HCV Advocate EASL 2009 Coverage
Debiopharm Presents Promising Phase IIa Results Showing Potent Antiviral Activity
The phase IIa study investigated the efficacy and safety of Debio 025 in combination with Peg interferon alpha 2a (peg-IFN alpha-2a) and ribavirin in previously null-responder genotype 1 HCV patients. Results demonstrated that Debio 025 at doses of 400 mg (with initial loading) and 800 mg daily for 29 days shows a statistically significant reduction of HCV RNA of respectively -1.96 log (-98.9%) and -2.38 log (-99.5%) when co-administered with Peg-IFN alpha-2a and ribavirin in previous null responders.
"These results in patients who are highly unlikely to respond to re-treatment with an interferon-based regimen, are very important to us, as they confirm that Debio 025 is a potent anti-HCV agent," said Rolland-Yves Mauvernay, President and Founder of Debiopharm Group. "We are making it our mission to find a cure for this widely spread and life threatening disease and these findings bring us one step closer to our goal."
About the phase IIa triple therapy study
Debiopharm investigated different dosing regimens of Debio 025 in combination with peg-IFNÃ¿Â±2a at 180 micrograms/week and ribavirin at 1000/1200 mg/day in genotype 1 chronic HCV patients that were previously null responders (< 2 log10 HCV-RNA reduction after 12 weeks with peg-IFN(alpha) 2a and ribavirin). Fifty patients were randomised in an open phase IIa study to receive one of five treatment regimens for 29 days. Afterwards patients continued treatment on Peg-IFN alpha-2a and Ribavirin. A loading dose of Debio 025 at the start of treatment accelerates the onset of action and enhances efficacy in the early stage of treatment.
About Debio 025
Debio 025 is a synthetic first-in-class Cyp inhibitor, being tested in humans as a potential anti-HCV drug. Debio 025 binds strongly to Cyp, host cell proteins thought to confer a replication advantage to HCV. Its potent inhibitory activity on the HCV replication was shown in the following clinical studies. Results of a phase Ib study demonstrate that Debio 025 monotherapy for 15 days induced a strong anti-HCV effect (3.6 log10 reduction) in HIV-1/HCV co-infected patients. (Hepatology, 47:817-26). Results of a phase IIa study with Debio 025 indicate that Debio 025 shows an important additive anti-HCV effect (4.6 log10 reduction) when co-administered with peg-IFN(alpha)2a to treatment-naive HCV patients. (Hepatology, in press)
Inc., a privately held biopharmaceutical company, announced that data from its
phase 2 study of AST-120 for the
treatment of patients with low-grade hepatic encephalopathy was presented April
25th at the 44th Annual Meeting of the European Association for the Study of
Liver Disease (EASL) in
The phase 2a study randomly assigned 47 patients with West Haven Scale (WHS) Grade 1-2 hepatic encephalopathy to 4 weeks of treatment with either AST-120 2g sachets (A) QID or lactulose (L) titrated to bowel movements. Forty-one patients were evaluable (n=21 A, 20 L) and 6 were excluded (n=3 L: non-compliance, n=3 A: other causes). Treatment response by WHS at Week 4 was similar between treatment groups (38.1% vs. 35.0%, A vs. L). AST-120 also produced an improvement in neurocognitive measures. A statistically significant reduction in pruritus, a secondary endpoint of the trial, was seen with AST-120 compared to lactulose. Adverse events related to diarrhea (p = 0.04) and flatulence (p = 0.02) were significantly less in patients treated with AST-120.
The improvement seen in neurocognitive measures is consistent with reports that neuropsychometric testing is required to truly measure deficits and detect changes in neurocognitive functioning in the MHE patient population.
"Patients with mild hepatic encephalopathy often don't comply with lactulose therapy because of the side effects," said Paul Pockros, M.D., division head of gastroenterology and hepatology at Scripps Clinic and the principal investigator of the study. "A safe, easily tolerated alternative such as AST-120 would be of great benefit in the management of these patients."
The ASTUTE Trial ("AST-120 Use for the Treatment of Hepatic Encephalopathy") is a Phase 2 multi-site, randomized, double-blind, placebo-controlled 8-week study in up to 150 patients with MHE. Patients will be evaluated on neurocognitive improvement at the end of the study, defined as the change in the global summary score of the RBANS or Repeatable Battery for the Assessment of Neuropsychological Status.
"The ASTUTE trial will use a battery of neuropsychometric tests to assess the efficacy of AST-120 in an MHE population," said Scott Harris, M.D., Ocera's chief medical officer, "Up to 60 percent of patients with cirrhosis have MHE and impaired neurocognitive function, a condition for which no drugs are approved."
AST-120 is a novel
microspherical carbon adsorbent with a selective adsorption profile for a
variety of unwanted substances in the digestive tract. These substances may be
responsible for a number of conditions, including Hepatic Encephalopathy (HE),
Irritable Bowel Syndrome (IBS), and pouchitis. They include ammonia, indoles
(serotonin, octopamine), histamine, secondary bile acids, advanced glycation
About Ocera Therapeutics, Inc.
Source: Ocera Therapeutics, Inc
April 28, 2009
(Copenhagen, Denmark) — Using a novel combination strategy — vaccination of
infants born to women infected with hepatitis B virus (HBV) who had high levels
The strategy was
developed by Robert de Man, MD, PhD, associate professor from the Department of
Gastroenterology and Hepatology,
HBV is most prevalent
The child is also at
risk. Pregnant women who are hepatitis B e antigen (HBeAg)–positive have a high
chance of transmitting HBV to the baby during birth. Most cases of HBV
mother-to-child transmission are controlled with a combination of active and
passive immunization of the baby. But children born to
mothers who are highly viremic for HBV (HBeAg-positive) have a 32% chance of
becoming infected during birth, despite prophylactic vaccination and hepatitis
B immunoglobulin. Data suggest that this occurs if maternal HBV
"Most babies receive HBV perinatally, but without any treatment around 70% to 90% of babies will become infected if the mother has a heavy viral load," Dr. de Man told Medscape Gastroenterology. He continued: "90% of these HBV-infected children will develop chronic HBV disease without intervention. This high chance of infection contributes to the continuing reservoir of ongoing disease. It is therefore essential to interrupt transmission at birth to lower total disease burden."
The study data show
that infants born to women with high levels of HBV
"The study results show that [the] 39% vaccination failure rate [is reduced] to 18% using this strategy. There is a clear group that benefits from this treatment," added Dr. de Man.
He emphasized that it is not clear whether maternal use of antiviral therapy is safe during pregnancy. Dr. de Man explained that despite limited data, a hepatic flare during pregnancy is dangerous for mother and child and that antiviral therapy in this setting is the outcome of a physician–patient decision made using the best information available.
There is no effective
treatment for hepatitis B in either adults or children, so prevention of
infection is essential. Deirdre Kelly, MD, professor of pediatric hepatology
Dr. Kelly believes that effective antenatal screening is essential to identify at-risk women who need active support and management during pregnancy.
"In mothers who
have high levels of HBV
Dr. de Man also drew attention to the need to assess the status of liver disease in pregnant women. The woman becomes tolerant or there is no worsening of liver disease in the majority of women during pregnancy. Liver enzymes frequently normalize, he said.
