HCV
Advocate easl 2007 News Review
EASL 2007 Index
Update -
Hepatitis C
·
Analysis: Shorter therapy for hepatitis C?
·
Achillion Presents Positive Data on Novel
Mechanism for Treating HCV at EASL Annual Meeting
Hepatitis B
·
Adefovir
And Lamivudine Combo Is Effective In Lamivudine-Resistant Hepatitis B Patients
·
Liver Cirrhosis Linked to Hepatitis B
Virus Genotypes and Mutants: Presented at EASL
Download PDF version of this News Review:
Analysis: Shorter therapy for hepatitis C?
By ED SUSMAN
BARCELONA, Spain, April 15 (UPI) --
Hepatitis C virus patients today face a yearlong, grueling treatment regimen in
hopes they can achieve a virtual cure of the disease, but preliminary trial
results indicate a drug in development could allow a dramatically shorter
treatment course.
"The result of this study has
elevated our hopes that we can reduce the time of treatment for this
disease," Ira Jacobson, chief of gastroenterology and hepatology at Weill
Medical College of Cornell University, New York, told United Press
International.
Jacobson was one of the investigators
who treated hepatitis C patients with the oral drug telaprevir, an
investigational small molecule that inhibits the protease enzyme of the virus,
preventing reproduction.
The interim results of the study were
presented at the weekend's conclusion of the 42nd annual meeting of the
European Association for the Study of the Liver, attended by more than 5,600
clinicians in Barcelona, Spain.
The encouraging results with
telaprevir were presented by John McHutchison, professor of medicine at Duke
University Medical Center in Durham, N.C., who said that a "highly
significant" number of patients were able to achieve complete viral
suppression -- undetectable levels on the most sensitive assay -- within four
weeks of treatment.
"About 79 percent or 138 of 175
patients infected with genotype 1 hepatitis C virus -- the most common and most
difficult to treat form of the disease -- were able to achieve undetectable
levels of the virus after four weeks of therapy with telaprevir plus pegylated
interferon alfa-2a and ribavirin compared to 11 percent of patients treated
with just pegylated interferon alfa-2a and ribavirin," he told UPI.
The current standard of care for
hepatitis C virus infection is 48 weeks of interferon - a once-a-week
injection, plus twice daily oral ribavirin. "By the time a patient gets to
the second 24 weeks of this treatment, he or she is often really
miserable," Jacobson said. The drugs have flu-like symptom side effects.
McHutchison said that an equally
important part of the interim results was a small study of 20 patients who
tested the theory that they if they could get the virus under control rapidly
-- by four weeks -- and then continued on medication for 12 weeks they could
stop taking all medication.
He said nine patients achieved the
criteria for stopping, and 20 weeks after discontinuation of medicine six of
those patients remained with undetectable virus levels.
"Even though the number of
patients who were able to achieve this was small, we believe we have achieved
proof of concept that we can shorten the treatment period using telaprevir,"
McHutchison told UPI.
"We have to realize that these
are interim results and we have to wait to see if this rapid viral response
does indeed become a sustained viral response," he said. A sustained viral
response - undetectable virus six months after ending treatment -- has been
shown to be tantamount to a durable cure.
"We agree that the data is very
encouraging," said Frank Duff, executive director for virology at Roche in
Nutley, N.J., who was not involved in the trial. Roche makes pegylated
interferon and ribavirin (Copegus) used in the trial.
"These are still early
results," he said. "We still need to run the data and see how this
pans out over the 48 weeks and that it does result in a sustained viral
response. But this is all going into a very positive direction."
He noted that Roche is also
investigating ways of shortening the treatment period. He pointed out that
patients infected with genotypes 2 and 3 of hepatitis C virus already have a
shortened 24-week therapy.
McHutchison said that in his trial,
adverse side effects that were associated with telaprevir included rash,
nausea, pruritus, diarrhea, anemia and vomiting. He noted that these are the
same side effects seen with ribavirin so there maybe some interaction between
the two medications.
