates of rapid virological response (RVR), or undetectable HCV RNA (< 10 IU/mL)
- At the end of treatment, 87% of people taking the GS-7977 lead-in regimen,
86% taking the dual combination for 24 weeks, and 93% taking the triple
combination achieved undetectable HCV viral load. - Even after finishing treatment, a few patients achieved further viral
suppression, resulting in SVR4 rates of 100% in all 3 arms. - Among genotype 2/3 patients, early viral suppression was also good, with
RVR rates ranging from 64% to 88%. - 24-week end-of-treatment response rates were 93% for people taking either
the GS-7977 lead-in regimen or the dual combination for 24 weeks, and 86%
for those taking the triple combination. - SVR4 rates were 88%, 100%, and 79%, respectively.
- Adding ribavirin -- which is known to help prevent relapse -- did not
improve response rates at this early post-treatment time point. - Sustained response rates were independent of IL28B gene pattern.
- Daclatasvir and GS-7977 in combination were generally well-tolerated.
- The most common adverse effects were fatigue, nausea, and headache.
- 2 people (6%) in the GS-7977 lead-in group, 5 (18%) in the dual
combination group, and 3 (10%) in the triple combination group experienced
serious adverse events. - 1 person each in the latter 2 arms stopped treatment early for this
reason. - Serious laboratory abnormalities, including anemia, were only seen in the
group that took ribavirin.
Overall, in this first report of data on an interferon-free regimen containing a NS5A inhibitor plus a NS5B
nucleotide polymerase inhibitor, the combination of daclatasvir plus GS-7977
cured more than 95% of genotype 1, 2, and 3 treatment-naive patients, including
all of those with genotype 1, the researchers concluded.
"Ribavirin contributed adverse effects but had no effect on virologic response," they added.
These findings were discussed at an EASL opening press conference, where it was
noted that daclatasvir developer Bristol-Myers Squibb and GS-7977 developer Gilead Sciences
do not currently have plans to further test this regimen in Phase 3 studies. Gilead is testing
GS-7977 in combination with several of its own compounds.
Continue Reading...
Press Release-
Interim results from the Phase II open-label study of daclatasvir, Bristol-Myers Squibb’s NS5A replication complex inhibitor, and GS-7977, a nucleotide NS5B polymerase inhibitor, in treatment-naïve patients
with hepatitis C genotypes 1, 2 and 3. In this interim analysis, a combination of the two oral, once-daily investigational compounds taken for 24 weeks, with or without ribavirin, achieved a rapid and sustained viral
response.
Overall, 100% of patients with genotype 1, 2, or 3 HCV achieved
viral load below the lower limit of quantification at Week 4 on treatment. In
the genotype 1 HCV treatment groups, 100% of patients achieved sustained
virologic response through four weeks off-treatment (SVR4). In the genotypes 2
and 3 treatment groups, 91% (40/44) of patients achieved SVR4.
Continue Reading........
Link-
EASL coverage @ CCO
*Free registration required - Worth the effort to view easy to understand format.
CCO - Interferon-Free Combination of Daclatasvir (NS5A Inhibitor) Plus GS-7977 (NS5B Inhibitor) Demonstrates High Rates of SVR4 in Treatment-Naive Patients With Chronic Genotype 1, 2, or 3 HCV Infection
Click here to register at CCO and here to view data
Slides @ NATAP-
Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR
gt1, 91% gt2)
On The Blog
EASL-All Oral Combo Daclatasvir and GS-7977=100% SVR Geno 1 and 91% SVR Geno 2 and 3
Headlines
Have BMS and Gilead found the 'killer app' for hep C?
Gilead, Bristol-Myers Report Positive Viral Responses In Hepatitis C Studies
Disappointment- GS-7977 plus ribavirin genotype 1 null responders
In the phase II Electron trial researchers reported in March all but one patient relapsed within days of
stopping Gilead'sGS-7977 plus ribavirin in a small arm of 10 genotype 1 null responders.
Medpage reported :
In earlier results from the phase II ELECTRON study, patients with genotypes
2 and 3 of the virus were completely cured after just 12 weeks of therapy with
PSI-7977 combined with ribavirin, Gane noted.
But researchers were also testing the combination in 10 patients with
genotype 1 hepatitis C who had previously not responded to standard therapy with
ribavirin and interferon, and in 25 genotype 1 patients who had not yet been
treated, Gane said.
The initial responses in both groups were similar to those seen in genotypes
2 and 3 -- a quick drop to undetectable levels of virus followed by complete
suppression throughout the 12-week treatment period, Gane said.
But all but one of the so-called null responders relapsed, with hepatitis C
levels rising sharply within days of stopping the drug, Gane reported. Data on
the treatment-naïve patients is not complete yet and will be reported in the
next few months, he added.
"It's still a drug we're excited about, but these data put some limits on its
use," Thomas said.
"The drug was curing [patients with] genotypes 2 and 3 in 12 weeks with just
ribavirin," he said, but that doesn't appear to be possible in the hardest-to-treat subgroup.
Read More:Medpage Today
Gilead Sciences - All oral combo GS-7977 plus ribavirin in naïve patients with genotype 1
Interim data from the Phase 2 ELECTRON study examining GS-7977 plus ribavirin in
treatment-naïve patients with genotype 1.
In ELECTRON of the 25 patients with genotype 1 who completed 12 weeks of treatment with GS-7977 and the ribavirin, 88 percent still had undetectable levels of virus four weeks after completion of treatment.
Mark Schoenebaum, an analyst at ISI Group, said the ELECTRON data was better than expected, since most analysts had expected a result around 50 percent.
Continue Reading - EASL-Early SVR Rates for GS-7977 Plus Ribavirin in Geno 1 Treatment-Naïve Hepatitis C Patients
Link-
Headlines
Gilead's Hepatitis C Drug Poised To Reach The Market As One Of The First 'All Oral' Combinations
EASL-Once Daily GS-7977 Plus Ribavirin in HCV Genotypes 1-3: The ELECTRON Trial
Introduction
Resistance Data:
E. Gane1, C. Stedman2, R. Hyland3, R. Sorensen3, W. Symonds3, R. Hindes3, M. Berrey
1New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, 2Gastroenterology Department, Christchurch Hospital, Christchurch, New Zealand; 3Gilead Sciences, Foster City, CA
- GS-7977 (formerly PSI-7977) is a potent, specifi c nucleotide analog developed for the treatment of patients chronically infected with hepatitis C virus (HCV)
- Safe and well tolerated in clinical studies
- Once daily, with or without food
- Potent antiviral activity
- High barrier to resistance
─ No virologic breakthrough to date
- We conducted a Phase 2 trial (ELECTRON) to evaluate the safety and effi cacy of GS-7977 and ribavirin (RBV) with and without pegylated interferon (PEG) in genotype (GT) 1-3 patients with chronic HCV infection
- Results from the fi rst 5 arms of ELECTRON using interferon-sparing/-free regimens in patients with HCV GT 2/3 and GT 1 prior null responders:1,2,3,4
─ SAFETY
- GS-7977 400 mg QD + RBV for 12 weeks was well tolerated with no attributable safety signal
─ POTENCY
- GS-7977 + RBV elicited rapid suppression of HCV RNA → 100% RVR
- All GT 2/3 treated with GS-7977 + RBV patients achieved SVR24
- Patients treated with GS-7977 monotherapy achieved 60% SVR24
- GT 1 prior null responders achieved 11% SVR4 with a 12-week GS-7977+ RBV regimen
- No virologic breakthrough has been observed during treatment with GS-7977
- Treatment-naïve GT 2/3 patients treated with GS-7977 + RBV + PEG for 8 weeks
- Prior null responder GT 1 patients treated for 12 weeks with GS-7977 + RBV
- Treatment-naïve GT 1 patients treated for 12 weeks with GS-7977 + RBV
- Previously treated GT 2/3 patients treated for 12 weeks with GS-7977 + RBV
Methods
Figure 1. ELECTRON Study Design
Null responders were defi ned as patients with <2 log10 IU/mL decline from
baseline HCV RNA after at least 12 weeks of PEG and RBV
- Treatment-experienced patients were defi ned as those who had any of the following responses after at least 12 weeks of PEG and RBV: • <2 log10 IU/mL decline from baseline in HCV RNA • ≥2 log10 IU/mL reduction in HCV RNA, but HCV RNA >LOQ at end of treatment • HCV RNA
LOQ (relapsers)
Results
Table 1. Baseline Patient & Disease Characteristics
Figure 2. On-treatment Viral Suppression
Table 2. Patients with HCV RNA
*1 subject relapsed at the SVR8 time point after having previously achieved SVR4
Table 3. Safety and Tolerability
*SAEs considered unrelated to GS-7977
†In >1 patient treated with GS-7977; no Grade 3 or 4 AEs occurred in treatment arms lacking PEG
- Population sequencing has been completed in 5 of 8 relapsers from the GT-1 prior null responder arm: no S282T was found
- Deep sequencing did not identify any S282T-containing mutants
Table 4. Grade 3 or 4 Laboratory Abnormalities in >1 Patient
Conclusions
- 88% of treatment-naïve GT 1 patients achieved SVR4 following 12 weeks of therapy with GS-7977 + RBV ─ This result suggests that 12 weeks of GS-7977 + RBV can potentially provide higher rates of SVR in treatment-naïve GT 1 patients than those achieved with longer durations of PI + PEG/RBV
- The combination of GS-7977 + RBV was well tolerated in all genotypes regardless of prior treatment history
- No virologic breakthrough occurred in any arm, suggesting a high barrier to resistance ─ To date, the S282T mutation has not been seen in any GS-7977/RBV regimen
- These results where GS-7977 400 mg once daily (QD) is being utilized in a variety of regimens and populations further demonstrate the utility of GS-7977 across a broad spectrum of HCV disease treatment
47th Annual Meeting of the European Association for the Study of the Liver
April 18 - 22, 2012
Barcelona, Spain
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Tel: (650)522-5373
Poster Number 1113
References and Acknowledgements
1. Lawitz E, et al. J Hepatol 2011;54:S543.
2. Gane E, et al. AASLD 2011
3. Gane E, et al. APASL 2012
4. Gane E, et al. CROI 2012
Thanks to all the patients and their families and:
• Christian Schwabe, Vithika Suri, ACS
• Catherine Stedman, Richard Robson, CCS
© 2012 Gilead Sciences
Link-
Once Daily GS-7977 Plus Ribavirin in HCV Genotypes 1-3: The ELECTRON Trial -
Gilead Sciences- GS-5885, GS-9451, GS-9190-(tegobuvir) Plus Ribavirin
Slides @ NATAP
Interim Sustained Virologic Response Rates in Treatment-Naïve HCV Genotype 1a and 1b Patients Treated
for 12 or 24 Weeks with an Interferon-Free All-Oral Quad Regimen
Gilead Sciences - GS-7977 in combination with PEG-IFN and ribavirin
In the ATOMIC study ninety percent of people with genotype 1 who never treated before for the first time show a clear sign of being cured of their infection using a 12-week treatment regimen containing Gilead Sciences’ nucleotide analogue GS-7977 plus pegylated interferon and ribavirin (peg-IFN/RBV), according to preliminary data from a Phase II clinical trial presented Thursday, April 19, at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona.
The new results, highlighting 12-week sustained virologic response (SVR 12) rates involving one group of patients in the ATOMIC study, were presented by Kris Kowdley, MD, of the Virginia Mason Medical Center in Seattle and his colleagues. The study, which is ongoing, has enrolled 316 people with genotype 1 HCV infection to receive either 12 weeks of GS-7977 plus peg-IFN/RBV, 24 weeks of GS-7977 plus peg-IFN/RBV or 12 weeks of GS-7977 plus peg-IFN/RBV plus an additional 12 weeks of either GS-7977 alone or GS-7977 plus ribavirin (but not pegylated interferon).
An additional 16 patients with genotypes 4 or 6 HCV infection are also enrolled in ATOMIC and will be receiving a 24-week course of GS-7977 plus peg-IFN/RBV. SVR 12 data are only available for the 52 patients in the first group, treated with GS-7977 plus peg-IFN/RBV for 12 weeks. All of the study volunteers had HCV viral loads above 50,000; none of the patients had cirrhosis of the liver.
According to Kowdley’s EASL report, 51 of the 52 patients completed 12 weeks of treatment; the remaining study volunteer was lost to follow-up during therapy. All 51 patients (100 percent) had an end-of-treatment response (ETR)—an undetectable HCV viral load after completing 12 weeks of therapy.
Data were available for 50 of the 51 study volunteers 12 weeks after completing therapy; one additional patient was lost to follow-up during this period.
Of the 50 evaluable patients, 47 of them—90 percent of the original 52 study group volunteers—still had an undetectable HCV viral load 12 weeks after completing treatment. Though HCV infection isn’t considered cured until viral load testing confirms no measurable viral replication for 24 weeks following the completion of therapy (SVR 24), an SVR 12 is highly indicative of a favored outcome.
Three patients were dubbed relapsers—their HCV viral loads rebounded following the completion of 12 weeks of GS-7977 plus peg-IFN/RBV therapy.
Overall, Kowdley and his colleagues report, GS-7977 was well tolerated. The frequency and severity of side effects were consistent with those typically associated with peg-IFN/RBV therapy. The most common adverse events during the 12 weeks of therapy were fatigue, headache, nausea, chills and insomnia.