However, postpartum, liver disease in the mother often becomes more active, with alanine aminotransferase levels flaring after delivery in around 40% of patients. He stressed the importance of monitoring the mother as well as the child. "The message is that all countries have screening programs at 12 to 16 weeks to detect hepatitis B in the mother and to be able to vaccinate the baby, but it is essential not to forget to evaluate the extent of the liver disease in the mother at 3 months after delivery. Many of these mothers are lost to care," Dr. de Man explained.
Dr. de Man and Dr. Kelly have disclosed no relevant financial relationships.
European Association for the Study of the Liver 44th
Annual Meeting: Symposium 7. Presented
"Physicians are constantly looking for ways to improve hepatitis C treatment outcomes by increasing response rates or reducing side effects and making treatment more tolerable for their patients," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "We undertook these large PEGINTRON studies to help investigators address these important clinical issues. Conducting these studies demonstrates Schering-Plough's longstanding commitment to investigating potential new treatment strategies for patients with hepatitis C."
Combination therapy with peginterferon and ribavirin is a recognized standard of care worldwide for treating chronic hepatitis C virus (HCV) infection. Patients with HCV genotype 1, the most common and hardest to treat form of hepatitis C, are typically treated for 48 weeks, while patients with HCV genotypes 2 or 3 are treated for 24 weeks.
The aim of the three PEGINTRON studies was to evaluate investigational regimens in these patient populations compared to current standard practice.
PEGINTRON Maintenance Therapy in Cirrhotic (Metavir
F4) HCV Patients Who Failed to Respond to Interferon/Ribavirin (IR) Therapy:
Final Results of the
In the primary efficacy analysis, 36 patients in the control arm and 27 in the treatment arm had clinical events (P=0.14), a non-statistically significant difference. However, in the secondary efficacy analysis there were 87 clinical events in the control arm and 63 in the treatment arm (P=0.01), a statistically significant difference. The main events causing the difference on secondary analysis were emergence or enlargement of varices (43 control vs. 16 treatment). In patients with pre-existing esophageal varices (n=82) there were significantly more events (n=14) in the observation arm compared to the treatment arm (n=4) (P=0.01). Overall the safety profile for PEGINTRON was similar to that in previous studies; however, there were more serious infections in the treatment group (25 vs. 3), although these were not linked to neutropenia. None were unexpected events, nor was there a pattern to them.
In the primary analysis, PEGINTRON maintenance therapy was not superior to observational control in preventing the occurrence of clinical events. However, there was a statistically significant reduction in clinical events of hepatic decompensation on protocol-defined secondary analysis as well as in subjects with pre-existing esophageal varices.
Extended Treatment Duration in Chronic Hepatitis C Genotype 1-Infected Slow Responders: Final Results of the SUCCESS Study(2)
The primary objective of the SUCCESS study was to evaluate the effect of extending treatment duration to 72 weeks with PEGINTRON and REBETOL(R) (ribavirin, USP) combination therapy in genotype 1-infected patients who have slow response to therapy, defined as having detectable virus (HCV RNA) with at least a 2 log10 reduction in viral load at treatment week 12 and undetectable virus at treatment week 24. In this large, prospective, randomized, multinational clinical trial, slow responders were randomized at treatment week 36 to receive PEGINTRON combination therapy for a total of 48 weeks (n=86) (standard approved duration) or 72 weeks (n=73). Patients with undetectable virus at week 12 (complete early virologic response), received treatment for 48 weeks (n=816), whereas patients who did not respond to treatment (less than a 2 log10 reduction in viral load at week 12) were discontinued from the study. In total, 1,419 patients were treated.
In this study,
sustained virologic response (
Reduced Dose and Duration of Peginterferon Alfa-2b + Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial)(4)
treatment of patients chronically infected with HCV genotype 2 or 3 (G2/3) with
peginterferon and ribavirin has been largely unsuccessful compared with
standard-duration treatment (24 weeks). The implications of a reduced
peginterferon dose in G2/3 patients were unknown. The primary objective of the
REDD 2/3 study was to evaluate the effect of reduced treatment duration or a
reduced PEGINTRON dose on
Eligible patients were
randomized to one of three arms: (A) PEGINTRON (1.5
mcg/kg/wk) for 24 weeks (approved dose), (B) PEGINTRON (1.0 mcg/kg/wk)
for 24 weeks (low dose) or (C) PEGINTRON (1.5 mcg/kg/wk) for 16 weeks (short
duration), each in combination with weight-based REBETOL (800-1200 mg/day).
Co-primary end points were non-inferiority between arms A and B and A and C.
1. Bruix J, Poynard T,
et al. PEGINTRON Maintenance Therapy in Cirrhotic (Metavir F4) HCV Patients Who
Failed to Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the
2. Buti M, Esteban R,
et al. Extended Treatment Duration in Chronic Hepatitis C Genotype 1-Infected
Slow-Responders: Final Results of the SUCCESS Study. Oral presentation at: 44th
annual meeting of the European Association for the Study of the Liver (EASL);
4. Manns M, Zeuzem S,
et al. Reduced Dose and Duration of Peginterferon Alfa-2b + Weight-Based
Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients
(REDD 2/3 Trial). Oral presentation at: 44th European Association for the Study
of the Liver (EASL); April 22-26,
Source: Schering Plough Corporation
- With half as many injections, in two pivotal Phase 3 trials, Albuferon (albinterferon alfa-2b) met the primary efficacy endpoint of sustained virologic response comparable to Pegasys (peginterferon alfa-2a) -
- Patients receiving 900-mcg Albuferon had comparable rates of serious and/or severe adverse events across the two Phase 3 trials, versus peginterferon alfa-2a -
- Submission of global marketing applications planned in fall 2009 -
ROCKVILLE, Md., April 25
/PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. (Nasdaq:
"The Phase 3 data presented at EASL show that Albuferon, with half the injections, achieved a rate of sustained virologic response comparable to Pegasys," said David C. Stump, M.D., Executive Vice President, Research and Development, HGS. "Importantly, the rates of serious and/or severe adverse events were also comparable in these studies.
SOURCE Human Genome Sciences, Inc.
Association of the Study of Liver Disease wrapped up on Sunday in
The companies called the INFORM-1 study "ground breaking" and rightly so in that this trial was the first time that two oral drugs -- both of which stop the hepatitis C virus from replicating itself, albeit in different ways -- were shown to be safe and effective in lowering viral loads in patients when taken in combination.
However, the viral load
reductions and number of patients with undetectable levels of virus achieved by
various dose combinations of
The INFORM-1 study is a
solid proof of concept that an all-oral combination therapy for hepatitis C is
possible, but Roche, InterMune and Pharmasset are going to have to show that
higher doses of the drugs, especially of InterMune's
Vertex had a fairly
quiet EASL conference, mainly because telaprevir is in the middle of phase
This data keeps telaprevir ahead of its hepatitis C rivals because no other drug has yet shown the ability to improve the cure rates for both patients new to therapy as well as those who have failed prior therapy.
Telaprevir was the "butt" of some negative EASL chatter due to an anecdotal report that the drug was causing severe anal itching in patient(s). One EASL attendee described the side effect as "fire in the hole."
All jokes aside, itchy rash is a well-known and documented side effect of telaprevir, but there have been no confirmed reports of anal pruritis (the medical term for anal itching) in any of the telaprevir studies presented to date. In fact, patient discontinuation rates due to telaprevir-induced rash appear to be on the decline, as doctors and patients learn how to better manage the side effect.
