Pegylated Interferon Lambda Boosts Response with Few Side Effects EASL
4/2/11
Current standard therapy for chronic hepatitis C virus (HCV) infection,
pegylated interferon alfa (Pegasys or PegIntron) plus ribavirin, cures only
about half of people with hard-to-treat HCV genotype 1 and can cause
difficult side effects including flu-like symptoms, depression, and loss of
red and white blood cells (anemia and neutropenia, respectively).
Interferon lambda is a cytokine (chemical messenger) produced by immune
cells in response to viral infection; as a type III interferon, it uses a
different signalling pathway than type I interferons such as interferon
alfa. Because interferon lambda uses a receptor present on fewer types of
cells, it is predicted to have better tolerability.
At the European Association for the Study of the Liver's International Liver
Congress (EASL 2011) last week in Berlin researchers presented findings from
a Phase 2b trial comparing pegylated interferon lambda vs pegyalted
interferon alfa in more than 500 chronic hepatitis C patients with various
HCV genotypes.
Below is an edited excerpt from a press release issued by interferon lambda
develop Bristol-Myers Squibb describing the study and its findings.
Investigational Compound PEG-Interferon Lambda Achieved Higher Response
Rates with Fewer Flu-Like and Musculoskeletal Symptoms and Cytopenias Than
PEG-Interferon Alfa in Phase IIb Study of 526 Treatment-Naive Hepatitis C
Patients
Higher virologic response rates achieved at 4 weeks (RVR) and maintained
through 12 weeks of treatment (cEVR) across all genotypes studied
Data presented at The International Liver Congress in Berlin
Princeton, N.J. -- April 2, 2011 -- Bristol-Myers Squibb Company (NYSE: BMY)
today announced results from the Phase IIb EMERGE clinical trial, in which
treatment with the investigational compound PEG-Interferon lambda and
ribavirin achieved higher rates of rapid virologic response (RVR)
[undetectable viral load (HCV RNA <25 IU/mL) at week 4] in genotypes 1, 2,
3, and 4, and complete early virologic response (cEVR) [undetectable viral
load at week 12] in genotypes 1 and 4 than the standard regimen of
PEG-Interferon alfa and ribavirin in treatment-naive patients chronically
infected with hepatitis C (HCV).
In this study, there were fewer flu-like and musculoskeletal symptoms and
cytopenia [blood cell deficiency], as well as fewer interferon and ribavirin
dose reductions for anemia in the PEG-Interferon lambda arms up to 12 weeks.
Rates of serious adverse events, depression and other common adverse events
(incidence > 10%) were similar across treatment arms up to week 12.
The EMERGE study findings were presented in a late-breaker oral session at
the International Liver Congress (ILC), the 46th annual meeting of the
European Association for the Study of the Liver (EASL) in Berlin, Germany.
"There is a significant unmet medical need for more therapies that can
benefit more hepatitis C patients. This is especially true for patients with
HCV genotypes 1 and 4, who generally have lower response rates to treatment
with PEG-Interferon alfa and ribavirin than patients with other genotypes,"
said Stefan Zeuzem, MD, chief of the department of medicine and professor of
medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt,
Germany. "The EMERGE study results demonstrate that PEG-Interferon lambda
may have the potential to help address this unmet need, and support further
studies of this new type of investigational interferon."
PEG-Interferon lambda is the first investigational type III interferon.
Interferon lambda mediates antiviral activity through a receptor that is
distinct from that used by interferon alfa and is present on fewer cell
types within the tissues of the body. This restricted distribution of the
interferon lambda receptor offers the potential for more targeted delivery
of interferon therapy.
Study Results
Viral Response: HCV Genotypes 1 and 4
In this study, HCV genotype 1 and 4 patients treated with PEG-Interferon
lambda achieved statistically significant (p<0.05) higher rates of cEVR
(primary study endpoint) versus PEG-Interferon alfa at all doses [lambda 240
mcg: 56.3% (n=103), lambda 180 mcg: 55.9% (n=102), lambda 120 mcg: 55.0%
(n=100) vs. alfa: 37.9% (n=103)]. These statistically significant (p<0.05)
higher viral response rates were seen as early as four weeks of treatment,
with greater rates of RVR at the two higher doses of PEG-Interferon lambda
(lambda 240 mcg: 16.5%, lambda 180 mcg: 14.7%, lambda 120 mcg: 6.0% vs.
alfa: 5.8%).
Viral Response: HCV Genotypes 2 and 3
In patients with HCV genotypes 2 and 3, treatment with all doses of
PEG-Interferon lambda achieved cEVR rates similar to PEG-Interferon alfa
[lambda 240 mcg: 83.3% (n=30), lambda 180 mcg: 96.6% (n=29), lambda 120 mcg:
90% (n=30), and alfa: 86.2%, (n=29)]. Statistically significant (p<0.05)
higher rates of RVR were achieved at the two higher doses of PEG-Interferon
lambda (lambda 240 mcg: 66.7%, lambda 180 mcg: 75.9%, lambda 120 mcg: 43.3%
vs. alfa: 31%).