Source
Link-
Slides @ NATAP
GS-7977 + PEG/RBV in HCV Genotype 1: The ATOMIC Trial An End To Response-Guided Therapy
Headlines
Gilead Announces Sustained Virologic Response Data for 12-Week Regimen of GS-7977 Plus Pegylated Interferon and Ribavirin in Genotype 1 Hepatitis C PatientsPromising New Hepatitis C Treatment Tested at Virginia Mason
BMS-650032 (Asunaprevir) BMS-790052 (Daclatasvir)
BMS-790052 is an investigational oral hepatitis C NS5A replication complex inhibitor. NS5A is one of the essential
components for HCV replication.BMS-650032 is an NS3 protease inhibitor, both in development for the treatment of chronic hepatitis C virus (HCV) infection
BMS-790052 and BMS-650032 were discovered by Bristol-Myers Squibb Research and Development. PEG-Interferon lambda was discovered by ZymoGenetics, Inc., a wholly-owned subsidiary of Bristol-Myers Squibb.
All-Oral Hepatitis C Virus Treatment with Bristol-Myers Squibb’s Investigational Compounds Daclatasvir and Asunaprevir Achieved Sustained Virologic Response in 77% of Difficult-to-Treat Patients.
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company
(NYSE: BMY) today announced results from a Phase II study in which treatment
with an all-oral, dual direct-acting antiviral (DAA) regimen of daclatasvir, an
investigational NS5A replication complex inhibitor, and asunaprevir, an
investigational NS3 protease inhibitor, achieved undetectable viral load 24
weeks post-treatment (SVR24) in 77% (33/43) of difficult-to-treat genotype 1b
hepatitis C (HCV) patients.
Difficult-to-treat patients in this study included null responders, or patients
who had previously not responded to treatment with peginterferon alfa and
ribavirin (alfa/RBV), and patients who were medically ineligible or intolerant
to previous treatment with alfa/RBV. In this study, serious adverse events
(SAE) included three patients with fever (pyrexia), one with hypochondriasis,
and one with hyperbilirubinemia which led to treatment discontinuation.
The study findings, presented in an oral session at the International Liver Congress (ILC),
the 47th annual meeting of the European Association for the Study of the Liver (EASL) in
Barcelona, Spain, confirmed the previously announced sentinel cohort
data.
“Currently there are no treatments available for hepatitis C genotype 1 that can be
administered without the concurrent use of alfa and ribavirin, which gives rise to a serious
unmet need for patients who are ineligible or intolerant to alfa/ribavirin,” said
principal investigator Fumitaka Suzuki, Toranomon Hospital, Tokyo, Japan. “The
results of this Phase II study with Bristol-Myers Squibb’s daclatasvir and
asunaprevir are encouraging as we study potential hepatitis C therapies for
this difficult-to-treat patient population.”Study Results The primary endpoint
of the study was the proportion of patients with sustained virologic response
12-weeks following treatment (SVR12).
In this study, the patents were divided into two treatment groups: Group A
consisted of 21 genotype 1b prior null responders and Group B consisted of 22
genotype 1b patients medically ineligible for alfa/RBV or with prior intolerance
to alfa/RBV.
Overall, 77% (33/43) of patients achieved SVR12 and maintained
virologic response through follow-up to SVR24. SVR24 was achieved by 91% (19/21)
of patients in Group A and 64% (14/22) of patients in Group B. Of the 43 patients enrolled
in the study, 39 completed 24 weeks of treatment. In this study, 94% (33/35)
patients who achieved SVR4 remained undetectable SVR24, and 100% (33/33)
of patients who achieved SVR12 remained undetectable at SVR24.
Viral breakthrough was observed in 7.0% (3/43) of patients and
post-treatment relapse was observed in 9.3% (4/43) of patients in the study.
All occurrences of viral breakthrough and post-treatment relapse took place in
the alfa/RBV ineligible/intolerant arm. There were no viral breakthroughs and
no post-treatment relapses in prior null responders.
Serious adverse events occurred in five patients. Three patients experienced
Grade 2/3 fever (pyrexia), one patient developed Grade 2 hypochondriasis, and one patient
developed Grade 4 elevated bilirubin levels (hyperbilirubinemia) that led to
study discontinuation at week 2. There were three additional discontinuations
due to adverse events: two transaminase elevations at weeks 12 and 16 and one
lymphopenia at week 52 (off-study) in a patient with alfa/RBV added at week
six. The most commonly reported on-treatment adverse events occurring in at
least three patients were headache (14/43), nasopharyngitis (14/43), liver
enzyme increases (12/43 ALT increase and 10/43 AST increase), diarrhea (Grade
1, 11/43), and fever (pyrexia, 8/43). There were no deaths in this study and no
clinically relevant changes in electrocardiogram parameters.
About the Study In this Phase II open-label clinical trial (AI447-017), an expanded cohort
of 43 Japanese patients with chronic HCV genotype 1b infection with null
response to prior alfa/RBV treatment (reduction in HCV RNA <2 log10 IU/mL with
12 weeks of alfa/RBV therapy) or patients ineligible for or intolerant to treatment with alfa/RBV
were treated with daclatasvir 60 mg once daily and asunaprevir 200 mg twice daily,
for 24 weeks. (Asunaprevir was initially dosed 600 mg twice daily in sentinel
cohort of 10 null responders.) The primary efficacy endpoint was the proportion
of patients with undetectable viral load (HCV RNA < 15 IU/mL) at 12 weeks
post-treatment (SVR12). Patients were followed to 24 weeks post-treatment (SVR24).
Continue Reading.............
Link-
Slides @ NATAP
Dual Oral Therapy with NS5A Inhibitor Daclatasvir (BMS-790052) and NS3 Protease Inhibitor
Asunaprevir (BMS-650032) in HCV Genotype 1b-Infected Null Responders or Patients Ineligible/Intolerant
to Peginterferon/Ribavirin
Boehringer Ingelheim - BI 201335 protease inhibitor and BI 207127 polymerase inhibitor
Study is the first to demonstrate a cure in cirrhotic patients using an interferon-free therapy
New data from the largest Phase II interferon-free trial to date, reveal that up to 82
percent of hepatitis C patients achieved a viral cure after just 28 weeks of
treatment. These results were shown in specific patients infected with two
prevalent types of hepatitis C (genotypes-1a CC and -1b), following treatment
with Boehringer Ingelheim’s investigational direct-acting antiviral
compounds.
These findings were demonstrated in the largest Phase II interferon-free trial to date, with a
total of 362 patients, including those patients with advanced liver disease.
All patients in the study received treatment with the interferon-free combination
of two investigational compounds, the once daily protease inhibitor BI 201335 and the
polymerase inhibitor BI 207127, both with and without ribavirin and with
varying treatment durations.
Of all the patients studied, including those with the hardest to cure type of hepatitis C
(genotype-1a non-CC), 68 percent achieved a viral cure after 28 weeks of treatment. Most
significantly, up to 82 percent of specific patients with one of the most
common HCV types found across Europe and Asia (genotypes-1a CC and -1b),
achieved viral cure after 28 weeks of treatment. The findings are unprecedented
in this patient population and indicate the future potential of eliminating the
need for interferon which still has to be administered with all current
treatment options.
Continue Reading....
Interferon-Free Combination Regimen Shows Promise
for the Treatment of Chronic HCV
By Chris Berrie
Source: DGNews
BARCELONA, Spain -- April 25, 2012 -- An interferon-free combination regimen
consisting of BI201335, a hepatitis C virus (HCV) protease inhibitor and
BI207127, a non-nucleoside RNA polymerase inhibitor, with or without ribavirin,
shows potent antiviral activity in patients with chronic HCV.
Sustained virological response (SVR) rates were achieved by 60% of patients
receiving interferon-free combination therapy with BI201335, BI207127, and
ribavirin at 12 weeks, researchers said here on April 21 at the 47th Annual
Meeting of the European Association for the Study of the Liver (EASL).
In the study, 362 treatment-naïve patients were randomised to 1 of 5
treatment arms: BI201335 120 mg QD plus BI207127 600 mg TID and ribavirin for 16
weeks (arm A), 28 weeks (arm B), or 40 weeks (arm C); BI201335 120 mg QD plus
BI207127 600 mg BID plus ribavirin for 28 weeks (arm D); or BI201335 120 mg QD
plus BI207127 600 mg BID without ribavirin for 28 weeks (arm E).
Patient baseline characteristics were well balanced between groups. However,
there were more patients in arm D with liver cirrhosis (17%).
SVR Rates for arms A, B, C, and D were 59%, 61%, 56%, and 68%,
respectively.
Only 39% of patients in arm E -- the group not receiving ribavirin --
achieved SVR, and thus randomisation in this arm was closed early.
Arm D received the most benefit from treatment, according to Stefan Zeuzem,
MD, Department of Medicine, Johann Wolfgang Goethe University Hospital,
Frankfurt, Germany, and colleagues.
Lower efficacy was seen among patients with genotype 1a and 1b without
cirrhosis.
The safety and tolerability profile of BI201335, BI207127, and RBV was
comparable to other direct acting antiviral regimens.
“This data justifies phase 3 studies investigating the BID regimen in HCV
patients,” said Dr. Zeuzem.
Funding for this study was provided by Boehringer Ingelheim.
[Presentation title: SVR4 and SVR12 With the Interferon-Free Regimen of BI
201335 and BI 207127 ± Ribavirin, in Treatment-Naïve Patients With Chronic
Genotype-1 HCV Infection: Interim Results of SOUND-C2. Abstract 101]
Link-
EASL Coverage @ CCO
*Free registration required *Free registration required
CCO
SOUND-C2 Interim Results: High Efficacy, Good Safety Profile of IFN-Free BI 201335, BI 207127, and RBV Combination Therapy in Treatment-Naive Patients With Genotype 1 HCV
Click here to register at CCO and here for SOUND-C2 data
Slides @ NATAP
SVR4 and SVR12 with an interferon-free regimen of BI 201335 AND BI 207127, +/- ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Interim results of SOUND-C2 -
The efficacy and safety of the interferon-free combination of BI 201335 and BI 207127 in genotype 1 HCV patients with cirrhosis: Interim analysis from SOUND-C2
On the blog
EASL-BI 201335 and BI 207127-Viral cure achieved without interferon in up to 82% of hepatitis C patients (GT-1a &
-1b*)
EASL- First ever data investigating interferon-free treatment in hepatitis C patients who have liver cirrhosis shows high viral cure rate: protease inhibitor BI 201335 plus the polymerase inhibitor BI 207127 plus ribavirin
EASL Poster-
SVR4 and SVR12 WITH AN INTERFERON-FREE REGIMEN OF BI201335 AND BI207127, +/- RIBAVIRIN, IN TREATMENT-NAÏVE PATIENTS WITH CHRONIC GENOTYPE-1 HCV INFECTION: INTERIM RESULTS OF SOUND-C2
EASL Poster-CHARACTERIZATION OF HCV NS3 VARIANTS THAT EMERGED DURING VIROLOGIC BREAKTHROUGH AND RELAPSE FROM BI 201335 PHASE II SILEN-C2 STUDY IN PEGIFN/RBV TREATMENT-EXPERIENCED PATIENTS
View Abstract
Headlines
Boehringer Ingelheim Hepatitis C Drugs Cured 82% in Trial
New data from descriptive sub-analysis of patients with compensated liver cirrhosis
Vertex-Telaprevir
Vertex today announced data from a retrospective subanalysis of the Phase 2 PROVE 2 study that showed that 100 percent (12/12) of patients with the IL28B CC genotype who were new to treatment achieved a viral cure (sustained viral response, or SVR) with a total of 12 weeks of treatment with INCIVEK™ (telaprevir) tablets, pegylated-interferon and ribavirin. These data support Vertex’s ongoing Phase 3b study that is evaluating a total treatment duration as short as 12 weeks in people with the IL28B CC genotype. Data from the PROVE 2 subanalysis and 13 other abstracts on INCIVEK and Vertex’s medicines in development for the treatment of hepatitis C will be presented at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain, April 18 to 22, 2012.
Vertex also announced today plans to open for enrollment a Phase 2b study to evaluate an all-oral (interferon-free) treatment regimen as short as 12 weeks in people with genotype 1 (1a and 1b) hepatitis C. The study is part of Vertex’s commitment to exploring multiple interferon-free combinations with its portfolio of four direct-acting antivirals that, in addition to INCIVEK, which was approved by the U.S. Food and Drug Administration (FDA) in May 2011, include a non-nucleoside polymerase inhibitor and two distinct nucleotide polymerase inhibitors. Vertex continues to evaluate ways to expand and improve treatment with ongoing studies of INCIVEK combination therapy. The company’s broad portfolio and development program support its goal of further shortening treatment time, improving convenience and tolerability and increasing viral cure rates for people with hepatitis C.
Source
Link-
EASL Coverage @ CCO
Retrospective Analysis of Viral Kinetics During Treatment With Telaprevir Plus PegIFN/RBV Underscores Validity of Futility Rules
Click here to register at CCO and here for Analysis of Viral Kinetics During Treatment
With Telaprevir Plus PegIFN/RBV
Telaprevir-Resistant Viral Variants EASL Poster - DEEP SEQUENCING SCREENING FOR TELAPREVIR-RESISTANT VIRAL VARIANTS IN PREVIOUS NULL RESPONDERS FAILS TO IDENTIFY THOSE PATIENTS AT RISK OF FAILING TELAPREVIR PLUS PEGINTERFERON/RIBAVIRIN THERAPY
View Abstract
Headlines
J&J Open to Expanding Hepatitis C Cooperation With Vertex
Vertex (VRTX) Reports Encouraging Data from Phase 2 PROVE 2 of INCIVEK; Begins Enrollment in Phase 2b
On The Blog
Vertex Update-Plans enrollment for Phase 2b study all-oral (interferon-free) treatment regimen
EASL-Drug interactions won't exclude HCV transplant or HIV co-infected patients from treatment
Merck - Boceprevir
Victrelis Shows Effectiveness for Prior Treatment Null Responders
Additional data from a Merck-sponsored clinical trial help clarify the efficacy of Victrelis (boceprevir) combined with pegylated interferon and ribavirin (peg-IFN/RBV) in people with genotype 1 hepatitis C virus (HCV) infection who were null responders to previous peg-IFN/RBV treatment. The latest results from the PROVIDE clinical trial were presented by Jean-Pierre Bronowicki, MD, PhD, of the Centre Hospitalier Universitaire de Nancy-Brabois in Vandoeuvre-lès-Nancy, France, and his colleagues at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona.