This should lead to
higher cure rates for telaprevir in the ongoing phase
Pharmaceuticals'(ANDS Quote) share price has not yet recovered from the
emergence last week of a rash associated with its experimental drug
However, Anadys only
has another quarter or two of cash left and doesn't have enough money on hand
to begin the next round of
J&J, Merck and
The other challengers
to telaprevir also presented new data at the EASL conference, but none seemed
ready yet for a full fight. Johnson & Johnson's(
By Cameron Johnston
COPENHAGEN, Denmark --
April 25, 2009 -- The addition of octreotide to sorafenib may offer a
synergistic benefit for patients with advanced hepatic cell carcinoma (
According to the investigators, who presented their findings on April 24, the combination therapy could represent a much-needed weapon for treating this select, and difficult to treat, population.
"Octreotide has been
used previously as monotherapy in patients with
Originally, 87 patients
The data presented at the poster presentation covered the first 43 patients, although more than 50 have now been evaluated. The patient cohort included 28 with hepatitis C, 10 with hepatitis B, and 1 with both B and C type disease. Four had disease of unknown etiology.
Patients were treated with sorafenib 800 mg/day for 28 days continuous dosing, followed by 1 week of rest. Octreotide 40 mg was introduced on day 10 of the cycle and given every month thereafter.
The analysis showed 1 partial response (2.3%), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, but Dr. Montella said this would be higher if the EASL criteria were used.
There were 32 cases of stable disease (74%) and 11 cases of progressive disease (23.7%). Median time to progression was 7.0 months (95% confidence interval [CI], 3.0-10.9 months).
Overall survival, at the time of the analysis was 9.9 months (95% CI, 8.2-11.6 months), but Dr. Montella said this has now increased to more than 10 months with 95% confidence intervals ranging from 8.2-17.0 months.
The most common adverse event was diarrhoea, which occurred in 27.9% of patients (4.6% grade 3). Hand-foot syndrome occurred in 9.3% of patients, and hypertension, abdominal pain, and rectal bleeding occurred in 6.9% of patients.
"I personally think that in this select group of liver cancer patients, octreotide can be a very useful drug," concluded Dr. Montella. "We can combine these 2 drugs together to produce some very interesting results in this population of patients."
[Presentation title: Sorafenib Plus Octreotide in Advanced Hepatocellular Carcinoma: Updated Results of a Multicenter Study. Poster 785]
viral response (
In this intent-to-treat
analysis, 51% and 52% of treatment-failure patients achieved
treated patients who didn’t achieve
PROVE 3 was a
randomized, double-blind, placebo-controlled Phase 2b study that enrolled
patients who failed prior treatment with peg-IFN and
A summary of available on-treatment and post-treatment antiviral data from the 24-week telaprevir-based regimen compared to the 48-week standard of care regimen is presented below:
PROVE 3 Sustained Viral Response rates; intent-to-treat analysis
 Non-responders are defined as patients who never achieved undetectable HCV RNA during or at the end of prior therapy.
 Relapsers are defined as patients who achieved undetectable HCV RNA at the completion of prior treatment, but relapsed during follow-up.
 Breakthroughs are defined as patients who had undetectable HCV RNA during prior treatment, but had detectable HCV RNA before the end of prior treatment.
Sixty-nine and 76% of
prior relapsers in the 24- and 48-week telaprevir-based treatment arms,
In PROVE 3, an overall
relapse rate of 13% (10 of 76 patients) was observed in patients in the 48-week
telaprevir-based treatment regimen arm, while patients in the control arm
relapsed at a rate of 53% (18 of 34 patients). A third arm of the study,
evaluating a 24-week telaprevir-based regimen, showed a similar
Safety and Tolerability in PROVE 3
In PROVE 3, adverse
events were generally consistent with those reported in prior Phase 2 telaprevir
trials including fatigue, nausea, headache, rash, pruritus, diarrhea, insomnia,
pyrexia, alopecia, and chills. In the PROVE 3 telaprevir treatment arms, rash
led to discontinuations in 5% of patients (17 of 339) and was manageable and
reversible upon cessation of treatment. A 1% discontinuation rate due to anemia
(3 of 339) was observed which was similar to that in the control arm.
Erythropoiesis stimulating agents (
Telaprevir (VX-950) is an investigational oral inhibitor of HCV protease, an enzyme essential for viral replication, and is one of the most advanced investigational antiviral agents in development that specifically targets HCV. Telaprevir is in Phase 3 clinical trials in treatment-naive and treatment-failure patients.
commercial rights to telaprevir in
Yttrium-90 (Y-90) glass microspheres is a safe and effective treatment for
patients with advanced
According to the
researchers, these findings create the foundation for a trial comparing and
combining radioembolisation with multi-targeted kinase inhibitor, sorafenib.
This would represent a new treatment option for sufferers of advanced
The aim of this
open-label phase II study was to evaluate the safety and efficacy of
radioembolisation in a European cohort of patients with locally advanced
Professor Guido Gerken,
Head of Department of Hepatology and Gastroenterology,
From November 2006 to
August 2008, researchers in this study assessed 71 patients with advanced
51/71 patients had a
follow-up of at least six months. 52/71 patients had liver cirrhosis. 7.30% of
the patients had portal vein thrombosis before therapy. Partial response rate
was detected in 52%. With consideration of necrosis (EASL criteria) partial
response was 80%. During the limited follow up, 2/70 patients died within the
first month after therapy. 11/70 patients died within at least 6 months after
therapy. Time to progression (
Source: Camilla Dormer, European Association for the Study of the Liver
- Combination of R7227, protease inhibitor, and R7128, nucleoside polymerase inhibitor, shows significant potency in reducing viral load in patients with hepatitis C
Roche, InterMune, Inc.
Results of the INFORM-1
study were presented today during the late-breaker session at the 44th Annual
Meeting of the European Association for the Study of the Liver (EASL) in
The trial, conducted in
Further studies will
test the activity and safety of the combination of R7227 and R7128 with and
without interferon and/or ribavirin. The current standard of care for HCV is a
combination of pegylated interferon plus ribavirin, which delivers overall
sustained virologic response rates (
exciting times in our fight against hepatitis C, and the investigation of the
innovative oral treatment regimen in INFORM-1, if validated in further study,
may radically change future treatment strategies in our patients with chronic
HCV infection," said Edward Gane, M.D., Associate Professor,
INFORM-1 Results in Brief
INFORM-1 is a randomized, double-blind, ascending dose Phase I trial which has enrolled a total of 57 patients.
Patients receiving the combination of R7227 and R7128 for 14 days -- without pegylated interferon or ribavirin -- experienced a median reduction in viral levels of -4.8 to -5.2 log(10) IU/mL in the highest doses tested. The addition of R7128 to R7227 resulted in sustained viral load reductions over the dosing period, with aproximately 63 percent of patients experiencing a decrease in viral levels below the quantification limit of the diagnostic assay (less than 40 IU/mL). Furthermore, 25 percent of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) after 14 days.
In the early low-dose groups, after only three days of dosing, the mean reduction in viral load levels was 0.6 log(10) IU/mL greater with combination treatment (-2.9), compared to the performance of the individual compounds when administered as a single agent (-0.46 and -1.84 for R7128 and R7227, respectively). This suggests an additive effect for the combination.