In the study, now being replicated in
Europe and the Americas, researchers randomly assigned 80 patients to the
standard of care and 180 other patients to various treatment schedules
involving telaprevir plus interferon and ribavirin.
The drug is being co-developed by
Vertex of Cambridge, Mass., and Tibotec, Cork, Ireland.
Achillion Presents Positive Data on Novel Mechanism for Treating HCV at EASL Annual Meeting
-NS4A
Antagonist Demonstrates Clinical Activity, a Novel Mechanism of Action and In
Vitro Compatibility with other HCV Inhibitors-
NEW HAVEN, Conn., April 16 /PRNewswire-FirstCall/ -- Achillion
Pharmaceuticals, Inc. (Nasdaq: ACHN) today announced the presentation of data
validating the clinical antiviral activity of one of Achillion's NS4A
antagonists, ACH-806, for the treatment of hepatitis C virus (HCV) infection at
the 42nd Annual Meeting of the European Association for the Study of the Liver
(EASL). In three separate presentations, Achillion researchers discussed the
potent antiviral activity in HCV-infected subjects, synergy with other classes
of HCV inhibitors, and the unique mode of action of a NS4A antagonist.
Achillion has shown that blocking NS4A, a viral protein that binds to a portion
of HCV protease, inhibits HCV replication. This program is part of a
collaboration and exclusive license agreement with Gilead Sciences for the
research, development and commercialization of compounds for the treatment of
chronic HCV.
In a late-breaker session on April 14th at
5:00 PM, John Pottage, M.D., Senior Vice President and Chief Medical Officer at
Achillion, discussed clinical data in a presentation titled, "Short-term
Antiviral Activity and Safety of ACH-806 (GS-9132), an NS4A Antagonist, in HCV
Genotype 1 Infected Individuals." The randomized, double-blind,
placebo-controlled dose-escalation trial measured the antiviral activity,
safety and pharmacokinetics of 300 mg of ACH-806 or placebo, dosed orally twice
daily as a monotherapy over 5 days. The mean change in HCV RNA (log10) at day 5
was a decrease of 0.91 from baseline for treated subjects versus an increase of
0.05 for control subjects. Elevations in serum creatinine (a marker of kidney
function) were observed in ACH-806 treated subjects and were reversible after
completion of dosing.
"This study provides the first
demonstration of human antiviral activity of an NS4A antagonist for HCV,"
said Dr. Pottage. "While we and our partner Gilead decided to discontinue
development of ACH-806 based upon the increase in serum creatinine levels, we
do not believe this effect was target-related. The antiviral activity of the
compound validates NS4A as a novel therapeutic target and therefore supports
our continued work with Gilead to identify and evaluate next-generation
compounds with the same mechanism of action."
A second presentation on April 12 at 6:30
PM, titled "In Vitro Evaluation of Combination Treatment of ACH-806 with
Interferon, VX-950 and NM 107," was led by Mingjun Huang, Ph.D., Senior
Director of Virology at Achillion, who discussed in vitro evaluations of
ACH-806 in combination with interferon, a protease inhibitor, and a polymerase
inhibitor. The data revealed that the NS4A antagonist did not show in vitro
cross-resistance with agents from these other HCV therapeutic classes, and that
NS4A antagonism appears to have a synergistic antiviral effect in combination
in vitro with the HCV protease inhibitor VX-950 and the polymerase inhibitor NM
107.
Finally, in a third presentation on April
12 titled "ACH-806: A Potent Inhibitor of HCV Replication with a Novel
Mechanism of Action," Dr. Huang described the novel mechanism of action of
NS4A antagonists. Achillion's studies demonstrated that these antagonists block
the formation of functional viral replication complexes, thereby preventing HCV
replication independent of protease or polymerase inhibition.
"The high mutation rate of HCV
necessitates the combination use of drugs with complimentary mechanisms of
action in order to suppress viral resistance. Therefore, the possibility that
candidates with the unique NS4A antagonism mechanism may be complementary to
protease and polymerase inhibitors will be an important benefit in treating HCV
infection," stated Pottage.