PROVIDE has been closely watched by hepatitis C care providers because little is known about Victrelis’s effectiveness in null responders—those who experienced minimal HCV viral load reductions while undergoing treatment with peg-IFN/RBV.
RESPOND-2, one of the key clinical trials designed to test Victrelis’s efficacy in treatment-experienced people living with genotype 1 HCV infection before the drug’s approval, only included people who had prior relapsing infection or prior partial responses to earlier therapy—prior null responders were not included in the trial.
To address this important knowledge gap, the PROVIDE study has enrolled people living with genotype 1 HCV infection who were null responders, partial responders or relapsers while receiving peg-IFN/RBV—without Victrelis—in previous Phase II or III clinical trials conducted by Merck.
Of the 168 volunteers enrolled in PROVIDE, 50 met the definition for null response (an HCV viral load that didn’t drop by at least 2 log during the first 12 weeks of treatment).
Once enrolled in PROVIDE, all study volunteers received a four-week course of peg-IFN plus weight-based dosing of RBV. From there, standard doses of Victrelis (800 mg three times daily) were added to peg-IFN/RBV for an additional 44 weeks.
Sixty-seven percent of the PROVIDE subjects were male, and 84 percent were white. The average age upon study entry was 52 years. More than three quarters of the patients had high HCV viral loads (in excess of 800,000); 10 percent had cirrhosis; and 61 percent had genotype 1a HCV infection.
Four patients in the study discontinued pre-IFN/RBV before adding Victrelis at week four—three patients were prior null responders and one was a prior partial responders/relapser.
The sustained virologic response rate at week 24 (SVR 24)—the percentage of people believed to be cured of their infection—among prior null responders was 40 percent (19 of the 47 prior null responders who remained enrolled in the study). Among the 91 prior partial responders and relapsers, the SVR 24 rate was 68 percent.
Study subjects who saw their HCV viral loads drop by at least 1 log (more than 90 percent) after the four-week peg-IFN/RBV dosing period—roughly 22 percent of prior null responders and 76 percent of prior partial responders/relapsers—were more likely to experience an SVR 24.
According to Brownowicki and his colleagues, 55 percent of prior null responders and 70
percent of prior partial responders/relapsers who saw their viral loads decrease by at least 1 log
during the first four weeks of treatment were cured of their infection following triple-drug therapy.
Seven percent of the PROVIDE participants discontinued therapy because of side effects. Roughly half of the patients in the study experienced anemia; one-third experienced dysgeusia (distorted sense of taste); and one-quarter experienced a drop in their neutorphil counts.
Victrelis and peg-IFN/RBV, the authors concluded, “achieved high SVR rates regardless of prior response to [peg-IFN/RBV]. The degree of interferon responsiveness after [peg-IFN/RBV] lead-in correlated with prior response and can help predict SVR for prior null responders.”
They add: “The safety profile is comparable to that previously reported for [Victrelis plus peg-IFN/RBV].”
Source
Boceprevir a useful option for patients who did not respond to earlier course of hepatitis C therapy
Michael Carter
Published: 23 April 2012
A regimen of boceprevir with pegylated interferon and ribavirin achieved cure rates of between 40 and 68% in
patients who did not respond to a previous course of hepatitis C therapy, data
presented to the 47th International Liver Congress in Barcelona last
week show.
The addition of boceprevir to standard hepatitis C
therapy (pegylated interferon/ribavirin) achieved a sustained virological
response 24-weeks post treatment (SVR24) in 40% of individuals with a prior null
response to treatment; in 56% of those who relapsed after an earlier course of
therapy; and in 68% of patients with a prior partial response.
Factors associated with the success of treatment
included baseline platelet count and viral load.
Boceprevir is a protease inhibitor which works
directly against hepatitis C. Its use with standard therapy – pegylated
interferon and ribavirin – has been shown to increase the chances of
treatment-naive individuals achieving a sustained virological response to
therapy.
However the treatment of individuals who have not
responded successfully to standard therapy remains a challenge. There are hopes
that directly acting antiviral agents such as boceprevir will provide important
new therapeutic options........
Continue Reading @ aidsmap.com
Link-
Slides @ NATAP
Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment with
Boceprevir (BOC) + PR: PROVIDE Study Interim Results -
Headlines
Two strategies for managing anemia in hepatitis C patients work equally well, Merck says
Merck Reports Phase III Results With Vicrelis - Anemia management on viral response evaluated in Hepatitis C patients
On The Blog
EASL-Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy
Telaprevir and Boceprevir
Recurrence after liver transplantation
In the first multicentric study of the efficacy and safety of the protease inhibitors (PI) Boceprevir or Telaprevir in patients with severe HCV genotype 1 (GT1) recurrence after liver transplantation(1), results show that 57% of patients achieve undetectable hepatitis C viral loads 24 weeks after treatment (SVR24) with pegylated Interferon-alfa-2b (PegIFN-α-2b), ribavirin (RBV) and either Boceprevir or Telaprevir.
Interactions between immunosuppressants and PIs were easily controlled.
Further new data shows that, in HCV GT1 and HIV co-infected patients, the addition of Boceprevir to PegIFN-α-2b and RBV results in higher rates of undetectable HCV RNA levels compared to treatment with only PegIFN-α-2b and RBV alone.(2) At the end of treatment (week 48), 63.9% of patients receiving Boceprevir, PegIFN-α-2b and RBV had undetectable HCV RNA, compared to 29.4% in the control arm. The study found the safety and tolerability profile of Boceprevir, PegIFN-α-2b and RBV was consistent with that observed in HCV-monoinfected patients.
The combination of these findings provides new hope for various difficult to treat hepatitis C populations. Professor Mark Thursz, EASL's Secretary General commented on the exciting new data: "Patients with HIV co-infection and patients who have been transplanted for HCV infection often have more aggressive disease and have been harder to treat. Worries about drug-drug interactions have caused concern about the use of protease inhibitors in these groups. The new trial data shows that the benefits of direct anti-virals can now be experienced by a wider group of patient populations."
Continue Reading..
Telaprevir and Boceprevir - Side Effects In Patients With Cirrhosis
Reuters Health Information
Telaprevir May Cause Severe Cutaneous Eruptions
NEW YORK (Reuters Health)
Apr 19 -
The antiviral agent telaprevir (Incivek) has been associated with severe cutaneous eruptions,
including the DRESS syndrome (drug reaction with eosinophilia and systemic
symptoms), a new report warns.
"I would like physicians to be aware of DRESS occurring in patients on telaprevir-based therapy, as its
effectiveness in hepatitis C is sure to make its use more ubiquitous in the
future," Dr. Peggy A. Wu from Beth Israel Deaconess Medical Center, Boston,
Massachusetts, told Reuters Health in an email. "Presentation tends to be
later, around 3-12 weeks, and common symptoms include fever and extensive rash."
In the March 1 online issue of the Journal of Hepatology, Dr. Wu and Dr. Steven T. Chen
reported on three patients out of 56 patients at risk (5%) who developed
probable or definite DRESS during therapy with telaprevir, peginterferon, and
ribavirin.
The three patients were a 60-year-old man in week seven of treatment, a 56-year-old woman who had
completed seven weeks of treatment, and a 55-year-old woman who presented a
week after completing 12 weeks of telaprevir therapy.
All three cases were managed successfully with discontinuation
of medications, topical class I corticosteroids, and systemic
antihistamines.
In phase II and III clinical trials involving over 3,800
patients, 3.7% of telaprevir-treated patients developed severe cutaneous adverse
events, the researchers note. The U.S. Food and Drug Administration approved
telaprevir for treating HCV infection on May 23, 2011 and included DRESS among
its warnings and precautions.
"The most feared complication of DRESS is end-organ damage, which in extreme cases
can be life-threatening," Dr. Wu said, "so it is important to identify the syndrome early to
stop the offending medications and monitor the disease."
"These are observations from a single institution during a finite amount of time," she added. "More
information is needed to determine the true incidence of DRESS in
telaprevir-treated patients, their prognosis, risk factors, and optimal treatment."
At this point there are no standard measures for preventing DRESS, according to Dr. Wu.
"Future studies may involve genotyping those who have DRESS on telaprevir-based
therapy and screening patients with associated HLA type or slow metabolism prior
to receiving the medication," she said. "Although testing for human herpes virus
6 reactivation is not commonly done in this country, its association with DRESS
has been made in other countries, and it may be worth screening for in the future."
SOURCE:http://bit.ly/HJbDoq
Keith Alcorn, Michael Carter
Published: 20 April 2012
Source - Telaprevir and boceprevir show high rate of serious side-effects in hepatitis C patients
with urgent need of treatment
A real-world study of new hepatitis C protease inhibitors in the group of patients who have been told they should not wait for newer, experimental antivirals has shown a much higher rate of serious adverse events and treatment discontinuations than in clinical trials, Dr Christophe Hézode reported on behalf of the French Compassionate Use of Protease Inhibitors in Cirrhotics cohort study at the 2012 International Liver Congress in Barcelona on Thursday.
However rates of virologic response after 16 weeks of treatment were high in this group of patients who had previously relapsed or failed to respond to pegylated interferon and ribavirin.
The programme and cohort study were established prior to the licensing of telaprevir (Incivo/Incivek) and boceprevir (Victrelis) in Europe in order to provide early access to the new drugs in patients with hepatitis C judged to be in urgent need of reatment. Under French law experimental drugs may be made available prior to licensing to patients with urgent clinical needs, if data on safety are collected.
The cohort study sought to evaluate outcomes in patients who received the drugs, and in particular to evaluate the tolerability and efficacy of the new drugs in patients with hepatitis C mono-infection and compensated cirrhosis with a previous history of non-response or relapse after standard treatment with pegylated interferon and ribavirin.
Early access was provided to telaprevir or boceprevir for 655 patients at 55 hospitals in France; 455 were eligible for inclusion in the cirrhosis analysis (296 telaprevir, 149 boceprevir).
The telaprevir regimen consisted of twelve weeks of telaprevir in combination with standard hepatitis C treatment, followed by a further 36 weeks of pegylated interferon and ribavirin. The boceprevir regimen comprised four weeks of lead-in treatment with pegylated interferon and ribavirin, followed by 44 weeks of boceprevir with pegylated interferon and ribavirin.
This study did not report on sustained virologic response after completion of treatment and efficacy and adverse event data cover the first 16 weeks of treatment. However, week 16 on-treatment virologic response data showed that 86% (177 of 205 patients) of telaprevir-treated patients and 71% (89 of 126) of boceprevir-treated patients had undetectable HCV viral load.
There was no randomisation, which precluded any comparison between the safety profiles of the two drugs.
Most of the patients were male and their mean age was 57 years.
Just under half (48.6%) of patients receiving telaprevir experienced a serious adverse event as did 38% of those treated with boceprevir. This high prevalence of serious side-effects contrasted to the rates of between 9% and 14% observed in the phase III studies which led to the licensing of the drugs. 14.5% of the telaprevir-treated patients and 7% of the boceprevir-treated patients discontinued treatment as a result of serious adverse events.
“The safety profile of telaprevir or boceprevir with pegylated interferon/ribavirin in cirrhotic patients was poor,”comment the investigators.
Grade 2 anemia (8.0- < 10.0 g/dl) developed in 19.6% of telaprevir-treated patients and 22% of individuals receiving boceprevir-based therapy. Grade 3-4 anemia (< 8.0 g/dl) was observed in 10% of those taking telaprevir and 10% of patients treated with boceprevir.
EPO therapy for anemia was provided to 56% of telaprevir patients and 66% of boceprevir patients. A fifth of individuals taking telaprevir and 10% of those treated with boceprevir required a blood transfusion
Serious (grade 3-4, < 50000/mm3) thrombopenia was also common. It developed in 13% and 7% of telaprevir and boceprevir-treated patients respectively. Neutropenia grade 3-4 ( < 1000/mm3) was observed in 5% of telaprevir and boceprevir-treated patients.
Although serious infections were rare (1% -2%), a large proportion of patients developed other grade 3-4 adverse events such as rash, pruritis and hepatic decompensation (53% telaprevir; 32% boceprevir).
“These data strongly suggest that triple therapy must be administered cautiously with intensive safety monitoring in…patients [with cirrhosis],” conclude the investigators.
Link-
On The Blog-New Antivirals Show Poor Safety in Hepatitis C With Cirrhosis
HIV and Hepatitis
EASL: Telaprevir and Boceprevir Effective but Cause Serious Side Effects in Patients With Cirrhosis
Telaprevir and VX-222
Link-
Slides @ NATAP
Patients of all IL28B Genotypes have High SVR Rates when Treated with VX-222 in
Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study
EASL-Poster - Characterization of HCV Variants in Genotype 1 Treatment-naïve Patients Administered the Combination of TVR and VX-222 in DUAL arms of ZENITH study
View Abstract
EASL Poster-All IL28B Genotypes Have High SVR Rates in Patients Treated with VX-222 in Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study
View Abstract
Novartis' hepatitis drug alisporivir on hold
Pancreatitis Forces Halt to HCV Drug Trial
By John Gever, Senior Editor, MedPageToday
Published: April 19, 2012
Three cases of acute pancreatitis, one fatal, have led the FDA to put a
clinical hold on a trial of an investigational oral drug for hepatitis C called
alisporivir, according to the product's manufacturer.