No treatment-related serious adverse events (SAEs), no dose reductions and no discontinuations were reported in the study. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
Next Steps in the Development Program
The companies are now
exploring twice-daily dosing of R7227 and higher total daily doses (600 mg twice-daily
and 900 mg twice-daily) than those explored in the first patient cohorts of
INFORM-1. The companies also plan to explore the innovative DAA combination
therapy in "treatment-experienced" patients with HCV, or those who
did not achieve
Other Clinical Studies with R7227 and R7128
In addition to clinical studies of combination DAA regimens such as those studied in INFORM-1, R7227 and R7128 each are proceeding rapidly in development in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin). A Phase IIb study with R7128 has now begun, while a Phase IIb study with R7227 is slated to begin in the summer.
Dial-In and Webcast Details
InterMune and Pharmasset
will host a live webcast of a discussion of the INFORM-1 results from the EASL
Among the highlights of his presentation, Dr. Zeuzem reported:
antiviral activity was observed in both the q8h and q12h dosing cohorts; the
most rapid declines in HCV RNA occurred in the
Viral rebound was
not observed in any patient receiving treatment with
support the continued evaluation of
Dr. Zeuzem, protocol
chair of the study, said, "Based on the totality of the viral kinetic
data, the q12h and q8h regimens delivered very convincing results and appeared
to perform very comparably in this 14-day study. The safety and tolerability
InterMune noted that a
Phase 2b triple combination trial of
Steven Porter, M.D.,
Ph.D., Chief Medical Officer of InterMune, said, "The Phase 1b triple
combination study was designed to inform the dose selection and study design of
Viral Kinetic Performance
After 14 days of triple
combination therapy, the median change in HCV RNA from baseline exceeded 5 logs
in five of the six cohorts and was -5.4 log and -5.7 log in the best performing
q12h and q8h cohorts, respectively. Considering all cohorts, HCV RNA was below
the limit of quantification in nearly three-quarters (71%, or 32 of 45) of
patients who received treatment with
Safety and Tolerability Profile
Only four Grade 3 AEs
were reported during study treatment, two of which (sciatica and back pain)
were deemed by the investigator to be unrelated to
Phase 1b Triple Combination Trial Design
The Phase 1b
randomized, double-blind, placebo-controlled, 14-day triple combination study
was conducted in treatment-naive patients chronically infected with HCV
genotype 1. The study objectives were to assess the safety, pharmacokinetic and
viral kinetic effects of various doses and regimens of
In November 2008,
Roche, InterMune and Pharmasset initiated the first all-oral combination study
of direct-acting antivirals (DAAs) in the absence of interferon or ribavirin,
known as the INFORM-1 study. Interim results from the INFORM-1 study will be presented
in an oral late-breaker session of the EASL meeting on
InterMune is a
biotechnology company focused on the research, development and
commercialization of innovative therapies in pulmonology and hepatology.
InterMune has an R&D portfolio addressing idiopathic pulmonary fibrosis
(IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio
includes pirfenidone for which a Phase 3 program in patients with IPF
(CAPACITY) has been completed and the compound is currently in the
pre-registration stage. The company also has a research program focused on a
pirfenidone analog named
Source: InterMune, Inc
By Michael Smith, North American Correspondent, MedPage Today
Reviewed by Robert
Jasmer, MD; Associate Clinical Professor of Medicine,
TORONTO, April 24 -- People with HIV do just as well as others after a liver transplant -- as long as they don't have hepatitis C as well, researchers said in Copenhagen.
In one of the few
studies with data on long-term outcomes, those with HIV had one- and five-year
survival rates of 86.5% and 74% respectively, according to John O'Grady, M.D.,
By comparison, HIV-negative liver transplant patients in the prospective UK Transplant Database had rates of 87.1% and 78%, which were not significantly different, Dr. O'Grady reported at the annual meeting of the European Association for the Study of the Liver.
"In terms of HIV, the clinical guidance is that theses patients do very well, (and) they should be considered for transplant in the normal way," he said. "They don't present any particular different clinical problem than the general liver transplant population."
On the other hand, he said, patients with both HIV and hepatitis C are a significantly greater challenge.
"They need to be counseled that severe recurrence of hepatitis may be a problem after the transplant," he said, adding that he and other specialists are anxiously awaiting new medications.
"We are desperate to get the newer agents, evolving agents, tested in this population at an early stage, because they have clearly an urgent need for drugs to control hepatitis C replication," Dr. O'Grady said.
Dr. O'Grady and his
colleagues analyzed outcomes of all patients having a liver transplant in the
The database includes 33 people with HIV, 847 with hepatitis C, and 5,435 HIV-negative patients. Of the HIV-positive patients, 22 also had hepatitis C.
The researchers compared patients with both HIV and hepatitis C, those with HIV, and those with hepatitis C only.
The analysis found that:
· Model for End Stage Liver Disease (MELD) scores were comparable between the three groups.
· Patients with both viruses lived, on average, for 29 months post-transplant, compared with 47.7 months for those with hepatitis C only, a difference that was significant at P=0.04.
· One- and five-year survival rates were 73% and 53% for those with both diseases, compared with 100% and 100% for those with just HIV, and 87% and 69% for those with just hepatitis C. The differences were significant at P=0.04.
Interestingly, despite the promising one- and five-year survival rates, patients with HIV had a mean post-transplant survival rate of 44 months compared with 57.1 months for HIV-negative patients, a difference that was significant at P=0.0001.
Dr. O'Grady said that difference is probably an artifact of the changing face of HIV -- the analysis included only a few patients transplanted early in the HIV pandemic, who tended to do very poorly.
In a univariate analysis, hepatitis C infection was a significant predictor of death after transplant in HIV-positive patients, with an odds ratio of 10 and a 95% confidence interval from 1.03 to 97.04.
But in a multivariate logistic regression model, the effect of hepatitis C was not independent of other covariates, such as MELD score and recipient and donor ages.
The researchers did not report study support or conflicts.
Joshi D, et al "
The study data will be
presented in a poster presentation tomorrow by Eric Lawitz, M.D., of
"We were pleased to see a 94 percent EVR rate in the treatment naïve patient population," said Dr. Lawitz, the study's lead author. "We believe that this increase in EVR over standard of care alone may indicate that the GI-5005 mechanism of action is complementary to the current standard care."
analyses of serum fibrosis (Fibrotest) and necrosis (Actitest) markers showed a
two-fold improvement in the proportion of patients with improved serum
Fibrotest, and a fifty percent reduction in the number of patients with
worsening Fibrotest scores after 24 weeks in the group receiving the triple
therapy. At the 24 week time point, the triple therapy improved serum Actitest
scores by up to 14 percent in treatment naïve patients when compared to
"We believe that
the improvement in
The GI-5005-02 clinical trial is a randomized, multi-center, Phase 2 study evaluating 140 patients, all with genotype 1 HCV infection. In the trial, 74 percent of patients had never received prior treatment, and the remaining 26 percent had failed prior treatment.