About
Hepatitis C
Hepatitis C is a viral liver disease,
caused by infection with the hepatitis C virus. Globally, it is estimated that
more than 170 million people have chronic hepatitis C, including about three
million in the United States. Chronic hepatitis C is a leading cause of
cirrhosis, a common cause of hepatocellular carcinoma, and is the leading cause
of liver transplantation in the United States.
About
Achillion
Achillion is a biopharmaceutical company
focused on the discovery, development and commercialization of innovative
treatments for infectious diseases. Achillion is currently developing
treatments for HIV infection, chronic hepatitis C infection and serious
hospital-based bacterial infections. For more information on Achillion
Pharmaceuticals, please visit the company's web site at http://www.achillion.com or call Achillion at 1-203-624-7000. ACHN-G
This press release includes forward-looking
statements within the meaning of the Private Securities Litigation Reform Act
of 1995 that are subject to risks, uncertainties and other factors, including
statements with respect to completion and success of Achillion's preclinical
studies and clinical trials of Achillion's drug candidates. Among the factors
that could cause actual results to differ materially from those indicated by
such forward-looking statements are: unexpected regulatory actions or delays;
uncertainties relating to results of clinical trials, including additional data
relating to ongoing clinical trials; Achillion's ability to obtain additional
funding required to conduct its research, development and commercialization
activities and Achillion's dependence on its collaboration with Gilead
Sciences. These and other risks are described in the reports filed by Achillion
with the U.S. Securities and Exchange Commission, including its Annual Report
on Form 10-K for the year ended December 31, 2006.
All forward-looking statements reflect
Achillion's expectations only as of the date of this release and should not be
relied upon as reflecting Achillion's views, expectations or beliefs at any
date subsequent to the date of this release. Achillion anticipates that
subsequent events and developments may cause these views, expectations and beliefs
to change. However, while Achillion may elect to update these forward-looking
statements at some point in the future, it specifically disclaims any
obligation to do so.
Contact:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
Media:
Kari Watson
MacDougall Biomedical Communications, Inc.
Tel. (508) 647-0209
SOURCE
Achillion Pharmaceuticals, Inc.
Psychiatric Disorders No Reason to Exclude Hepatitis C Patients From Peginterferon-Alfa2b Plus Ribavirin Treatment: Presented at EASL
By Jill Stein
BARCELONA, SPAIN -- April 16, 2007 -- A
history of psychiatric disorders should not be a contraindication to treatment
with peginterferon-alfa2b plus ribavirin in patients with genotype 2 or 3
hepatitis C, according to data presented here at the European Association for
the Study of the Liver (EASL).
Jean-Philippe Lang, MD, chief, psychiatry
service, Centre Hospitalier Erstein, Erstein, France, reported results in 641
patients infected with G2/G3 virus who were treated with peginterferon alpha-2b
plus ribavirin.
"Clinical trial data indicate that
adherence differentially affects response to therapy depending on hepatitis C
genotype," Dr. Lang said in his presentation on April 14th. For patients
with genotype 1, adherence is closely related to treatment outcome, with higher
sustained virological response (SVR) rates reported in adherent patients.
For genotype 2 or 3 patients, SVR rates are
similar among G2/G3 patients who meet the 80:80:80 rule and among those who are
less adherent.
With the 80:80: 80 rule, at least 80% of
the planned peginterferon-alfa and 80% of planned ribavirin doses are taken for
at least 80% of the duration of the planned treatment.
Overall, 460 patients had no prior
psychiatric disorders, and 181 had prior psychiatric disorders. The 2 groups
were similar with respect to most baseline demographic, virological, and
histological characteristics.