An official at Novartis broke the news at a press conference held Thursday at
the European Association for the Study of the Liver meeting in Barcelona.
Responding to a reporter's question, Nikolai Naoumov, MD, confirmed that the
FDA had ordered a halt to a trial involving alisporivir.
"The FDA has notified Novartis to put the program on clinical hold," Naoumov
said. "The reason is that in the last few months we had a cluster of three
patients who developed acute pancreatitis and one last week who died,
unfortunately. So, as a result, this is to assess the risk. All these patients
had been treated with alisporivir plus PR [pegylated interferon and ribavirin].
We know pancreatitis is on the label of interferon, and we are working to see if
adding alisporivir potentiated a known side effect."
Alisporivir is an orally active inhibitor of cyclophilin, a protein found in
most vertebrates that appears to be necessary for hepatitis C virus (HCV)
replication. It was initially developed under the name DEB-025 by the Swiss firm
Debiopharm, which has licensed rights in most of the world to Novartis.
The HCV community has been hopeful that cyclophilin inhibitors such as
alisporivir would not need to be given with interferon drugs, but could instead
replace them.
Interferon therapy causes debilitating flu-like symptoms that continue
throughout the months-long course of treatment. Results in clinical studies of
alisporivir have suggested a more favorable side effect profile and efficacy
that has prompted speculation about interferon-free treatment regimens for
HCV.
Source
Hepatitis C drug alisporivir is effective, but pancreatitis a concern
Liz Highleyman
Produced in collaboration with hivandhepatitis.com
Alisporivir (formerly Debio 025) in interferon-free combinations cured more
than 80% of patients with hepatitis C virus (HCV) genotype 2 or 3, researchers
reported at the 47th International Liver Congress(EASL 2012) last
week in Barcelona. The drug has been put on hold, however, due to a small number
of recipients developing life-threatening pancreas inflammation.
The advent of direct-acting antiviral agents for hepatitis C has brought
about a new era of treatment, but many patients and clinicians are eager to see
all-oral regimens that do not include interferon and its difficult
side-effects.
Alisporivir is a cyclophilin blocker that stops HCV from replicating in
cells. Unlike many of the new drugs in development, it targets a component in
host cells rather than the virus itself. Previous small studies showed that it
is active across HCV genotypes and has a high barrier to resistance.
Jean-Michel Pawlotsky from Hôpital Henri Mondor in Paris and colleagues
evaluated alisporivir in an international exploratory study (VITAL-1) that
included 340 previously untreated people with hepatitis C genotype 2 or 3, types
considered easier to treat than genotype 1.
About two-thirds of participants were men, about half were white and half
were Asian, and the average age was about 42 years. One-third had genotype 2,
the remainder genotype 3.
Participants in this open-label phase IIb trial were randomly assigned to one
of five treatment arms: 1000mg once-daily alisporivir monotherapy, 600mg
once-daily alisporivir plus ribavirin, 800mg once-daily alisporivir plus
ribavirin, 600mg once-daily alisporivir plus pegylated interferon or standard
therapy using pegylated interferon/ribavirin.
All alisporivir recipients started with......
Continue Reading.....
Link-
Headlines
Novartis halts hepatitis drug trial after death
Novartis: Experimental Hepatitis C Drug Development On Hold
Setback for Novartis Hepatitis Drug
EASL Poster
ALISPORIVIR (ALV) PLUS PEG-INTERFERON/RIBAVIRIN (PR) IN HCV G1 TREATMENT-EXPERIENCED PATIENTS ACHIEVES PRIMARY ENDPOINT WITH SUPERIOR EFFICACY AT TREATMENT WEEK 12 COMPARED TO RETREATMENT WITH PR
EASL Poster
ALISPORIVIR PLUS RIBAVIRIN IS HIGHLY EFFECTIVE AS INTERFERON-FREE OR INTERFERON-ADD-ON REGIMEN IN PREVIOUSLY UNTREATED HCV-GT2 OR GT3 PATIENTS: SVR12 RESULTS FROM VITAL-1 PHASE 2B STUDY
Roche - Danoprevir
Roche reports high rates of sustained viral clearance with investigational hepatitis C treatment danoprevir
Roche announced data showing high SVR12 rates (maintaining undetectable viral levels 12 weeks after stopping treatment) and good tolerability with its second generation protease inhibitor danoprevir in IFN-containing regimens for hepatitis C (HCV). In the DAUPHINE study up to 93% of genotype 1 and 100% of genotype 4 patients achieved SVR12 with ritonavir-boosted danoprevir, IFN and ribavirin, considered a clinical cure1.
“The high sustained viral response rates and encouraging safety data show danoprevir is potent and well-tolerated.” said Hal Barron, M.D., Head of Global Product Development and Chief Medical Officer for Roche. “Roche’s HCV portfolio includes multiple investigational drugs with different modes of action, allowing us to develop tailored treatments that aim to address the future needs of patients with chronic hepatitis C.”
In a second study, INFORM-SVR, 71% of genotype 1b patients achieved SVR12 with boosted danoprevir, the nucleoside analogue polymerase inhibitor mericitabine and ribavirin as part of an IFN-free regimen2.
DAUPHINE and INFORM-SVR will be presented at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) congress in Barcelona.
The prevalence of different HCV genotypes across the world, as well as increasing numbers of patients with harder-to-treat disease, co-morbidities or cirrhosis means that patients may have varying needs for future treatment combinations
Continue Reading...
Link-
Slides @ NATAP
RAPID AND SUSTAINED ACHIEVEMENT OF UNDETECTABLE HCV RNA DURING TREATMENT WITH RITONAVIR-BOOSTED DANOPREVIR/PEG-IFNα-2A/RBV IN HCV GENOTYPE 1 OR 4 PATIENTS: DAUPHINE WEEK 36 INTERIM ANALYSIS
RITONAVIR SUBSTANTIALLY REDUCES REACTIVE METABOLITE FORMATION OF THE HCV PROTEASE INHIBITOR DANOPREVIR BOTH IN VITRO AND IN VIVO
RITONAVIR SUBSTANTIALLY REDUCES REACTIVE METABOLITE FORMATION OF THE HCV PROTEASE INHIBITOR DANOPREVIR BOTH IN VITRO AND IN VIVO
EASl Poster-Danoprevir plus Peg-IFNa-2a/ribavirin for 12weeks results in durable viral suppression and low rates of resistance throughout treatment and follow-up: Results from the ATLAS study
View Abstract
EASL Poster-Low rate of on-treatment resistance to danoprevir boosted byritonavir (DNVr) combined with Peg-IFNa-2a/ribavirin: 12 week interim analysis from DAUPHINE study
View Abstract
EASL Poster-HIGH SUSTAINED VIROLOGICAL RESPONSE RATES WITH RESPONSE-GUIDED DANOPREVIR PLUS PEGINTERFERON ?LFA-2A (40KD) AND RIBAVIRIN IN TREATMENT-NAIVE, HCV GENOTYPE 1 PATIENTS: ATLAS STUDY FINAL RESULTS
View Abstract
Headlines
Roche reports high rates of sustained viral clearance with investigational hepatitis C treatment danoprevir
On The Blog
EASL-Danoprevir:Roche reports high rates of sustained viral clearance
Medivir - TMC435
Results from the final ASPIRE analysis show that TMC435 administered in combination with PegIFN/RBV in genotype 1 HCV patients who had relapsed, showed partial response, or no response after a prior course of PegIFN/RBV resulted in as many as 80 percent of patients acheiving SVR24.
The virus was cleared 24 weeks after treatment ended in 80 percent of patients who took a once daily TMC435 dose of 150 milligrams for 48 weeks. The sustained cure rate was 70 percent among patients who took 100 milligrams of the drug for 12 weeks.
In the TMC435 arms, 53 to 68 percent of patients achieved rapid virologic response [RVR; HCV RNA<25 (undetectable)], compared to 2 percent of the placebo group.
For patients in the TMC435 treatment groups dosed with TMC435 100 mg and 150mg, 61-70 percent of patients and 67-80 percent of patients achieved SVR24, respectively, compared to 23 percent of patients achieving SVR24 in the placebo arm.
For null-responders to prior HCV therapy dosed with TMC435 150 mg, 51 percent of patients in the TMC435 treatment groups achieved SVR24, compared to 19 percent in placebo group. When treated with TMC435 150 mg, 75 percent of prior partial responders and 85 percent of patients who previously relapsed reached SVR24, versus 9 and 37 percent taking placebo, respectively.
Once-daily TMC435 was well tolerated in this population with comparable incidence of adverse events between TMC435 and placebo groups except for influenza-like illness, pruritus, and rash (any type). Results showed comparable on treatment changes in hemoglobin levels and neutrophil counts between groups and mild, isolated and reversible increases in bilirubin amongst TMC435 treated subjects.
Continue Reading...
From Medscape Medical News
New Protease Inhibitor TMC435 Cures Most HCV Patients
Daniel M. Keller, PhD
April 24, 2012 (Barcelona, Spain) — In patients infected with
hepatitis C virus (HCV) genotype 1 for whom previous treatment with pegylated
interferon plus ribavirin (PR) failed to eliminate the virus, treatment with
TMC435 plus PR was significantly more effective than PR plus placebo. TMC435 is
a once-daily oral therapy that inhibits HCV NS3/4A protease.
Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at
the J.W. Goethe University Hospital in Frankfurt, Germany, presented the results
of the international, double-blind, placebo-controlled phase 2b ASPIRE clinical
trial here at The International Liver Congress 2012.
The 462 patients in this trial were assigned to 48 weeks of active therapy with 1 of 4 treatment
regimens: TMC435 + PR for 12 weeks, followed by PR + placebo weeks for 36 weeks;
TMC435 + PR for 24 weeks, followed by PR + placebo for 24 weeks; TMC435 + PR for
48 weeks; or PR + placebo for 48 weeks (control group).
In patients receiving TMC435, the dose was 100 or 150 mg daily. All patients were followed
for 24 weeks after the 48-week treatment period.
Eligible men and women were 18 to 70 years of age, had a body weight of 40 to 125 kg, were chronically
infected with HCV genotype 1 HCV, and had plasma HCV RNA greater than 10,000
IU/mL. They had to have received at least 1 previous course of PR for at least
12 consecutive weeks.
Patients were ineligible for the trial if they had decompensated liver disease
or liver disease from any cause other than HCV; if they had hepatocellular
carcinoma; if they were infected with HIV, hepatitis B
virus, or any HCV that was not genotype 1; or if they had any laboratory or
hematologic abnormalities.
At baseline, about two thirds of the patients were men, median age was about 50 years,
body weight ranged from 80.0 to 84.8 kg, and 83% to 89% had HCV RNA greater than 800,000 IU/mL.
Previously in each group, about 40% had relapsed, 35% had partially responded, and 25% had not
responded.
In the 3 TMC435 groups (both the 100 and 150 mg doses), 53% to 68%
of patients achieved rapid viral responses, compared with 2% in the control
group (P < .001 for all groups vs control group). Rapid viral
response meant there was undetectable virus in the blood at week 4.
The sustained viral response rates at 24 weeks (SVR24) ranged from 61% to 80% for
the TMC435 groups, compared with 23% in the control group.
In the TMC435 groups, compared with the control group, previous responders had the highest
SVR24 rates (85% vs 37%), followed by previous partial responders (57% to 75% vs
9%), followed by previous nonresponders (46% to 51% vs 19%).
No patients with advanced liver fibrosis achieved a virologic cure in the control group, whereas
with TMC435, "there was a substantial chance for the patients to achieve
sustained virologic response rates," Dr. Zeuzem reported.
TMC435 Well Tolerated
Discontinuation of treatment because of viral breakthrough was
9% to 17% in the TMC435 groups and 53% in the control group. Viral relapse
occurred in 6% to 18% of the TMC435 group and 44% of the control
group.
The incidence and severity of adverse events were similar in the
TMC435 and control groups. Serious adverse events affected 6% to 10% of patients
in the TMC435 groups and 6% in the control group. Grade 3/4 adverse events
occurred in 28% to 36% of the TMC435 groups and in 26% of the control group. The
most frequently reported adverse events in patients receiving TMC435 were
headache, fatigue, and influenza-like illness, but these events were present at
equivalent levels in the control group.
However, pruritus was more common in the TMC435 groups than in the control group
(35% VS17%). Similarly, more rash of any type occurred in the TMC435 groups than
in the control group (23% to 30% vs 18%). However, less than 1% of patients receiving
TMC435 experienced rash of grade 3 or lower.
The incidence of adverse events leading to treatment
discontinuation and serious adverse events was similar in all groups. Decreases
in and recovery of hemoglobin values and neutrophil counts were equivalent in
all groups. However, the TMC435 groups showed mild and reversible increases in
bilirubin not accompanied by changes in any other liver parameters.
For patients receiving 150 mg of TMC435, 85% of previous relapsers achieved SVR24,
75% of previous partial responders achieved SVR24, 51% of previous nonresponders
achieved SVR24, and 31% to 82% of patients with cirrhosis achieved
SVR24.
Dr. Zeuzem and colleagues conclude that in patients with HCV
genotype 1 who failed previous PR therapy, once-daily TMC435 plus PR was
significantly more effective in producing a sustained viral response than PR
plus placebo.
In comparing the different durations of administration of
TMC435, Dr. Zeuzem explained that "TMC435 for 12 weeks in combination with
pegylated interferon and ribavirin for 48 weeks achieves optimal biologic
response rates." Longer treatment with TMC435 did not produce any better
virologic responses.
The drug is now entering phase 3 trials for both
treatment-naive and treatment-experienced patients.