GlobeImmune Inc. is a private company developing targeted molecular immunogens, Tarmogens, for the treatment of cancer and infectious diseases. The company's lead product candidate, GI-5005, is a Tarmogen for the treatment of chronic hepatitis C infection (HCV). GI-5005 is designed to complement both the current standard of care and emerging novel therapies for HCV. The company's lead oncology program, GI-4000, targets cancers caused by mutated versions of the Ras oncoprotein. GI-4000 is being investigated in clinical trials for the treatment of pancreas cancer as well as other cancers that contain mutated Ras, including non-small cell lung cancer and colorectal cancer.
Data were presented from
the phase IIa trial (OPERA-1) for TMC435
at the ongoing 44th Annual Meeting of the European Association for the Study of
the Liver (EASL) in
TMC435 is an investigational protease inhibitor, being developed by Tibotec in collaboration with Medivir (STO:MVIRB), for the treatment of hepatitis C virus (HCV).
Data for TMC435 in treatment naïve genotype-1 HCV patients have been presented in an oral lecture. Furthermore, data in patients with genotype-1 HCV infection who failed previous IFN-based therapy were presented during a late breaker poster session.
TMC435 in treatment-naïve genotype-1 HCV patients
The results from 25, 75 and 200 mg in treatment-naive patients are summarized below:
1. Viral load reduction, (RNA log10 IU/mL), at week 4 on triple therapy groups (SoC and TMC435) was 5.5 and 5.4 log10 IU/mL for the 75 mg and 200 mg TMC435, QD respectively.
2. Undetectable levels (< 10 IU/mL) in 8/9 patients in the 75 mg group and 7/10 in the 200 mg group was observed after 4 weeks of treatment with triple therapy.
weeks (4 weeks triple + 8 weeks SoC), 6/9, 9/9 and 10/10 had undetectable virus (< 10 IU/mL) in the 25mg, 75 and 200 mg groups, respectively.
4. No breakthroughs observed after 4 weeks of triple therapy in any of the groups (25, 75 or 200 mg).
5. No treatment related discontinuations, most AEs were mild to moderate.
6. No evidence of TMC related hepatic, renal, CV or blood (haematopoietic) adverse events.
7. Mild and reversible increases in bilirubin observed in highest dose groups (200 mg).
8. Substantial decreases of liver transaminases were observed.
TMC435 in patients that failed previous IFN-based treatment
The results from 75, 150 and 200mg are summarized below:
1. Potent, dose-dependent, antiviral activity after 4 weeks treatment with triple therapy with 4.3, 5.5 and 5.3 log 10 IU/mL reduction for 75, 150 and 200 mg QD groups, respectively, compared to 1.5 in the placebo group
2. Three viral breakthroughs were observed in prior non-responders with G1b, 2 in 75 mg and 1 in the 150 mg QD group.
3. At Day 28, 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients achieved plasma HCV RNA levels <25 IU/mL in the 75, 150 and 200 mg QD treatment groups, respectively, compared with no patients (0/9) in the placebo group
4. 2/9 (22%), 5/9 (56%) and 3/10 (30%) patients in 75, 150 and the 200 mg groups reached undetectable levels (< 10 IU/mL) after 4 weeks of treatment, compared to 0/9 patients on placebo.
5. There were no serious adverse events and no treatment discontinuations due to adverse events, which generally were of mild to moderate grade.
6. Liver enzymes were reduced by TMC treatment.
7. Bilirubin increases were observed in some patients on TMC, mostly with the 200 mg group. These elevations were reversible and generally mild.
In treatment-naïve patients infected with HCV genotype-1, TMC435 in combination with SoC over 4 weeks of treatment:
• demonstrated potent antiviral activity
• was generally safe and well tolerated
• was not associated with AE-related treatment discontinuations
These results support the development of TMC435 for treatment-naïve patients infected with HCV genotype-1.
experienced patients infected with HCV genotype 1, 28 days of once-daily
treatment with TMC435 (75, 150 and 200 mg) as part of a triple therapy regimen
with PEGIFN-2a and
• demonstrated potent, dose-dependent antiviral activity.
• was generally safe and well tolerated.
• was not associated with AE-related treatment discontinuations.
By: Business Wire
Drug discovery company
SCYNEXIS, Inc. today presented positive results from a Phase 1b single-agent,
randomized, double-blind, placebo-controlled study of its lead, oral, antiviral
In this 15-day study,
“In this single-agent
establish proof-of-concept for
About the Clinical Trial
The clinical study was
conducted as a Phase 1b, randomized, double-blind, placebo-controlled,
multi-dose study in adult volunteers with genotype 1 chronic hepatitis C
SCYNEXIS is a premier
drug discovery and development company delivering effective and innovative drug
pipeline solutions to pharmaceutical and global health partners. The Company,
which is located in
Phase IIb Trial will Further Assess Efficacy, Safety and Tolerability of MK-7009
April 23, 2009 - Results from an ongoing Phase IIa study showed that MK-7009, an investigational oral
hepatitis C virus (HCV) protease inhibitor under development by Merck &
Co., Inc., Whitehouse Station, N.J., U.S.A.,, in combination therapy
significantly improved rapid viral response, defined as viral suppression to
undetectable levels within 28 days, compared to placebo in combination therapy
in previously untreated (treatment-naïve) patients infected with chronic HCV
genotype 1, one of the most difficult to treat genotypes of HCV 
(p<0.0001). All patients received
MK-7009 or placebo in combination with pegylated interferon and ribavirin
According to the World Health Organization, an estimated 180 million people are infected with HCV worldwide, 130 million of whom are chronic HCV carriers at risk of developing liver cirrhosis and/or liver cancer. It is estimated that million persons are infected each year.
"In this ongoing study, MK-7009 in combination therapy rapidly lowered and generally maintained the amount of virus in the blood to below detectable levels in previously untreated HCV patients," said Robin Isaacs, vice president and therapeutic head for Infectious Diseases, Merck Research Laboratories. "These preliminary results help us understand the efficacy and tolerability profile of MK-7009 and support the further development of MK-7009 for the treatment of HCV."
These findings are the
primary analysis from an ongoing, randomized, placebo-controlled, double-blind
study of MK-7009 in treatment-naïve, chronic HCV patients. In this study, 95 patients were randomized
across five treatment arms with regimens of MK-7009 300 mg or 600 mg twice
daily, MK-7009 600 mg or 800 mg once daily, or placebo, for 28 days. Patients
in all treatment arms received standard doses of peg-IFN/
Suppression of viral load to undetectable levels by day 28
After 28 days of therapy, 69 to 82 percent of patients in the regimens containing MK-7009 (n= 68 included in the per-protocol analysis) versus 6 percent of patients in the placebo regimen (n=18 included in the per-protocol analysis) achieved undetectable HCV RNA levels (p<0.0001). More than 80 percent of patients in the regimens containing MK-7009 versus 11 percent of patients in the placebo regimen experienced viral suppression to below LLOQ (<25 IU/mL) on day 28.
Viral suppression continued in the majority of patients following termination of MK-7009 treatment at day 28. At day 42, HCV RNA was undetectable in 77 to 94 percent of the patients in the regimens that had contained MK-7009 versus 12 percent of patients in the regimen that had contained placebo (p<0.0001). Additionally, all subjects in the 600 mg twice daily regimen group achieved HCV RNA to below LLOQ (<25 IU/ml) from Day 21 through Day 42.