Safety
In this study, rates of adverse events commonly associated with interferon
treatment were lower with PEG-Interferon lambda than with PEG-Interferon
alfa. These adverse events included flu-like symptoms (lambda 240 mcg: 9.7%;
lambda 180 mcg: 9.9%; lambda 120 mcg: 12.5%; alfa: 42.9%), musculoskeletal
symptoms (lambda 240 mcg: 14.2%; lambda 180 mcg: 14.5%; lambda 120 mcg:
18.0%; alfa: 46.6%), neutropenia < 750/mm3 (lambda 240 mcg: 0.0%; lambda 180
mcg: 0.8%; lambda 120 mcg: 0.0%; alfa: 15.2%), anemia with hemoglobin < 10
g/dL (lambda 240 mcg: 12.9%; lambda 180 mcg: 15.4%; lambda 120 mcg: 20.5%;
alfa: 43.9%.) and thrombocytopenia < 50K/mm3 (lambda 240 mcg: 0.0%; lambda
180 mcg: 0.0%; lambda 120 mcg: 0.0%; alfa: 14.4%).
The proportion of patients that required interferon dose reductions were:
lambda 240 mcg: 12.7%; lambda 180 mcg: 3.8%; lambda 120 mcg: 0.8%; alfa:
18.8%, and the proportion of patients that withheld and/or reduced ribavirin
were: lambda 240 mcg: 11.2%; lambda 180 mcg: 4.6%; lambda 120 mcg: 10.2%;
alfa: 20.3%. The proportion of patients who required ribavirin dose
reductions for anemia were: lambda 240 mcg: 0.7%; lambda 180 mcg: 1.5%;
lambda 120 mcg: 2.3%; alfa: 12.8%.
Rates of serious adverse events, depression and other common adverse events
(> 10%) were similar across treatment arms. Higher rates of elevated liver
enzymes [AST or ALT >5x the upper limit of normal (ULN)] were seen in the
highest-dose PEG-Interferon lambda treatment arm compared with
PEG-Interferon alfa (lambda 240 mcg: 17.4%; lambda 180 mcg: 2.3%; lambda 120
mcg: 0.8%; alfa: 7.6%), and direct bilirubin was also elevated (>1.2 mg/dL)
in the highest-dose PEG-Interferon lambda treatment arm compared with
PEG-Interferon alfa (lambda 240 mcg: 7.6%; lambda 180 mcg: 3.9%; lambda 120
mcg: 0.8%; alfa: 0.8%); all resolved spontaneously without sequelae or
following interferon dose modification and/or discontinuation.
About the EMERGE Phase IIb Study
The EMERGE study is a two-part, randomized, controlled, multicenter, phase
II study of PEG-Interferon lambda in 526 treatment-naive patients with
chronic hepatitis C genotype 1, 2, 3 or 4. Part one of EMERGE was a Phase
IIa study, and results were previously presented at the American Association
for the Study of Liver Diseases (AASLD) 2010 Liver Meeting. Part two of
EMERGE is an ongoing, blinded Phase IIb study designed to evaluate the
safety, efficacy, and pharmacokinetics of PEG-Interferon lambda vs.
PEG-Interferon alfa, both in combination with ribavirin. The 526 patients
were randomized into four dose groups: PEG-Interferon lambda 240 mcg
(n=134), PEG-Interferon lambda 180 mcg (n=131), PEG-Interferon lambda 120
mcg (n=128) and PEG-Interferon alfa 180 mcg (n=133).
The study will continue for 48 weeks in genotype 1 and 4 patients and 24
weeks in genotype 2 and 3 patients. The primary endpoint of the study is the
proportion of patients who achieve complete early virologic response (cEVR).
About PEG-Interferon lambda
PEG-Interferon lambda is the first investigational type III interferon in
Phase IIb development for the treatment of hepatitis C. Native human
interferon lambda proteins are generated by the immune system in response to
viral infection, and signal through a different receptor than native human
interferon alfa proteins. Lambda receptors are present on fewer cell types
within the human body than alfa receptors. This restricted distribution of
the interferon lambda receptor offers the potential for more targeted
delivery of interferon therapy.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is
to discover, develop and deliver innovative medicines that help patients
prevail over serious diseases. For more information, please visit
http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
Reference
S Zeuzem, S Arora, B Bacon, et al. Pegylated interferon-lambda
(pegIFN-[lambda]) shows superior viral response with improved safety and
tolerability versus pegIFN-[alpha]-2a in HCV patients (G1/2/3/4): EMERGE
phase IIb through week 12. 46th Annual Meeting of the European Association
for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract
422.
Other Source
Bristol-Myers Squibb. Investigational Compound PEG-Interferon Lambda
Achieved Higher Response Rates with Fewer Flu-Like and Musculoskeletal
Symptoms and Cytopenias Than PEG-Interferon Alfa in Phase IIb Study of 526
Treatment-Naive Hepatitis C Patients. Press release. April 2, 2011.