Session moderator Mark Thursz, MBBS, MD, secretary general of the European
Association for the Study of the Liver and professor of hepatology in the Department of
Medicine at Imperial College, London, United Kingdom, asked Dr. Zeuzem if hepatologists
need to continue to use SVR24 as the end point of a trial or if the follow-up period can
be shortened by using sustained viral response at 12 weeks (SVR12) as the end
point.
Dr. Zeuzem explained that current trials "typically use an SVR at
week 12 of the follow-up period, and the concordance rates are extremely high
[with SVR24]; therefore, SVR12 is the new standard."
He does not think there is a major difference between SVR12 and SVR24 for
treatment-naive patients, nonresponders, or relapsers with an interferon-containing
protocol such as this one. "I'm a little bit more conservative in trials using completely
new drugs, [such as]...interferon-free regimens and all-oral regimens," Dr. Zeuzem said. He
would like to see trials demonstrating the equivalence of SVR12 and SVR24 in
those cases before adopting SVR12 for those drug regimens.
Dr. Thursz told Medscape Medical News that he, too, believes that SVR12 will be
the new end point and will replace SVR24 as new drugs enter trials. "The only
proviso is for people who've previously been treated and have been classified as
null responders — that's a group of people with hepatitis C [in whom] the virus
has not dropped by 2 logs [after 12 weeks of treatment]," he said. "These people
are going to be really difficult to treat and very resistant to pretty much any
kind of medication. I have some reservation about that group; otherwise, SVR12
is undoubtedly going to be, as it were, the standard."
Another group of particular concern is patients with advanced fibrosis or cirrhosis.
"We know, certainly with interferon-based therapies, that response rates are much
lower in that group. Then there is some concern in cirrhotics, particularly cirrhotics
who've decompensated, that the metabolism of the drugs is going to be slightly
different and may cause some problems," Dr. Thursz cautioned.
Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca,
Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX,
Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx
Pharmaceuticals. Dr. Thursz has disclosed no relevant financial
relationships.
The International Liver Congress 2012: Abstract 2.
Presented April 19, 2012.
Link-
ASPIRE @ CCO
ASPIRE: TMC435 Plus PegIFN/RBV Significantly Improves SVR24 Rates Over
PegIFN/RBV Alone in Patients With Genotype 1 HCV Who Failed Previous PegIFN/RBV
Therapy
Click here to register at CCO and here to view data on ASPIRE
Slides @ NATAP-
TMC435 with peginterferon and ribavirin in treatment-experienced HCV genotype 1 patients: the ASPIRE study, a randomised Phase IIb trial
TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon / ribavirin treatment: Virologic analyses of the ASPIRE trial
On The Blog
EASL-TMC435 Demonstrates Statistically Higher Viral Cure Rates (SVR24) Compared to Placebo in HCV Patients Who Had Failed Prior Treatment
Headlines
Medivir Hep C Drug Cures 80% of Patients Post-Treatment
Medivir Announces TMC435 in an Expanded Clinical Collaboration
Regulatory News:
• Expanded clinical study program evaluating a combination of TMC435 and daclatasvir (BMS-790052)
• TMC435 and BMS-986094 (formerly INX-189), two direct-acting antivirals in combination, will be
evaluated in clinical trial Medivir AB (OMX:MVIR)(STO:MVIRB), the research-based speciality pharmaceutical company focused on the development of high-value treatments for infectious diseases, announces that its development
partner, Janssen R&D Ireland has broadened its clinical collaboration agreement with Bristol-Myers Squibb Company (NYSE:BMY).
• This announcement
concerns an expansion of the clinical collaboration agreement between Tibotec Pharmaceuticals (now Janssen R&D Ireland) and Bristol-Myers Squibb (NYSE:BMY) announced by Bristol-Myers Squibb on 2nd December 2011
• Bristol-Myers Squibb and Janssen have agreed, pending the outcome of the upcoming phase II study, to further study daclatasvir (BMS-790052) and TMC435 in a phase III trial.
• Bristol-Myers Squibb and Janssen have agreed to conduct a drug-drug interaction study with TMC435 and BMS-986094. Results from the DDI study will guide the further evaluation of the use of TMC435 and BMS-986094 in
HCV patients.
TMC435 and daclatasvir (BMS-790052)
In the agreement announced on 2nd December 2011, TMC435, a once daily potent NS3/4A protease inhibitor (PI) in
phase III development for the treatment of genotype-1 chronic hepatitis C virus (HCV) infection will be investigated in a combination in a phase II trial with Bristol-Myers Squibb´s investigational NS5A replication complex inhibitor,
daclatasvir (BMS-790052), also in phase III development.
In the upcoming phase II study the companies will evaluate the potential to achieve sustained viral response 12 and 24 weeks post treatment in null responder and interferon intolerant patients with HCV genotype 1. This study is planned to start later in 2012.
TMC435 and BMS-986094 (INX-189)
The expanded clinical agreement also includes clinical evaluation of a combination of TMC435 and the nucleotide
polymerase NS5B inhibitor BMS-986094, formerly known as INX-189. A drug-drug interaction (DDI) study with TMC435 and BMS-986094 will be conducted. Results from the DDI study will guide the further evaluation of the use of TMC435 and BMS-986094 in HCV patients Charlotte Edenius, Executive VP Research; Development, of Medivir commented: “We are very excited to see this expanded collaboration between Janssen and Bristol-Myers Squibb and to be investigating TMC435 with the nucleotide BMS-986094 and to expand the clinical collaboration evaluating TMC435 with daclatasvir. This represents one of several strategies to explore TMC435 in interferon free regimens; a development we believe will be an important advancement in the HCV field for patients.”
About TMC435
TMC435 is a highly potent once-daily (q.d.) investigational drug that is being jointly developed by Janssen R&D Ireland and Medivir to treat chronic hepatitis C virus infections in genotype 1 patients.
TMC435
- On-going global phase III program in brief:
• TMC435-C208 or QUEST-1 in 375 treatment-naïve genotype-1 patients
• TMC435-C216 or QUEST-2 in 375 treatment-naïve genotype-1 patients
• TMC435-C3007 or PROMISE in 375 genotype-1 patients who have relapsed after prior interferon-based treatment
• Phase III program in Japan, includes 417 genotype-1 treatment naïve and treatment experienced patients
• TMC435-C3001 is a phase III efficacy,
safety and tolerability study comparing TMC435 versus telaprevir, each in combination with Pegylated Interferon α-2a (PegINF) and ribavirin (RBV), in hepatitis C genotype-1 infected patients who were null or partial responders to
prior PegINF/RBV therapy
• TMC435-C3011 is an open label, single arm phaseIII trial to explore the efficacy, safety and tolerability of TMC435 150 mg once daily, in combination with PegIFN/RBV in 100 treatment naïve or treatment experienced, hepatitis C genotype-4 infected patients
Source
For additional information from these studies, please see www.medivir.com and www.clinicaltrials.gov
Headlines
Bristol-Myers Expands Hepatitis C Accord With J&J, Medivir
Janssen Creates new Division to Launch TMC435 and Help Conquer Hepatitis C in EMEA
Identix- IDX719
IDX719 Demonstrates Pan-Genotypic Activity at Single Doses in HCV-Infected Patients Achieving Greater Than 3 log10 Viral Load Reductions in the 100 mg Dose Group Across Genotypes 1, 2 and 3; Three-Day Proof-of-Concept Study Underway
From the release:
According to data from a phase I clinical trial of IDX719, an NS5A inhibitor for the treatment of hepatitis C virus (HCV) infection, demonstrating potent pan-genotypic antiviral activity with single doses.
In January 2012, Idenix initiated a phase I clinical study of IDX719. The first part of the study evaluated the safety, pharmacokinetics and food effect of IDX719 in 40 healthy volunteers at single doses ranging from 5 to 100 mg.
Eight healthy volunteers received 100 mg of IDX719 daily for seven days. All doses were well tolerated and pharmacokinetic data supports once-daily dosing in future studies. In the second part of the phase I study, single-ascending doses of IDX719 achieved substantial viral load reductions in the following cohorts of HCV-infected patients:
Continue Reading On The Blog - Idenix Pharmaceuticals Provides Update on Hepatitis C Clinical
Development Programs
Achillion - ACH-1625, ACH-3102 and ACH-2928
EASL-Achillion Clarifies End of Treatment Data From Phase 2a Trial With ACH-1625 Based Regimen in Hepatitis C
April 23
Achillion Pharmaceuticals, Inc.today provided clarification with respect to end of treatment (EOT) data from segment 2 of its Phase 2a trial of ACH-1625 that was presented during the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress 2012 in Barcelona, Spain on April 21, 2012.
In this study, 58 patients were randomized to receive ACH-1625 at a once daily dose of 200 mg, 400 mg, or 800 mg in combination with pegylated interferon and ribavirin (P/R) for twelve weeks. At of the time of the poster presentation, a total of 22 patients had completed 12 weeks of ACH-1625 plusP/R followed by 12 weeks of P/R as per response guided treatment (RGT.) All (22/22, or 100%) patients had undetectable levels of HCV RNA at the end of the 24 weeks of treatment.
EOT was defined in the EASL poster presentation as any patient who returned for an EOT visit, which also included those patients who withdrew from the study prior to week 12. The additional EOT data is defined as patients who achieved extended rapid virological response (eRVR) and received a total of 24 weeks of therapy consisting of 12 week of ACH-1625 plus P/R followed by 12 weeks of P/R alone.
The rapid virological response (RVR) at week 4, cEVR at week 12 and EOT results for all patients returning for an EOT visit (30 patients) presented in the poster, as well as detailed results for patients who received a total of 24 weeks of therapy consisting of 12 weeks of ACH-1625 plus P/R followed by 12 weeks of P/R alone, are provided in the table below.
ACH-1625
EASL Poster - CHARACTERIZATION OF HCV NS3 PROTEASE VARIANTS FROM PATIENTS ENROLLED IN A 28-DAY PHASE 2A TRIAL OF ACH-1625 DAILY DOSING PLUS PEGIFN-ALPHA 2A/RBV
View Abstract
On The Blog
EASL-Achillion Clarifies End of Treatment Data From Phase 2a Trial With ACH-1625 Based Regimen in Hepatitis C
EASL-100% Complete EVR From Phase 2 Trial With ACH-1625 Based Regimen in Hepatitis C
Abbott-Enanta PharmaceuticalsABT-450/r, plus ABT-333 and ribavirin
From Medscape Medical News
Two Oral Drugs Clear HCV Without Interferon
Daniel M. Keller, PhD
May 2, 2012 (Barcelona, Spain) — Twelve weeks of treatment with a combination
of 2 direct-acting antiviral drugs plus ribavirin achieved a sustained virologic
response rate of more than 80% in patients chronically infected with genotype 1
hepatitis C virus (HCV), Eric Lawitz, MD, from Alamo Medical Research in San
Antonio, Texas, reported here at the International Liver Congress 2012.
In a pilot study of 11 treatment-naive noncirrhotic patients, 91% achieved a
sustained virologic response at 12 weeks after the end of treatment (SVR12), and
82% had a sustained virologic response at 36 weeks (SVR36).
Currently, the only approved regimens for the treatment of patients with
genotype 1 HCV contain interferon. For patients who cannot tolerate interferon,
there are no other options.
The 2 direct-acting antiviral drugs are ABT-450, a potent inhibitor of the
HCV NS3 protease, and ABT-072 (Abbott Labs), a nonnucleoside inhibitor of HCV
NS5B RNA polymerase. Both drugs are dosed orally once daily. ABT-450 is boosted
with ritonavir (ABT-450/r) to maintain high ABT-450 exposure and to allow
once-daily dosing.
This trial is the first to evaluate the 2 drugs plus ribavirin in an
interferon-free regimen for the treatment of HCV genotype 1.
The researchers enrolled only patients who were of the interleukin-28B CC
genotype, which is the genotype most amenable to treatment with pegylated
interferon and ribavirin, in case the trial regimen failed.
Patients were treated with ABT-450/r plus ABT-072 daily plus ribavirin for 12
weeks and then followed for 48 weeks after the end of treatment. To be eligible
for the study, patients had to be 18 to 65 years of age; had to have HCV
genotype 1 infection for at least 6 months, no evidence of cirrhosis or bridging
fibrosis, and no coinfection with hepatitis B or HIV; and had to be eligible for
treatment with pegylated interferon plus ribavirin.
Baseline characteristics were similar in the the 2 groups (mean age, 56.4
years; mean weight, 79.6 kg). Mean HCV RNA level was 6.93 ± 0.22 log10 IU/mL, and all
patients had HCV RNA levels above 800,000 IU/mL.
Rapid, Sustained Virologic Responses
All 11 patients achieved a rapid virologic response and an extended rapid
virologic response. Sustained virologic responses at 12, 24, and 36 weeks
occurred in 91%, 91%, and 82% of the cohort, respectively.
There were no virologic breakthroughs on therapy, but 2 patients relapsed
after therapy ended — one at week 12 and the other at week 36.
All patients experienced adverse effects, but most were mild and included
headache, nausea, fatigue, dry skin, and rash. One person had a fasting glucose
level above 250 mg/dL, and 2 had indirect bilirubin elevations without
concomitant transaminase elevations 1 week after treatment initiation, which
resolved with continued dosing. The elevation was consistent with the known
effect of ABT-450 on the OATP1B1 bilirubin transporter.
The were no study drug interruptions or discontinuations and no early trial
discontinuations. There were also no deaths or serious adverse effects.
Session moderator George Papatheodoridis, MD, associate professor of medicine
and gastroenterology at the Medical School of Athens University, staff member at
Hippokration General Hospital in Athens, Greece, and member of the European
Association for the Study of the Liver Governing Board Scientific Committee,
told Medscape Medical News that in light of the small sample size, the
1 late relapse at 36 weeks may or may not be important.