Tolerability and safety profile of MK-7009
There were no serious adverse events and no discontinuations due to an adverse event during the first 42 days of the study. The most commonly reported adverse experiences (> 20 percent in one or more treatment arms) in patients receiving MK-7009 versus patients receiving placebo, respectively, were nausea (28 to 40 percent versus 26 percent), headache (16 to 45 percent versus 37 percent), fatigue (5 to 35 percent versus 32 percent), flu-like symptoms (20 to 26 percent versus 16 percent), anorexia (5 to 25 percent versus 11 percent), diarrhea (6 to 25 percent versus 21 percent), indigestion (0 to 22 percent versus 21 percent), rash (10 to 17 percent versus 21 percent) and vomiting (0 to 40 percent versus 5 percent). The incidence of vomiting was higher in the treatment arm containing MK-7009 600 mg twice daily (40 percent) versus the treatment arm containing placebo (5 percent); vomiting did not require anti-emetic treatment and did not lead to discontinuation or dose reduction of MK-7009.
Phase IIb study to further assess efficacy, safety and tolerability of MK-7009
A Phase IIb study has
been initiated to evaluate the safety, tolerability and efficacy of MK-7009
when administered concomitantly with peg-IFN/
The study will measure the safety and tolerability of MK-7009 at all dose regimens as compared to placebo through 48 weeks. Additionally, the study will evaluate the proportion of patients in the MK-7009 600 mg treatment regimens achieving sustained viral response, i.e., undetectable viral load 24 weeks after the end of all study therapy, as compared to patients in the placebo regimen.
- Mean maximum HCV RNA viral load decrease 3.0 logs or greater at all weekly dose levels -
PRINCETON, N.J. &
The Phase 1b clinical
trial was designed to evaluate the safety and antiviral activity of
Antiviral activity was seen in all cohorts, with a mean maximum decrease in HCV RNA viral load of at least 3.0 log10 in all single agent and combination cohorts receiving weekly dosing. Of the 22 patients dosed weekly, 86% showed a 2 log10 or greater decrease in HCV RNA at Day 29 and 50% had less than 1,000 HCV RNA copies. Of the six patients treated weekly with 3.0 mcg/kg single agent, 50% achieved a rapid virologic response (RVR; undetectable HCV RNA copies at 4 weeks).
The EASL poster presentations will be made available on the ZymoGenetics website at www.zymogenetics.com.
ALISO VIEJO, Calif., April 23 /PRNewswire-FirstCall/ -- Valeant Pharmaceuticals (NYSE: VRX) today announced that results from the week-60 analysis for its Phase IIb dose-finding clinical trial for taribavirin, a prodrug of ribavirin which is in development for the treatment of chronic hepatitis C in conjunction with a pegylated interferon, was presented today at the European Association for the Study of Liver (EASL) 44th Annual Meeting in Copenhagen, Denmark.
The results were
presented in an abstract entitled "Efficacy And Safety of Weight-Based
Regimens of Taribavirin or Ribavirin, Given With Peginterferon Alfa-2b, At 12
Weeks After Treatment (
The company previously reported week 12 and 48 results from this Phase IIb trial. The study consists of 48 weeks of treatment with a 24-week post-treatment follow-up period during which period the week 60 results were collected from the arms receiving 20mg/kg and 25mg/kg taribavirin and the ribavirin control arm. Similar to the week 12 and 48 results, the 60-week viral response data continue to show comparable reductions in viral load for weight-based doses of taribavirin and ribavirin in a difficult-to-treat population of subjects infected Hepatitis C genotype 1. At the end of week 60, the statistically significantly lower anemia rate for patients receiving taribavirin in the 20mg/kg and 25mg/kg arms versus the ribavirin control arm has been maintained at a rate similar to the end of treatment (week 48).
Table: Efficacy/Safety (intent-to-treat)
The most common adverse events during treatment were fatigue, nausea, flu-like symptoms, headache and diarrhea. The incidence rates for these adverse events among treatment arms were generally comparable except with respect to diarrhea, where incidence of diarrhea was approximately twice as common in patients receiving taribavirin compared to patients receiving ribavirin. However, the diarrhea was generally mild and not treatment limiting for taribavirin or ribavirin patients.
The Phase IIb trial is a U.S. multi-center, randomized, parallel, open-label study in 278 treatment-naive, genotype 1 patients evaluating taribavirin at weight-based doses of 20 mg/kg, 25 mg/kg, and 30 mg/kg per day in combination with pegylated interferon alfa-2b. The control group was administered weight-based dose ribavirin (800/1000/1200/1400mg daily) and pegylated interferon alfa-2b. Overall treatment duration is 48 weeks with a post-treatment follow-up period of 24 weeks.
Taribavirin is an
investigational compound that has not been found by the Food and Drug
Administration (FDA) or any other regulatory agency to be safe or effective in
the diagnosis, mitigation, treatment or cure of any disease or illness. It may
not be sold or promoted in the
About Study 204
In the Phase IIb study
(previously disclosed as Study 204), 278 treatment naive, genotype 1 patients
were randomized with the following patient demographics: mean age 48.8 yrs,
61.1% male, 30% African-American or Latino, 80.7% viral load ¿400,000 IU/mL and
82.1 kg mean weight. Week (TW) 60 efficacy and safety results for the
Valeant Pharmaceuticals International (NYSE: VRX) is a multinational specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of neurology and dermatology. More information about Valeant can be found at www.valeant.com.
Parc d'Innovation, Illkirch, France, April 23rd, 2009 - Transgene S.A. (Euronext Paris: FR0005175080) today announced additional interim results from its ongoing Phase I clinical study of its therapeutic vaccine TG4040 (MVA-HCV) conducted in treatment-naive patients chronically infected with the Hepatitis C Virus (HCV), and its decision to initiate a Phase II trial, planned for the beginning of 2010, in combination with standard of care (pegylated interferon alpha plus ribavirin).
A detailed analysis of
these results was presented today at an oral session of the EASL (European
Association for the Study of Liver disease) annual meeting held in
· All studied doses were safe and well-tolerated. The most frequent adverse events were minor to moderate injection site reactions and influenza-like symptoms. No adverse event leading to discontinuation or treatment modification and no serious adverse event related to TG4040 were reported.
· Overall, 6 out of 15 patients experienced a decrease in viral load ranging from 0.5 to 1.4 log10 IU / mL from baseline.
· For the 2 patients showing the most significant viral load reduction (0.8 and 1.4 log10), this decrease coincided with an increase of vaccine-specific T-cell response (up to three times baseline levels). Furthermore, for one of those two patients, IFN-gamma-producing cells peaked one to two weeks after the third injection and remained detectable until the last follow-up analysis (six months), while during the same period the viral load remained significantly low. For those patients with no or minimal change in viral load, no immune responses to NS3 and NS4B viral antigens related to the vaccine, or to NS5A non-related to the vaccine were detectable by IFN-gamma ELISpot at any time during follow up.
Philippe Archinard, Chief Executive Officer of Transgene, stated: "These additional Phase I results are encouraging as they support the expected mechanism of action of TG4040 that aims at inducing an effective HCV-specific T cell-based immune response associated with the control of viral replication. The data also confirm the very good safety profile of TG4040. This promising exploratory study allows us to actively prepare the next clinical steps, which will involve the initiation of a large proof of concept controlled Phase II clinical trial that will seek to demonstrate synergy of TG4040 in combination with standard of care. We anticipate the product's entry into this controlled Phase II trial early next year."