Mean duration of treatment (28.4 vs 29.4
weeks, P = .87), rate of early treatment cessation (13% vs 13%, P = .89),
adherence to ribavirin plus peginterferon at month 6 (54% vs 51%, P = .566) and
SVR (92% vs 83%, P = .151) did not differ significantly between the groups with
past psychiatric disorders and the group without past psychiatric disorders.
Dr. Lang said that the study is the first
prospective, community-based investigation to assess treatment adherence among
patients with G2/G3 HCV infections.
The study was supported by Roche.
[Presentation title: A Prospective,
Multicenter, Observational Study on Adherence With Viral Hepatitis C treatments
(CHEOBS) Study: Impact of Past Psychiatric Disorders on Sustained Virologic
Response (SVR). Abstract 607]
Adefovir And Lamivudine Combo Is Effective In Lamivudine-Resistant Hepatitis B Patients
http://www.medicalnewstoday.com/
Jill Stein
Long-term treatment with adefovir dipivoxil
(ADV, HepseraR) and lamivudine provides multiple benefits in
lamivudine-resistant patients with chronic hepatitis B, researchers announced
at the 42nd Annual Meeting of the European Association for the Study of the
Liver (EASL).
The results, reported by an Italian group,
showed that the combination decreased the risk of genotypic resistance to
adefovir and prevented both virological rebound and clinical resistance for up
to three years.
Long-term therapy with lamivudine is
initially effective but genotypic hepatitis B resistance develops in about 25%
of patients at one year and in 71% by four years, principal investigator
Professor Pietro Lampertico, who is an assistant professor of gastroenterology
at the University of Milan, said.
Add-on ADV therapy has been established as
an effective treatment strategy for patients developing lamivudine resistance
but the long-term risk of genotypic resistance to ADV and the impact of ADV
combined with lamivudine on the progression of cirrhosis has not been known, he
added.
In the trial, 145 patients received 10 mg/d
of adefovir as add-on therapy to ongoing lamivudine treatment.
HBV DNA was assessed every two months, and
drug resistance was assessed annually in viremic patients.
Most patients achieved a virological and
biochemical response (80% and 84%) for up to three years. None developed a
virological or clinical breakthrough regardless of the degree of viral
suppression.
No patient developed genotypic resistance for
rtA181V and rtN236T. Three patients developed the rtA1811T mutation as a mixed
viral population with rtA181A while responding to therapy.
Combination therapy prevented clinical
decompensation in all cirrhotic patients.
Professor Lampertico concluded that the
data demonstrate that the adefovir-lamivudine combination is an effective and
safe treatment strategy for lamivudine-resistant patients for at least three
years.
Approximately one million individuals are
infected with the hepatitis B virus in Europe every year. Of these, roughly
90,000 become chronically infected carriers.
The study was sponsored by Gilead. www.gilead.com
Liver Cirrhosis Linked to Hepatitis B Virus Genotypes and Mutants: Presented at EASL
By Jill Stein
BARCELONA, SPAIN -- April 16, 2007 --
Hepatitis B virus (HBV) genotype C and A1762/G1764A mutants are independent
risk factors for liver cirrhosis, according to data reported here at the 42nd
Annual Meeting of the European Association for the Study of the Liver (EASL).
Y. L. Chen, MD, consultant, division of
hepatology, National Taiwan University, Taipei, Taiwan, and colleagues
investigated the effects of genotype, pre-core and basal core promoter (BCP)
mutants of HBV, independently and interactively, on the progression of liver
cirrhosis.
"Reported risk factors for chronic
hepatitis b virus-related cirrhosis include active viral replication, presence
of hepatitis B e antigen (HBeAg), advanced age, increased alanine
aminotransferase level, and coinfection with the hepatitis delta virus,"
Dr. Chen said in a presentation on April 13th.
"It has been shown that patients with
genotype C are more often HBeAG positive and have more active viral replication
than genotype B patients, and genotype C results in a more advanced liver
disease and a lower response rate to antiviral therapy," he added.
There have been some reports that the BCP
and precore mutants result in a loss of HBeAg. However, the effects of these
mutants on the development of liver cirrhosis remains unclear, he said.