"If these very late relapsers are just 1% or 2%, then it will be of no
clinical relevance.... If it's really 1 of 11 (so close to 10%), these late
relapsers will be very important," he said. "Because these are new regimens, we
don't know how the responders will behave in the long term, so I think the SVR12
should be the gold standard for reporting the results of the trials. [In
addition], all trials should still have at least 1 HCV RNA follow-up...1 year
after these SVR12 determinations."
Dr. Lawitz reports financial relationships with Abbott, Achillion
Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer
Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix
Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex,
Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough,
Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex
Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has
disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 13. Presented April 19,
2012.
Excerpt- TheStreet
PILOT enrolled treatment-naive patients to receive 12 weeks of ABT-450 -- a protease inhibitor that requires blood-level "boosting" with ritonavir -- in combination with the non-nucleoside NS5B polymerase inhibitor ABT-072 and
ribavirin. It must be noted that all patients had favorable "C/C" genetics, making it an easy group to treat. Nonetheless, Abbott reported an impressive 91% SVR24.
One patient in PILOT suffered a late relapse after 36 weeks of follow up which dropped the SVR36 "cure" rate to 82%. These are some of the longest follow-up results yet with next-generation, all-oral regimens so the relapse was noteworthy. I'm not sure if the relapse is an isolated event, and no one I spoke with had a definitive answer. Keep the question of whether interferon-free regimens might leave patients more susceptible to late relapse in mind -- it needs to be watched closely going forward.
In Abbott's second CO-PILOT study, patients received 12 weeks of ritonavir-boosted ABT-450 and the "non-nuc" ABT-333. Patients in the two treatment-naive arms achieved SVR12 rates of 93% and 95% (These patients were a mix of easy- and hard-to-treat patients more comparable to competitors' studies). I was impressed with these data, as were most physicians at EASL. A third arm in the CO-PILOT study enrolled "non-responders" but generated only a 47% SVR12; these patients need a more robust regimen.
The downside to the CO-PILOT regimen is complexity: ABT-450 is administered once daily, as is ribavirin and ritonavir, whereas ABT-333 is dosed twice daily.
Further, ritonavir has numerous drug-drug interactions. Physicians I spoke with at EASL were mixed about whether or not patients could be sufficiently compliant in the real-world setting. I doubt it. Abbott plans to co-formulate future combinations, which will include other drugs (the company also has a NS5A inhibitor.)
Continue reading....
Non-Interferon-Based Combination Therapy Offers
High Response Rates for Hepatitis C Patients
By Chris Berrie
Source: DGNews
BARCELONA, Spain -- April 25, 2012 -- Combining ABT-450 with
ritonavir (ABT-450/r) plus ABT-333 plus ribavirin (RBV) is well tolerated,
provides high sustained virological response (SVR) in treatment-naïve
patients infected with hepatitis C virus (HCV) genotype 1, and shows
relatively high SVR in previous interferon-based nonresponders, researchers
said here at the 47th Annual Meeting of the European Association for the
Study of the Liver (EASL).
At present, there are no treatment options for HCV-infected patients who
are ineligible or intolerant to the interferons.
“This is the first study combining ABT-450 with ABT-333 with ribavirin
without interferon in genotype 1 patients who were either treatment-naïve or
previous treatment failures,” stated Fred Poordad, MD, Chief of Hepatology
and Liver Transplantation at the Comprehensive Transplant Center of
Cedars-Sinai Medical Center, Los Angeles, California, presenting this
open-label study here on April 21.
The study design included 3 arms, the first 2 of which treated naïve
patients with chronic HCV genotype 1 infection using ABT-333 400 mg twice
daily plus RBV 1,000-1,200 mg once daily plus ABT-450/r either 250/100 mg
once daily (arm 1; n= 19) or 150/100 mg once daily (arm 2; n = 14). The
third treatment arm was similar to arm 2, but treated prior partial or null
responders to previous pegylated interferon plus RBV treatments
(arm 3; n = 17).
The treatments were for 12 weeks, with 48 weeks follow-up.
These patients were mainly male, with a mean age of just over 50 years,
and were largely HCV genotype 1a. For IL28B genotype, 52.6% were CC in arm A
and 35.7% in arm B, with no IL28B CC in arm 3.
The primary endpoint was extended rapid virological response (eRVR) based
on HCV RNA lower than the limit of detection from treatment weeks 4 to 12. As
the intent-to-treat analysis, these reached 90%, 79% and 59% in arms 1, 2,
and 3,respectively.
Similarly, for SVRs at weeks 4 (SVR4) and 12 (SVR12), high levels of
response were achieved for arms 1 (95%, 93%, respectively) and 2 (95%, 93%).
These SVR4 and SVR12 responses were also relatively high for the previous
nonresponding patients in arm 3 (47%, 47%).
Comparisons across IL28B CT versus TT showed no differences in SVR12 either for
treatment-naïve patients, as arms 1 plus 2 (100% vs 100%) or for
previous nonresponders (50% vs 40%).
Based on clonal sequencing, Dr. Poordad highlighted the resistant variants
at baseline and at virologic failure in the previous nonresponders of arm 3.
“It is important to note that patients who had virologic failure
developed resistance variants to both the protease inhibitor as well as the
polymerase inhibitor,” he noted.
In the safety analysis, there were no deaths or serious adverse
events throughout, with only 1 adverse event leading to premature
discontinuation, in arm 1. Four patients showed adverse events assessed as
severe, without requiring study-drug interruption or discontinuation:
hyperbilirubinaemia, fatigue, pain, and vomiting.
The treatment-emergent adverse events and the laboratory abnormalities
noted were largely the same type and levels across the 3 treatment arms. Dr.
Poordad also noted that the transient asymptomatic elevation of indirect
bilirubin that was seen is consistent with the known effect of ABT-450 on the
bilirubin transporter OATO1B1.
“It does appear that ABT-450 with ritonavir, ABT-333 plus ribavirin for
12 weeks has the potential to achieve very high SVR in a high proportion
of patients without interferon,” he concluded.
Funding for this study was provided by Abbott.
[Presentation title: A 12-Week Interferon-Free Regimen of ABT-450/r +ABT-333 + Ribavirin
Achieved SVR12 in More Than 90% of Treatment-Naïve
HCV Genotype-1 Infected Subjects and 47% of Previous Non-responders. Abstract
1399]
Link-
Slides @ NATAP-
A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well
Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV
IL28B-CC Genotype-1-Infected Subjects
EASL Poster-ABT-450/ritonavir (ABT-450/r) combined with pegylated interferon alpha-2a/ribavirin after 3-day monotherapy in genotype 1 (GT1) HCV-infected treatment-naïve subjects: 12-week sustained virologic
View abstract
Headlines
Abbott Reports Two Hepatitis C Relapses in 'Pilot' Trial
Abbott Hepatitis C Therapy Cures Patients Failed by Other Drugs
On The Blog
EASL-Abbott Presents Positive Results from Interferon-Free Phase 2 "Co-Pilot" Study for the Treatment of Hepatitis C-ABT-450/r, plus ABT-333 and ribavirin
ABT-450/r, ABT-072-ribavirin
On The Blog
EASL-Oral HCV Combo Effective for Genotype One
Presidio -PPI-383
PPI-383 is a potent, pan-genotypic inhibitor of HCV discovered at Presidio, which exhibits a favorable pharmacokinetic and safety profile in multiple animal species following oral dosing. PPI-383 binds to the Palm II pocket of the HCV polymerase (NS5B) and possesses excellent biochemical and pharmaceutical properties critical to successful drug development, including a potential for once-daily oral dosing and minimal potential for drug-drug interactions. PPI-383 is currently undergoing further preclinical evaluation to support initiation of clinical studies alone and in combination with PPI-668 next year.
Link-
Slides @ NATAP
IDENTIFICATION AND CHARACTERIZATION OF PPI-383, A NEXT GENERATION HCV NS5BNON-NUCLEOSIDE
INHIBITOR WITH POTENT ACTIVITY AGAINST ALL MAJORHCV GENOTYPES
Continue Reading On The Blog - EASL-Presidio Announces a New Clinical Candidate, PPI-383, a Novel Pan-Genotypic Non-Nucleoside Polymerase Inhibitor for HCV
Santaris Pharma - Miravirsen
Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, will present final data from a Phase 2a trial showing that miravirsen given as a four-week
monotherapy treatment provided robust dose-dependent anti-viral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL) that was sustained well beyond the end of therapy.
Continue Reading On The Blog - EASL-Final Phase 2a Study Results For Miravirsen Showing Dose-dependent, Prolonged Antiviral Activity In Hepatitis C Patients
Link-
EASL
EASL:Hepatitis C-NEW DATA SUGGESTS INTERFERON-FREE THERAPY AROUND THE CORNER
EASL-Peginterferon Lambda Achieved SVR24 Rates Comparable to Peginterferon Alfa with Fewer Side-Effects
HIV and Hepatitis Coverage of the 46th Annual Meeting of the European
Association for the Study of the Liver
EASL: International Liver Congress Focuses on Hepatitis C Treatment, Metabolic Liver Disease
Lambda-Bristol-Myers Squibb Company
From Medscape Medical News
Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3
Daniel M. Keller, PhD
April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults
with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more
effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV
genotypes 2 or 3. The study is the first report of sustained virologic response
with lambda.
Stefan Zeuzem, MD, professor of medicine and chief of the
Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt,
Germany, who presented the results here at the International Liver Congress
2012, showed data demonstrating that 180 μg of lambda, compared with alfa,
produced a more rapid virologic response and a greater sustained virologic
response at 24 weeks (SVR24), and was associated with fewer adverse events and
less need for a dose reduction of lambda and of the accompanying
ribavirin.
Treatment of chronic HCV with alfa interferons and ribavirin
is limited by hematologic toxicity and other adverse effects. Lambda has marked
activity against HCV and a restricted distribution of receptors in the body,
which could make organ systems outside the liver less susceptible to its
effects.
Dr. Zeuzem and colleagues performed a blinded randomized study
of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age,
118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA
levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily
ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg
(n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus
alfa 180 μg weekly for 24 weeks.
At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years),
sex (range, 52% to 70% male), body mass index
(range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log10 IU/mL).
Most participants were white (range, 76.7% to 89.7%). The proportion of
genotype 2 patients was 41.4% in the 120 μg group,
58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group.
A large majority of patients in each group had low liver fibrosis scores.
Lambda Effective With Fewer Adverse Events Lambda/ribavirin
treatment was associated with an early and rapid drop in HCV RNA in a
dose-dependent manner. After 2 weeks of treatment, the greatest reductions were
seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid
decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going
forward in phase 3 trials.
HCV RNA was undetectable at week 4 in 75.9% of
patients in the 180 μg group and in 30.0% in the alfa group (P <
.05). Complete early virologic response (meaning HVC RNA was detectable at week
4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa,
but the difference was not statistically significance. In the lambda groups,
96.6% of patients achieved a complete early virologic response and 75.9%
achieved SVR24.
With lambda 180 μg, 70.6% of genotype 2 patients achieved
SVR24, as did 83.3% of genotype 3 patients.
Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater
during the follow-up period, were low, at about 21% in the lambda 180 μg
group and about 25% in the alfa group.
Although all groups experienced a high level of adverse events (in the
range of about 95%), some long associated with alfa therapy — "in particular,
flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were
significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in
the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3
lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said,
as were musculoskeletal symptoms (20.7% vs 63.3%).
However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or
insomnia) was greater in the lambda groups than in the alfa group (41.4% vs
33.3%).
There were no discontinuations because of adverse events in the 180
μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there
were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the
alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for
ribavirin.
Serious adverse events affected less than 4% of patients in
the 180 μg and alfa groups. There were no serious adverse events directly
related to treatment in the lambda groups.
It has been reported that lambda causes elevations in serum bilirubin, but in this trial at
the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation
(in the range of 1.6 to 2.5 times the upper limit of normal).
There were no reductions in neutrophil or platelet counts associated with any dose of lambda.
There were drops in both in the alfa group as long as therapy continued. Low hemoglobin
(below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with
alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin
dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in
the 180 μg group; only 6.9% were classified as having low hemoglobin, and none
required a ribavirin dose reduction.
Session moderator George Papatheodoridis, MD, associate professor of medicine
and gastroenterology at the Medical School of Athens University and Hippokration
General Hospital in Greece, and a member of the Governing Board Scientific Committee of
the European Association for the Study of the Liver (EASL), summarized the findings for
Medscape Medical News.
"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but
definitely we can say that the safety profile is better.... The only side effect that was higher, and
we cannot explain that, is the psychiatric side effects," he said.
In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the
use of interferons could be fairly limited in the treatment of HCV in the
future. "I don't know what role interferon lambda may find when and if it gets
licensed. After 2 or 3 years, it is possible that most of the patients will be
treated with interferon-free regimens," he explained.
Mark Thursz, MD,
professor of hepatology in the Department of Medicine at Imperial College,
London, United Kingdom, and secretary general of the EASL, alluded to this point
during a news conference, drawing attention to the safety profile of lambda.
Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a
smaller drop...in the lambda- than in the alfa-treated patients," he said. "More
important are these data on neutrophils and platelets.... You can see no drop in
patients who were treated with the lambda interferon.... For patients who still
need an interferon and in whom problems with cell counts are going to be an
issue, this is a solution."
Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does
not indicate any damage to the liver, but is perhaps the effect of "this interferon on
the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's
a lab finding without major clinical significance."
Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers
Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio
Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis
and Dr. Thursz have disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 10.
Presented April 19, 2012.