About the TG4040 Phase I Trial programme
The current trial is an
open-label, multi-centre, dose-escalation study testing the safety and
biological activity of TG4040 in treatment-naive patients chronically infected
by HCV (genotype 1). The trial is being conducted in three clinical sites in
In March 2008, the study was extended to include 27 patients in 3 additional cohorts. This extension aimed at fine-tuning the timing of the boost with cohorts 5 and 6 receiving boost injection respectively at 2 and 4 months, and at evaluating safety in more advanced liver diseases in cohort 4. Fourteen additional patients have been included in the study so far. We anticipate results of the study extension in the third quarter 2009.
In January 2006, Transgene was awarded a E1.3 million grant by the Lyonbiopôle Competitiveness Cluster for the development of its therapeutic vaccine TG4040 against hepatitis C chronic infection. The funding, which originates from the French Ministry of Industry, is expected to cover approximately 30% of the research and development costs for the programme.
Another Phase I trial
is being conducted in
Transgene's TG4040 product is based on the MVA virus carrying and expressing non-structural proteins (NS3, NS4 and NS5B) of the hepatitis C virus. The MVA vector is a highly attenuated strain of vaccinia virus that combines an extensive history of safety with the ability to stimulate a strong immune response to antigens.
By Ransdell Pierson
* Best response seen for any drug in mid-stage trials
* But anemia seen in half of treated patients
* 39 to 51 pct of treated patients needed EPO for anemia
But half the patients
taking the boceprevir experimental
medicine developed anemia -- a potential commercial disadvantage to a similar
pill called telaprevir that Vertex Pharmaceutical Inc (
Both drugs work through a new mechanism -- by blocking a protein called protease that the virus needs to replicate -- and are considered potential big-selling products. As many as 4 million Americans are believed to be infected with the virus, the leading reason for liver transplants.
Results of the Phase II
boceprevir trial, involving 595 patients who were infected with the virus but
had not previously been treated, were presented in
During the first month of the study, all patients received the two standard hepatitis C treatments sold by Schering-Plough -- a long-acting form of interferon called Pegintron and the anti-viral pill ribavirin.
One group of patients then added boceprevir to Pegintron and ribavirin for 44 weeks, while another group took only Pegintron and ribavirin over the same period.
After the 48-week trial
concluded, 75 percent of those in the boceprevir group had a sustained
virologic response (
"This is the highest sustained virologic response reported for any Phase II study of patients with genotype 1," said Dr. Paul Kwo, an associate professor at Indiana University School of Medicine, the study's chief investigator.
By contrast, only 38 percent of patients who did not get boceprevir drove the virus down to undetectable levels in the same 48-week period.
determined that after only 28 weeks of treatment with boceprevir, Pegintron and
ribavirin, 56 percent of patients achieved
Anemia was seen in about half of patients taking boceprevir, and in a third of patients taking only Pegintron and ribavirin.
Erythropoietin (EPO), a widely used anemia treatment, was used by 39 percent to 51 percent of patients taking boceprevir, and by 26 percent of those taking only Pegintron and ribavirin.
"Management of anemia with EPO is a common practice in hepatitis C treatment today," said Kwo, who noted that ribavirin and protease inhibitors both increase the risk of anemia.
A lesser incidence of anemia was reported last year for Vertex' rival telaprevir in mid-stage trials -- ranging from 29 to 37 percent of patients. Telaprevir knocked the virus to undetectable levels in about two thirds of patients.
Kwo, who has also tested the Vertex product, said data from late-stage trials of boceprevir and telaprevir will provide a clearer indication of relative anemia risk for the two new protease inhibitors.
Geoffrey Porges, a
biotech analyst for Sanford Bernstein who is attending the
"It would be very unusual for a drug to go forward and more or less require the use of another drug that's not even approved for that indication," Porges said.
considered one of the most important of Schering-Plough's experimental drugs.
Merck & Co (
Shares of Merck were down 0.57 percent to $22.85, while Schering-Plough fell 0.14 percent to $21.64, both in late morning trading on the New York Stock Exchange.
(Additional reporting by Bill Berkrot) (Reporting by Ransdell Pierson; Editing by Lisa Von Ahn and Gunna Dickson)
Inc. (Nasdaq: ANDS) announced that
In the study,
Steve Worland, Ph.D.,
Anadys' President and CEO, commented that "The potent antiviral activity
demonstrated at all three doses in this study is very encouraging for the
The Phase Ib study was
a randomized, double-blind, placebo-controlled, multiple ascending dose trial
conducted to evaluate the safety, tolerability and antiviral activity of orally
pleased with the antiviral activity and safety of
Anadys continues to
make progress on all aspects of the
14 Day Healthy Volunteer Study
completed dosing healthy volunteers in a 14-day study conducted to extend the
safety and pharmacokinetic profile of
Long-term Toxicology Studies
In September 2008,
Anadys initiated long-term, chronic toxicology studies of
In addition to the
results of the Phase Ib HCV patient study, Anadys is presenting additional data
on the preclinical profile of
worldwide rights to
In October 2008, Anadys
initiated patient dosing in the Phase Ib study of
In an earlier Phase I
study in healthy volunteers,
In the preclinical
Source: Anadys Pharmaceuticals, Inc
In Part I of the study,
a 48-week boceprevir regimen achieved a 75 percent
likelihood (predictability) of attaining
"These results are
very exciting and provide important insights to help further define response
guided therapy using a P/R lead-in boceprevir regimen with peginterferon and
ribavirin backbone treatment," said Paul Kwo, M.D., associate professor of
medicine and medical director, liver transplantation, Department of Medicine,
Division of Gastroenterology/Hepatology, Indiana University School of Medicine,
Indianapolis, and lead investigator of the study. "Building on these
results, the boceprevir Phase
Part II of the HCV
SPRINT-1 study explored a low-dose ribavirin strategy in which boceprevir was
given in combination with PEGINTRON and low-dose REBETOL for 48 weeks.
Another key finding of
the HCV SPRINT-1 study is that treatment-emergent anemia appeared to be
associated with higher
Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. The incidence of skin adverse events (rash or pruritus) observed in the boceprevir arms was similar to that seen in the PEGINTRON and REBETOL control arm.
Treatment discontinuations due to adverse events in Part I of the study were between 9 and 19 percent for patients in the boceprevir arms, compared to 8 percent for the control arm. Treatment discontinuations for boceprevir patients due to viral breakthrough were fewer in the 28- and 48-week lead-in arms (4 and 5 percent, respectively) compared to the no lead-in arms (7 and 12 percent, respectively).