The trial included 3,573 untreated
individuals, who were hepatitis B surface antigen (HbsAg) positive and
anti-HCV-seronegative.
Serum samples in these individuals were
tested for HBV viral load and genotype.
A subcohort of 1,477 individuals with HBV
DNA levels greater than or equal to 3104 copies/mL was tested for precore
(G1896A) and BCP mutants (A1762T/G1764A).
The incidence rates of liver cirrhosis per
100,000 person-years for participants infected with HBV genotype B and C were
746.9 sand 1532.04, respectively.
The incidence rates for persons infected
with wild and mutant type HBV precore stop codon 1896 were 1915.1 and 862.4,
respectively.
For individuals infected with wild and
typical mutant type HBV BCP 1762/1764, rates were 885.3 and 2146.8,
respectively.
The effects of precore mutant on liver
cirrhosis risk was most significant in HBeAg negative subjects and in subjects
with HBV DNA levels less than 106 copies/mL, while the effect of BCP mutants
was predominant in HBeAg-positive subjects.
"Taking subjects with wild type on
both precore and BCP as referent, subjects with precore wild type and BCP
mutant had a significantly higher risk of developing liver cirrhosis, while
those with pre-core typical mutant and BCP wild type had a significantly lower
risk," Dr. Chen said.
[Presentation title: Risk of Liver
Cirrhosis Associated With Genotype and Mutants of Hepatitis B Virus. Abstract
222]
Hepatitis C Patients With Advanced Kidney Disease Benefit From Peginterferon-Alfa-2a: Presented at EASL
By Jill Stein
BARCELONA, SPAIN -- April 16, 2007 -- Low-dose
peginterferon-alfa-2a is effective in patients with chronic hepatitis C virus
(HCV) infection who are undergoing haemodialysis for end-stage renal disease
(ESRD), according to the interim results of an ongoing trial.
Markus Peck-Radosavljevic, professor,
division of gastroenterology and hepatology, University of Vienna, Vienna,
Austria, presented these results here on April 14th at the 42nd Annual Meeting
of the European Association for the Study of the Liver (EASL).
"Patients with ESTD and chronic HCV
are at increased risk of disease progression and decreased graft survival after
transplantation," Dr. Peck-Radosavljevic explained.
The preliminary results were from 80
non-cirrhotic, interferon-naïve patients with chronic HCV and ESRD who were undergoing
dialysis and were randomised to peginterferon alfa-2a (40KD) 135 mcg/week or 90
mcg/week for a total of 48 weeks of treatment.
The primary endpoint was sustained
virological response, defined as undetectable serum HCV RNA (<50 IU/mL) 24
weeks after the end of treatment.
The 2 treatment groups were similar with
respect to gender, mean age, mean body weight, mean level of alanine
aminotransferase (ALT), ALT quotient, HCV genotype, mean HCV RNA and mean
number of dialysis sessions per week.
Results at 12 weeks showed that in patients
receiving peginterferon alfa-2a 135 mcg/week, there were significantly more
virological responders at week 12 than in the group receiving 90 mcg/week (61%
vs 37%, respectively). However, a significant difference was not observed at
week 24.
Only in the difficult-to-treat patients
with high viral loads was a clinically relevant difference still present
between the 2 dose groups at week 24 (45% vs 25%).
The frequency of adverse events and
laboratory abnormalities was similar in the 2 treatment arms.
"These interim results show that
treatment with peginterferon-alfa 2a (40 KD) is effective and has acceptable
tolerability in chronic HCV patients who have ESRD and are undergoing
haemodialysis," Dr. Peck-Radosavljevic said.
The study was supported by Roche.
[Presentation title: Use of Low-Dose
Peginterferon Alfa-2a (40KD) (Pegasys) to Treat Hepatitis C-Infected, End-Stage
Renal Disease Patients undergoing Hemodialysis: Interim Results from a
Randomized Study. Abstract 628]