Link-
EASL: Interferon Lambda as Effective as Alfa for Hepatitis C but with Much Better Safety Profile
Slides @ NATAP
Peginterferon Lambda-1A (Lambda) Compared With Peginterferon Alfa-2A (Alfa) in Treatment- Naive Patients With HCV Genotypes 2 or 3: First SVR24 Results From EMERGE Phase IIb
EASL Poster
PEGINTERFERON LAMBDA-1a (LAMBDA) COMPARED TO PEGINTERFERON ALFA-2A (ALFA) IN TREATMENT-NAÏVE PATIENTS WITH HCV GENOTYPES (G) 2 or 3: FIRST SVR24 RESULTS FROM EMERGE PHASE IIB
On The Blog
EASL-Peginterferon Lambda Achieved SVR24 Rates Comparable to Peginterferon Alfa with Fewer Side-Effects
Vitamin-D
EASL Poster-Chronic and progressive hepatitis due to genotype 1 HCV-infection modify vitamin-D-metabolism
View Abstract
Variations of vitamin D levels in genotype 1 hepatitis C patients undergoing antiviral therapy correlate with stage of fibrosis but not with treatment outcome
View Abstract
VITAMIN D STATUS IS ASSOCIATED WITH COMPLETE EVR BUT NOT SVR IN CHRONIC
HEPATITIS C GENOTYPE 1 INFECTION: ANALYSIS OF THE AUSTRALASIAN CHARIOT STUDY
COHORT
View Abstract
Fluvastatin with pegylated interferon/ribavirin
EASL Poster - Combination of fluvastatin with pegylated interferon/ribavirin therapy reduces
the viral relapse rate in chronic hepatitis C infected with HCV genotype 1b
View Abstract
Therapeutic vaccine
Promising findings for therapeutic hepatitis C vaccine
TG4040
New and experimental hepatitis C treatment >
Liz Highleyman
Produced in collaboration with hivandhepatitis.com
Published: 09 May 2012
An investigational hepatitis C virus (HCV) therapeutic vaccine significantly
improved the likelihood of sustained response to interferon-based therapy,
according to a proof-of-concept study reported at the
47th International Liver Congress (EASL 2012) last month in Barcelona.
Interferon-based therapy and new direct-acting antiviral agents are not able
to cure all patients with chronic hepatitis C. But the fact that some people
respond very well to therapy - and that some are able to spontaneously clear HCV
without treatment - suggests it may be possible to further boost the natural
immune response to the virus.
Heiner Wedemeyer from Hannover Medical School in Germany and colleagues
conducted a Phase 2 study of TG4040, a therapeutic vaccine being developed by
the French company Transgene that is designed to stimulate immunity against HCV
when combined with interferon. TG4040 is a recombinant vaccinia poxvirus (MVA)
vaccine containing sequences encoding the NS3, NS4, and NS5B proteins from
genotype 1b HCV.
The open-label HCVac trial included 153 treatment-naive genotype 1 chronic
hepatitis C patients; about 80% had subtype 1b. Most were white men and the
average age was about 43 years. Approximately 25% had the favorable IL28B CC
gene pattern associated with good interferon response. About 10% of people who
received TG404 had advanced fibrosis (stage F3), compared with only 1 person in
the standard therapy control group.
Participants were randomly allocated (2:2:1) into 3 treatment arms. All
received standard-of-care (SOC) pegylated interferon alfa-2a (Pegasys) plus
ribavirin for 48 weeks. In addition, the first group received 6 injections of
TG4040 beginning 4 weeks after treatment initiation (SOC lead-in), the second
group started TG4040 12 weeks before beginning pegylated interferon/ribavirin
(TG4040 lead-in), and the control arm did not receive TG4040.
The primary endpoint was complete early virological response (cEVR) 12 weeks
after starting pegylated interferon/ribavirin.
Results
TG4040 alone reduced HCV RNA by > 0.5 log IU/mL in 43% of patients during
the TG4040 lead-in (range 0.5-5.1 log decline).
In an intent-to-treat analysis, complete early virological response rates
(EVR) were 44% in the SOC lead-in arm and 62% in the TG4040 lead-in arm,
compared with 29% in the control arm, a statistically significant
difference.
In an analysis of evaluable patients, corresponding cEVR rates were 46%, 64%,
and 30%, respectively.
In a week 24 intent-to-treat analysis, 67%, 76%, and 65%, respectively,
maintained undetectable viral load.
End-to-treatment response (ETR) rates were 56% in the SOC lead-in arm and 62%
in the TG4040 lead-in arm; evaluation of the TG4040 lead-in group was ongoing,
but all 19 patients evaluated so far were undetectable.
Discontinuation rates were relatively high, 40% in the SOC lead-in arm, 34%
in the TG4040 lead-in arm, and 35% in the control arm, with the most common
reason being virological failure (futility) at week 12 or 24.
Most patients experienced some adverse events, but these were typical of
those seen with interferon. 33% in the SOC lead-in arm and 59% in the TG4040
lead-in arm had adverse events attributed to the vaccine, mainly injection site
swelling or itching.
Seven people (11%) in the SOC lead-in arm, 6 (10%) in the TG4040 lead-in arm,
and 2 (6%) in the control arm stopped due to adverse events.Three vaccine
recipients developed severe thrombocytopenia and 1 developed aplastic
anemia.
"[The] primary objective of the study, improvement of cEVR, [was] reached in
TG4040 lead-in arm," the investigators summarized. "TG4040 pre-vaccination
impacts significantly the slope of viral load decrease after [pegylated
interferon/ribavirin] initiation."
TG404 demonstrated a "good safety profile," but blood toxicity events are
being further studied.
"TG404 as an active immunotherapy should be evaluated in combination with
interferon-free direct-acting antiviral treatment regimens," they
recommended.
"These data are important for TG4040 as they confirm the efficacy profile of
our therapeutic vaccine," Transgene CEO Philippe Archinardin said a company
press release. "As far as we know, they are unheard of for an immunotherapy in
HCV.
Reference
H Wedemeyer, E Janczewska, M Wlodzimierz, et al. Significant improvement
of complete EVR in HCVac phase II clinical trial when adding TG4040 therapeutic
vaccine to PegIFNa2a and ribavirin. 47th International Liver Congress (EASL
2012). Barcelona, April 18-22, 2012. Abstract 1403.
Other source
Transgene SA.Transgene reports positive follow up phase 2 data on its HCV
therapeutic vaccine TG4040. Press release. April 23, 2012.
New Drugs Require New Terms for HCV Virologic Response
New Drugs Require New Terms for HCV Virologic Response
Daniel M. Keller, PhD
Source - Medscape
May 8, 2012 (Barcelona, Spain) — The
development of drugs to treat hepatitis C virus (HCV) is progressing rapidly,
but the terminology to quantify virologic response is lagging. A consortium of
interested organizations is creating nomenclature for virologic responses in
trials of direct-acting antiviral drugs, which are small-molecule inhibitors of
viral enzymes that hold the promise of interferon-free treatment regimens.
During a poster session here at the International
Liver Congress 2012, Donald Jensen, MD, professor of medicine at the University
of Chicago Medical Center in Illinois, presented the rationale for and
principles of the nomenclature being developed by the Hepatitis C Virus Drug
Development Advisory Group (HCV DrAG).
HCV DrAG is a project of the Forum
for Collaborative HIV Research, which has a subgroup devoted to HCV research
with experts from the American Association for the Study of Liver Diseases, the
European Association for the Study of the Liver (EASL), and the Infectious
Diseases Society of America. The forum is a broad consensus panel that includes
industry representatives, members of American and European drug regulatory
agencies, academic investigators, and representatives of advocacy
groups.
Direct-acting antiviral drugs have potent antiviral actions and
appear to produce a more rapid virologic response, with or without interferon,
than interferon-based regimens without the new drugs. More intuitive and
flexible virologic measures are needed that can adapt to these advances in HCV
treatment.
"We wanted to do this before all the new oral therapies hit the
market," Dr. Jensen told Medscape Medical News.
He said current terminology can be confusing when describing virologic response to the new
therapies. "We felt that there was a need to have this description of virologic
responses more consistent across studies — something that could also be used in
manuscripts and in clinical practice," he said. A panel of experts set out to
develop a nomenclature "that was intuitive, that made sense, and that was
descriptive of virologic responses during the course of therapy for hepatitis C."
Considerations for Nomenclature Development Comparisons
between drugs or regimens is difficult or impossible without a common
nomenclature. The propsed nomenclature will assign a description of the time
frame and the level of response to the measures, as opposed to a qualitative
description such as "rapid virologic response."
The proposed terminology for key decision points in treatment trials takes into
account the assay-specific lower limits of quantification of HCV RNA (as opposed to
lower limits of detection), with responses defined as quantifiable or unquantifiable
levels of HCV RNA.
Key components in expressing virologic response are the week of
treatment, the quantifiable decline in viral load from initiation of treatment
(expressed as log10 decline), any lead-in treatment duration (days or weeks),
and whether the target HCV RNA was detected or not.
The panel explains that the lower limit of quantitation (LLOQ) of a
virologic assay should be clearly specified. (One common problem in current
trials is the use of different commercial assay systems.) The target may or may
not be detected at levels below the LLOQ.
HCV viremia at levels less than the LLOQ in trials without a lead-in treatment
period — what has been called a rapid virologic response — would now be W4U,
meaning an unquantifiable HCV RNA level at week 4, whether detectable or undetectable.
The old complete early virologic response will now be W12U, denoting a week 12
unquantifiable HCV RNA level.
For trials with a lead-in (LI) period at, for example, weeks 0 to
4, and unquantifiable levels at week 8 (the old rapid virologic response), the
new nomenclature would specifically refer to it as LI4w-W8U. Each term
would be appended with TD or TND to denote whether target HCV RNA
was detected or not detected.
One holdover from the current system is sustained virologic response (SVR).
"We decided to keep SVR...but it will be sustained virologic response with a bracket after it"
to denote how long the response has been sustained, Dr. Jensen noted. "We're
going to keep [it] because I think that's a concept that will be consistent with
future therapies."
Having a uniform reporting system will allow the comparison of results across
clinical trials. In addition, the system will be able to adapt as virologic response
times become shorter.
Beyond clinical trials, specific terminology will aid in the development of treatment
guidelines for clinical practice.
The panel has submitted a manuscript for publication.
Dr. Jensen hopes that industry will adopt the system for their clinical trials
and that journals will require the system as the accepted nomenclature. The US
Food and Drug Administration and the European Medicines Agency, as part of the
HCV DrAG working group, have stated that they would like the nomenclature to be
adopted.
Dr. Jensen predicts that in the future, if very effective drugs
come along and therapy becomes standardized, many of the current or proposed
measures of virologic response will go by the wayside, and patients will be
treated with a fixed course of therapy with an expectation of cure, as is now
common with antibiotics for many infections.
George Papatheodoridis, MD,
associate professor of medicine and gastroenterology at the Medical School of
Athens University, staff member at Hippokration General Hospital in Athens,
Greece, and member of the EASL Governing Board Scientific Committee, told
Medscape Medical News that he would like to see a consensus terminology
adopted, but he does not expect that it will happen soon.
Nomenclature is not the only problem in defining a response, Dr. Papatheodoridis noted.
He referred to a presentation at the congress in which researchers found a
discrepancy in the viral levels of 28% of the more than 1000 samples tested with
a new polymerase chain reaction (PCR) assay and the original PCR assay. With the
original assay, 75% of samples had undetectable HCV DNA; with the new assay,
only about 50% did. Such a difference might be reflected in the "response-guided
therapy we're using now with the telaprevir or boceprevir combination," he
said.
With the drugs currently in development, the companies decide which
assays to use to report their findings. "All the trials are controlled by the
companies. They are not controlled by us," Dr. Papatheodoridis
explained.
"Another problem, which is very relevant in clinical practice,
is the timing of the HCV RNA determination," Dr. Papatheodoridis explained. We
don't know if a difference of a few days is relevant. If you have some new
excellent drug that achieves a 100% SVR 100%, you don't care, but these are not
yet available.
Mark Thursz, MBBS, MD, professor of hepatology in the
Department of Medicine at Imperial College London, United Kingdom and secretary
general of EASL, agreed that measures of virologic response designed for
interferon-based regimens are inadequate in an era of direct-acting antiviral
drugs, "because the dynamics are much quicker now. A new set of specific targets
are going to be really important when we assess how well the new drugs are
working."
Dr. Jensen, Dr. Papatheodoridis, and Dr. Thursz have
disclosed no relevant financial relationships.
The International Liver
Congress 2012: Abstract 897. Presented April 20, 2012.
http://www.medscape.com/viewarticle/763459
Also See; SVR24-SVR12-SVR4
Spontaneous Clearance
Delaying Treatment in New Cases of Hepatitis C Infection Considered Unnecessary
By Chris Berrie
Source: DGNews
BARCELONA, Spain -- April 25, 2012 -- Early immediate treatment is
highly effective in new cases of hepatitis C virus (HCV) and should not be delayed,
despite the fact that, in a real-life setting, 10% to 50% of new HCV
cases have been observed to clear spontaneously, researchers stated here at
the 47th Annual Meeting of the European Association for the Study of the
Liver (EASL).
Immediate treatment was confirmed as highly effective in both symptomatic
and asymptomatic patients by the HEP-NET Acute HCV-3 Study Group of
Germany.
Delayed treatment to allow for spontaneous HCV RNA clearance
resulted in increased dropout from treatment and should be avoided, as this
provides lower overall response rates, explained investigator Katja
Deterding, MD, Hannover Medical School, Hannover, Germany, speaking here on
April 20.