Researchers at EASL
also presented early phase clinical data for
In the study,
About the HCV SPRINT-1 Study
In this Phase II study,
known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir
(800 mg TID) was evaluated in three treatment regimens: 4 weeks of PEGINTRON
(1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient
weight) therapy followed by the addition of boceprevir to the combination for
24 or 44 weeks (totaling 28 or 48 weeks of treatment), boceprevir in
combination with PEGINTRON and REBETOL at the doses described above for 28 or
48 weeks, and, in Part II of the study, boceprevir in combination with
PEGINTRON and low-dose REBETOL (400-1000 mg daily based on patient weight) for
48 weeks. In Part I of the study, the boceprevir regimens were compared to a
control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily
based on patient weight) alone for 48 weeks (an approved treatment regimen). In
Part II of the study, boceprevir in combination with PEGINTRON and low-dose
REBETOL for 48 weeks was compared to a contemporaneous control of PEGINTRON,
full-dose REBETOL and boceprevir for 48 weeks. The primary endpoint of the
The HCV SPRINT-1 study
was conducted at sites across the
Rationale for Lead-In Regimen
The use of the P/R lead-in prior to the addition of boceprevir was shown in the HCV SPRINT-1 study to reduce the incidence of viral breakthrough regardless of treatment duration. The rationale for the lead-in treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, therefore patients have the protease inhibitor added at a time when the backbone drug levels have been optimized and viral load (HCV RNA) has been reduced. In addition, the patient's immune system will have been activated and primed by PEGINTRON at the time that boceprevir is added to the regimen. This approach may minimize the period of time when there is a "functional monotherapy" with a direct antiviral agent, potentially reducing the likelihood for the development of resistance.
About Ongoing Boceprevir Phase
Patient enrollment has
been completed in two ongoing randomized, double-blind, placebo-controlled
registration studies evaluating boceprevir in combination with PEGINTRON and
REBETOL compared to standard of care with PEGINTRON and REBETOL alone. More
than 1,500 patients were enrolled in these studies at
The HCV SPRINT-2 study evaluates the efficacy of 28- and 48-week lead-in regimens of boceprevir (800 mg TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks in treatment-naive adult patients with chronic HCV genotype 1. The study enrolled a total of 1,099 patients, including 158 African-American/Black patients.
The HCV RESPOND-2 study evaluates 36- and 48-week lead-in regimens of boceprevir in combination with PEGINTRON and REBETOL at the same doses as described above compared to a control of PEGINTRON and REBETOL alone for 48 weeks in adult patients with chronic HCV genotype 1 who failed prior treatment (relapsers and nonresponders) with peginterferon and ribavirin combination therapy. The study enrolled a total of 404 patients.
In both registration studies, RVR criteria at 4 weeks of boceprevir treatment (treatment week 8) is used to determine which boceprevir patients can stop all treatment at 28 weeks (HCV SPRINT-2) or 36 weeks (HCV RESPOND-2).
Source: Schering-Plough Corporation
Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and
development of drugs for the treatment of human viral diseases, reported data
from its three hepatitis C development programs being presented this week at
the 44th Annual Meeting of the European Association for the Study of the Liver
(EASL) in Copenhagen, Denmark. These presentations include data on
"Idenix's primary goal is to discover and develop the leading HCV antiviral platform," said Jean-Pierre Sommadossi, Ph.D., chief executive officer of Idenix. "With drug candidates in each of the three major classes of direct-acting HCV antivirals in our pipeline, we believe that we are well positioned to design an optimal combination therapy."
A phase I/II
proof-of-concept clinical trial of
pharmacokinetic and toxicology profile of
Inc., headquartered in
Source: Idenix Pharmaceuticals, Inc
first-proof-of-concept for a
In the first clinical
trial of a therapeutic vaccination using naked
It is estimated that some 3% of the world's population is infected with HCV. In industrialised countries, hepatitis C accounts for 70% of chronic hepatitis cases. One of the main concerns is that HCV infection remains asymptomatic until advanced stages of the disease.
Clearance of HCV
infection correlates with activation of the host T cell response. Therefore, in
this study, researchers developed a T cell vaccine based on a codon-optimised
HCV non-structural (NS) 3/4A
Sallberg of Laboratory Medicine, the Karolinska Institutet,
In this study, a volume
of 0.5 ml saline containing ChronVac-C®
In the 167µg group, no severe side effects were observed, two patients mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose, no severe side effects were observed, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses, both patients had reductions in the viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient, no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose, no severe side effects were observed, and one patient developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1.2 log10 and 2.4 log10, respectively. Thus, 67% (four out of six) of patients in the two highest dose groups had reductions in the viral load exceeding 0.5 log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
Source: Camilla Dormer, European Association for the Study of the Liver
The first identification of GP130 somatic activating mutations* in human tumours was announced at EASL 2009, the Annual Meeting of the European Association for the Study of Liver Disease in Copenhagen, Denmark.
recurrent somatic mutation activating GP130 in inflammatory hepatocellular
tumours reveals a new pathway of tumourigenesis in humans, according to
researchers. This finding reinforces the role of inflammation in
hepatocarcinogenesis and particularly in the malignant transformation of
hepatocellular adenomas (
Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by an over-expression of inflammatory proteins. IHCA are usually developed in women and their occurrence is frequently associated with obesity and alcohol intake. Recently, somatic mutations were identified that activated GP130 in 60% of IHCA (Rebouissou et al, Nature, 2009), thus defining GP130 as a new oncogene in human tumours. This study aimed to evaluate frequency of GP130 mutations in a wide series of tumours.
Dr Jessica Zucman-Rossi
of Inserm U674,
Researchers in this study screened a series of 400 well-characterised hepatocellular tumours including hepatocellular adenomas, carcinomas, hepatocholangio-carcinoma, fibrolamellar carcinomas and intra-hepatic cholangiocarcinomas. 100 tumours from different organs were also collected. To search for mutations, GP130 exons were screened in all samples and the function of 7 different mutants was analysed in HEP3B.
A somatic mutation was
identified in 65% of the IHCA including 24 different small in-frame deletions
or duplications. A spectrum of mutations shows that mutations clearly target
the IL-6 binding site in GP130. Also demonstrated was the fact that the
expression of the most frequent GP130 mutants in HEP3B cells activates
*Somatic activating mutation of GP130 = the modification of only a few "coding letters" of the gp130 gene that leads to activation of the inflammatory response and escape of tumour hepatocytes from external control.
Source: Camilla Dormer, European Association for the Study of the Liver
The specific impact of
metabolic syndrome on mortality in hepatitis C patients has been revealed by
new research to be presented on Sunday April 26 at EASL 2009, the Annual
Meeting of the European Association for the Study of the Liver in
According to the
results of the research, type 2 diabetes (DM), obesity and hypertension (
Metabolic syndrome is a combination of medical problems that increase risks of cardiovascular disease and diabetes. It affects one in five people, and prevalence increases with age. Recent data have suggested that metabolic syndrome is associated with adverse outcomes in HCV patients. This study set out to assess which aspects of metabolic syndrome are of most risk to such HCV patients and to quantify their specific impact on mortality.
Researchers in this
study utilised the Third National Health and Nutrition Examination Survey
The cohort included
15,866 individuals with complete data. Among those, 264 patients were
HCV-positive, and 13,004 were considered controls. HCV patients had more IR
(37.4±3.2% vs. 22.8±0.9%, p< 0.0001) and higher rate of DM (9.2±2.3% vs.
5.5±0.3%, p=0.0885) than controls. In comparison to the HCV-negative patients,
HCV patients had higher overall mortality (
Dr Younossi added "This is the largest population-based study to provide the strongest evidence confirming an association between components of MS, especially type 2 diabetes and obesity, with adverse mortality outcomes for HCV infected patients. These data should help us not only develop better targeted treatment strategies for HCV patients but also encourage public health policies to address the increasing epidemic of obesity and type 2 diabetes that may affect a large number of population, including those infected with HCV".
Source: The European Association for the Study of the Liver