The primary aim of this study was to compare the efficacy and safety
of immediate pegylated interferon alpha-2b (PEG IFN alpha-2b) treatment for
6 months versus delayed PEG IFN alpha-2b plus ribavirin (RBV) treatment for
6 months in new cases of HCV infection.
Symptomatic patients were randomised to either immediate treatment of PEG
IFN alpha-2b for 24 weeks (n = 55) or PEG IFN alpha-2b/RBV treatment for 24
weeks after a 12-week delay and according to HCV RNA positivity or negativity
(n =52). Asymptomatic patients (n = 25) also underwent immediate treatment
with PEG IFN alpha-2b for 24 weeks.
Randomisation provided 49 patients in the intention-to-treat
(ITT) immediate-treatment population, with 37 reaching sustained virological
response after 24 weeks of follow-up (SVR24), at 76% (37/49). This provided a
completer SVR24 of 90% (37/41) (ie, including the patients who completed the
full treatment), with only 2 viral breakthroughs and 2 relapses.
For asymptomatic patients, the same treatment of 24 patients resulted in an
ITT SVR24 of 75% (18/24), and a completer SVR24 of 95% (18/19), with 1
viral breakthrough. This was not significantly different from the symptomatic
group.
After the 12-week delay, 22 of the remaining 44 patients (50%)
showed spontaneous HCV negativity. Dr. Deterding noted that the factors
associated with these patients were female gender and HCV genotype 1, with no
association with IL28B genotype.
In the following 4-weekly testing, this spontaneous HCV negativity group had
4 patients test positive over the following 36 weeks, 3 of whom
completed treatment and reached SVR. Eleven of the original
delayed-treatment-arm patients with spontaneous SVR provided 21% (11/52)
spontaneous sustained HCV clearance.
For the final 22 patients with delayed treatment, 14 achieved SVR24.
When combined with the 3 SVRs and the spontaneous 11 SVRs, this provided an
ITT SVR24 for the original delayed treatment of 54% (28/52) -- significantly
lower than that for immediate treatment (76%; P =.023). Only 15 of
these delayed and treated patients completed, however, for a completer SVR24
of 93% (14/15) -- not significantly different to that seen with immediate
treatment (90%).
Considering the positive factors associated with spontaneous HCV RNA
clearance, however, Dr. Deterding also noted that, “if adherence can be
assured … delayed treatment might be recommended in particular for women
infected with genotype 1.”
Funding for this study was provided by Merck, Sharp & Dohme (MSD) GmbH, Germany.
[Presentation title: Early Versus Delayed Treatment of Acute Hepatitis C:
The German HEP-NET Acute HCV-3 Study -- A Randomized Trial. Abstract
048]
Link-
EASL Poster-FEMALE SEX AND VARIATIONS IN IL28B ARE INDEPENDENTLY
ASSOCIATED WITH SPONTANEOUS CLEARANCE OF ACUTE HCV INFECTION
View Abstract
Hepatocellular carcinoma
Brivanib did not improve overall liver cancer survival, but did
show anti-tumour activity
Cancer Liz Highleyman |
30 April 2012
The experimental cancer drug brivanib did not lengthen overall survival for
patients with hepatocellular carcinoma, but it did increase time to progression,
demonstrating that it had anti-tumour activity, researchers reported at the
47th ...
Nonalcoholic Fatty Liver Disease Raises Liver Cancer Risk
From Medscape Medical News
Daniel M. Keller, PhD
April 25, 2012
(Barcelona, Spain) — A study with a large multicenter cohort has shown that
nonalcoholic fatty liver disease (NAFLD) is a predisposing factor for
hepatocellular carcinoma (HCC) in the absence of other liver diseases, and
frequently without cirrhosis.
Here at the International Liver Congress 2012, Helen Reeves, BMedSci, BM, PhD,
senior lecturer and honorary consultant gastroenterologist at Newcastle Hospitals
in the United Kingdom, presented evidence that obesity is a worldwide problem
and, as a result, the prevalence of NAFLD is rising.
Dr. Reeves spoke on behalf of the Fatty Liver Inhibition of
Progression consortium, which was formed in January 2010 to address the
problem. A central goal of the consortium is to create an "observatory" of HCC,
NAFLD, and metabolic syndrome to characterize the diseases with high-quality
data and sample collection.
The consortium has been collecting data for 3 years on patients with HCC
and no other liver disease and who imbibe less than 50 g/day of alcohol.
Unless the features of metabolic syndrome or NAFLD were present on liver histology
or ultrasound, cases were considered cryptogenic.
A Minority of Cases Are Cryptogenic
"The fact is that only very few of these patients develop their hepatocellular cancer in the
absence of metabolic syndrome, so just 20 of 221, which is 9%, had no metabolic
risk factor," Dr. Reeves reported. Of the 201 remaining cases, 187 had metabolic
syndrome risk factors, 66 had fatty liver diagnosed on ultrasonography, and 37
had fatty liver diagnosed on liver biopsy.
Alcohol consumption appeared to play a minor role at most.
Fifty-five percent of participants rarely or never drank alcohol, 33% drank moderately
in the past but no longer drink, and only 12% consume alcohol now but not more than 50 g/day.
Mean age at HCC diagnosis was 69 years, almost 4 times as many men as women were
diagnosed, and fatty liver was previously diagnosed in 50% of the cohort. HCC was detected
with scheduled monitoring in 48%; for most of the rest, it was detected with
ultrasound for other reasons or from symptoms.
A single liver nodule was detected in 58% of the cohort, and 75% had preserved
liver function (Child-Pugh grade A). Dr. Reeves said that despite the high prevalence
of preserved liver function, 55% of the participants were graded as Barcelona Clinic
Liver Cancer stage C or D, indicating symptomatic disease at the time of presentation.
"Forty-three percent developed their cancer in the absence
of cirrhosis," Dr. Reeves told the delegates. The ratio of men to women was
similar in those with and without cirrhosis, as was body mass index and the
prevalence of diabetes. Still under analysis are the alcohol and smoking history
of the cohort.
"What was significantly different was the size of the largest
nodule.... [It] was significantly greater in those who did not have cirrhosis,"
she explained (30 vs 48 mm; P < .001). Patients with cirrhosis were
more likely to have encephalopathy at the time of diagnosis than patients
without cirrhosis (12% vs 3%; P = .04), and trended toward more ascites
(33% vs 18%, P = .062).
Only about 10% of the patients received no definitive treatment for their liver cancer
and were referred for best supportive palliative care. For the rest, only a few received
liver transplants, but many received radiofrequency ablation, transarterial chemoembolization,
medical therapy with sorafenib, or other treatment.
Dr. Reeves concluded that NAFLD is a predisposing condition for HCC in the absence of other
liver diseases, and that NAFLD-associated HCC often occurs in the absence of
cirrhosis. She said many of the patients were eligible for potentially curative
therapies, and the consortium will continue to follow this cohort to observe
outcomes.
Mark Thursz, MBBS, MD, secretary general of the European
Association for the Study of the Liver and professor of hepatology in the
Department of Medicine at Imperial College, London, United Kingdom, told
Medscape Medical News that, ironically, there is good news for patients
with hepatitis C, in that several new drugs are coming along. "You can see cures
just around the corner for high proportions of patients. Nonalcoholic fatty
liver is much more difficult to deal with. It's quite difficult to change
people's lifestyles."
He noted that NAFLD is now the leading cause of
liver disease in North America, and will be in Europe before too long. "The fact
that people are developing cancer before they develop cirrhosis — that's a
concern because our current guidelines tell us we should be instituting
surveillance programs for cancer in cirrhotic patients," Dr. Thursz said.
"Extending that into precirrhotic patients is going to be quite challenging to
resources, and the selection of patients is then going to be really
critical."
He said the risk factors for NAFLD are well known and include
abdominal fat, diabetes (or at least insulin resistance), low
high-density-lipoprotein cholesterol, and high low-density-lipoprotein
cholesterol.
"We can't predict with any accuracy which individual patient
has progressive disease, as opposed to pure fat in the liver," he said.
There is no noninvasive way to tell if a patient has pure
steatosis, has fat and inflammation, or has fat, inflammation, and fibrosis.
"It's the latter group that is at risk" for HCC, he warned.
Dr. Thursz and Dr. Reeves have disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 5. Presented April 19,
2012.
Authors and Disclosures
Journalist Daniel M Keller, PhD
Daniel M. Keller is a freelance writer for Medscape.
Daniel M. Keller has no disclosures.
http://www.medscape.com/viewarticle/762632
Short-Term Aramchol Reduces Liver Fat Content Safely in Patients With NAFLD and NASH
By Chris Berrie
Source: DGNews
BARCELONA, Spain -- April 25, 2012 -- Arachidyl amido cholanoic acid
(aramchol) is safe and well tolerated and reduces liver fat content with
short-term treatment in patients with nonalcoholic fatty liver disease
(NAFLD) and nonalcoholic steatohepatitis (NASH), according to a study
presented here at the 47th Annual Meeting of the European Association for the
Study of the Liver (EASL). Aramchol also induces positive trends in several
metabolic parameters.
“Aramchol is a family of about 2,000 different molecules of bile acid and
fatty acids with a very strong amide bond that combines them together,”
explained Allen Baharaff, MA, GalMed Medical Research Ltd., Tel Aviv, Israel,
on April 19. This action stabilises the cholic acid conjugate, protecting the
fatty acid moiety and directing it to the liver bile.
The action of Aramchol is based on partial inhibition of
stearoyl-CoA desaturase 1, a key regulator in lipid metabolism. Aramchol also
upregulates the ABCD1 cholesterol transporter pump. The combination of these
effects reduces adiposity, increases energy expenditure, reduces de novo
hepatic lipogenesis, and improves insulin sensitivity.
To evaluate the safety, tolerability, and short-term effects of aramchol
in adult NAFLD and NASH patients, the researchers randomised 60
biopsy-confirmed patients to daily oral placebo (n = 20) or aramchol 100 mg
(n = 20) or 300 mg (n = 20) over 3 months.
The primary endpoint of this double-blind, placebo-controlled phase 2 trial
was change in liver fat concentration, as determined by nuclear magnetic
resonance spectroscopy.
The researchers found that the placebo increase of 6.4% was reversed
by aramchol 100 mg, for a nonsignificant 2.9% reduction, and reached
significance (P =.02) for aramchol 300 mg, at a 12.6% reduction.
Similarly, as a marker for these conditions, the serum adiponectin
levels showed a trend (P =.09) from reductions with placebo and
aramchol 100 mg (0.7 vs 0.3 µg/mL) to an increase with aramchol 300 mg (0.2
µg /mL).
Baharaff also noted a trend for improved endothelial function (placebo,
33.6%; aramchol 100 mg, 24.4%; aramchol 300 mg, 62.9%) and parallel
reductions in liver alanine transaminase between placebo and aramchol.
“None of these effects were due to changes in weight,” he added.
In the safety analysis, no treatment-related severe adverse events were
seen throughout the treatments and the recovery period. The adverse-events
profiles were also similar across the treatment groups, with no patients
discontinuing because of adverse events.
The researchers concluded that, in addition to showing reduced liver
fat content, the higher aramchol dose provided positive trends in several
metabolic parameters. Baharaff indicated the need for further evaluation of
aramchol in future clinical trials, potentially also at increased doses.
Funding for this study was provided by GalMed Medical Research Ltd.
[Presentation title: A Phase II, Randomized, Double-Blind,
Placebo-Controlled Trial of Aramchol for the Treatment of
Non-alcoholic Fatty Liver Disease (NAFLD & NASH). Abstract
1418]
Guidelines
EASL:New Clinical Practice Guideline on Alcoholic Liver Disease Published
2012-New guidelines on the management of hepatocellular carcinoma (HCC).
EASL-April 2012 Revised Clinical Practice Guidelines on the Management of Chronic Hepatitis B
Press release for the International Liver Congress 2012, Barcelona
Documents to download
Childhood Obesity Increases HCC
Gut Microbiota Transplantation
EU Burden of Liver Disease
Difficult to treat HCV and response guided
IFN-free therapy and IFN-Lambda
CPG Press Release
Off The Cuff
From Seeking Alpha
Headlines
5 Biotech Stocks That Could Soar On New Hepatitis C Drugs
-Vertex, Abbott, Achillion, Johnson & Johnson and GlaxoSmithKline
The Street
Headlines
Bristol-Myers Missing Hep C Data Raises Red Flags, May Boost Gilead, Idenix
Gilead, Bristol Put Profits Ahead of Best Care for Hep C Patients
Gilead, Bristol Hep C Drug Data Arrives at EASL
New York Times
Headlines
Collaboration on Hepatitis Drugs Lags
The Motley Fool
Celebrate the Hep C Wins, for Now
Seeking Alpha
Gilead's Hepatitis C Drug Poised To Reach The Market As One Of The First 'All Oral' Combinations
The Street
Grading Hep C Stocks Exiting EASL-The future of hepatitis C therapy belongs to interferon-free regimens.
Achillion shares fall on doubts over hep-C drug
EASL Coverage
Aug 2012
2012 EASL-Three Hepatology experts comment on hepatitis C abstracts
April 2012
2012 EASL On Demand Internet Symposium
This Internet symposium will review and discuss the key studies on chronic
hepatitis C management and treatment presented at EASL. The symposium will
feature four well-known and recognized thought leaders in the HCV field, with
three serving as presenting faculty/discussants and one as program
moderator.
2012 Annual Meeting of the European Association for the Study of the Liver*
April 18-22, 2012 | Barcelona, Spain
*CCO is an independent medical education company
that provides state-of-the-art medical information to healthcare professionals
through conference coverage and other educational programs.
*Free registration required
Click here to register
Coverage @ NATAP
Coverage @HIV and Hepatitis