HCV Research and News: PEG-Interferon lambda (IL-29)

Showing posts with label PEG-Interferon lambda (IL-29). Show all posts

November 23, 2011

New HCV Drugs at AASLD

July 3, 2011

Therapeutics: New drugs hit the target

Jana Schlütter

Nature 474,S5–S7(09 June 2011) doi:10.1038/474S5a Published online 08 June 2011

With two recently approved drugs and dozens more in the pipeline, hepatitis C treatment will improve over the next decade.

When Charles Gore talks about some of his colleagues, there is more than a hint of urgency in his voice. Although he cleared his hepatitis C virus (HCV) infection after receiving the standard treatment, two of his staff at the World Hepatitis Alliance, an advocacy organization, recently had liver transplants. “And they are lucky,” says Gore, who is president of the alliance. “This treatment does not help about 50% of the patients who are infected with the most common form of the virus. So their liver becomes worse, and many of them cannot get a transplant. They are facing death.”

Around the globe, patients who have not been cured by the current treatment, a combination of interferon-α and ribavirin, are waiting for new drugs. So far, their doctors have had nothing to offer them but another 48-week-round of the same drug combination, which had its last upgrade in 2001 when researchers attached a molecule called polyethylene glycol to interferon-α. This 'pegylation' allows interferon-α to stay in the body much longer, reducing the frequency of injections from three per week to one. But the side effects are just as harsh, including flu-like symptoms, anaemia and depression. And although the patient being treated may be too weak to work or enjoy family life, the virus often manages to survive and prosper under these conditions. At most, 20% of patients are cured by this second course of treatment. Still, there was no alternative.

This situation is about to change. Two powerful weapons against chronic HCV infection have been licensed: the protease inhibitors telaprevir, from Vertex Pharmaceuticals, based in Cambridge, Massachusetts, and boceprevir, from drug company Merck, headquartered in Whitehouse Station, New Jersey. When either drug is added to the current therapy, the cure rate increases for patients who have so far been spared the daunting year-long treatment: that is, 'treatment-naive' patients. The drugs also offer hope to those increasingly desperate patients who have not been helped by the standard treatment: instead of around a 20% chance of a cure, these 'treatment-experienced' patients now have a 30–90% chance. “We are approaching a new era of management of this disease,” says Mark Thursz, a hepatologist at Imperial College London and current secretary-general of the European Association for the Study of the Liver (EASL).

The drug manufacturers have tailored these protease inhibitors to HCV genotype 1, one of at least six forms of HCV. Genotype 1 is particularly widespread in the United States and Europe and is one of the least responsive to the standard treatment. The clinical studies coming out now, Thursz says, “show that the new drugs can tame the pit bull terriers of the hepatitis C world: the genotype 1 viruses.”

In addition to telaprevir and boceprevir, there are dozens of compounds in the pipeline, and that's only counting the ones that drug manufacturers are willing to disclose. These drugs target many aspects of the virus's life cycle — the stages it goes through in the liver cell to reproduce itself. Used in combination, the new agents might be able to target all HCV genotypes at once, while improving the cure rate and preventing drug resistance from emerging. Although most of these drug candidates are being added to the current treatment, an interferon-free regimen has recently shown promise — a possibility that could substantially reduce treatment side effects and increase adherence.

Direct hits

In the current regimen, interferon-α boosts the patient's immune system, and ribavirin is a general inhibitor of virus replication. By contrast, the new drugs target HCV directly. Telaprevir and boceprevir block HCV's NS3/4A protease. After an HCV particle attaches to and enters a liver cell, it releases its RNA, which is subsequently translated into a single polyprotein (see 'The life of HCV'). This long chain is cleaved into functional proteins by NS3/4A, which acts like a pair of molecular scissors. Without the protease, functional viral enzymes and structural proteins are not generated, so HCV cannot complete its life cycle.

SOURCE: CIESEK, S. & MANNS, M. P. NAT. REV. GASTROENTEROL. HEPATOL. 8, 69–71 (2011).

This March, the drug companies reported results of phase III clinical trials of telaprevir and boceprevir, each coupled with the current therapy, at EASL's International Liver Congress in Berlin. Two-thirds to three-quarters of treatment-naive patients with HCV genotype 1 are likely to clear the virus permanently. And treatment time is expected to be halved for patients in this group who have undetectable levels of virus after four weeks of treatment.

More hotly anticipated were the data for the treatment-experienced patients, including relapsers, whose virus had become undetectable but rebounded after their previous treatment ended; partial responders, whose viral load decreased by at least 99% but never became undetectable; and null responders, who previously had little success in fighting the virus. Telaprevir was tested in the Realize trial, which involved 662 patients from Europe and the United States. Adding telaprevir for 12 weeks to a 48-week-treatment course increased the cure rates from 24% to as high as 88% in relapsers, from 15% to 59% in partial responders, and from 5% to 33% in null responders. Boceprevir was tested in 403 patients in centres across the United States and Europe in the Respond-2 trial. Adding boceprevir for 32–44 weeks caused the cure rate to climb from 29% to 69-75% in relapsers and from 7% to 40-52% in partial responders. (Null-responders did not participate in this trial.)

“To have direct-acting antivirals against hepatitis C and to see such increases in cure rates is a huge step forward,” says Stefan Zeuzem, a hepatologist at the Goethe University Medical Center in Frankfurt, Germany, who was involved in both the Realize and Respond-2 trials. But these drugs are not cheap. “Cost will be a major issue,” he says. “However, we are preventing liver cancer and other end-stage liver diseases, which makes it worthwhile. We are aiming for a cure, not just a few more weeks to live.”

Both of these drugs also have side effects. More than half of the patients treated with telaprevir developed a rash, with 3–6% having a rash severe enough to halt treatment. Boceprevir is associated with anaemia (similarly to telaprevir) and can cause a metallic taste in the mouth, both of which affect nearly half of all patients. These problems are in addition to those caused by interferon-α and ribavirin, meaning that nearly every patient in the clinical trials suffered from at least one side effect. “It's still a tough treatment,” says Gore. “For patients, it's very important that clinicians manage these side effects well.”

If side effects cause patients to abandon treatment on the new regimen, this could lead to HCV developing resistance to the new drugs. The new protease inhibitors cannot be given alone and must be given with interferon-α and ribavirin to prevent protease-inhibitor resistance emerging. Thursz adds that as boceprevir and telaprevir are similar compounds, resistance to one will probably translate into resistance to the other (so-called cross-resistance), restricting future treatment options.

HCV is a highly mutation-prone virus, with many genetic variants present in any one host. Before treatment starts, variants that are resistant to a particular drug make up a minority of the viral population. Under selective pressure of the antivirals, however, these variants could become the dominant strains. “We understand resistance and have to manage it,” says Jean-Michel Pawlotsky, a hepatitis specialist at the University of East Paris in Créteil, France, and director of the French National Reference Center for Viral Hepatitis B, C and delta. He recommends that these new drugs should be administered at expert centres that can monitor resistance issues: “It is better to be well-treated than just treated,” he says.

Despite the high cure rates, not every HCV-infected patient will benefit from the new drugs. Possible drug–drug interactions are not yet fully understood. And there are no data for the many patients who are co-infected with HIV or for patients with end-stage renal disease, decompensated (or extremely advanced) liver cirrhosis or a recent liver transplant. Furthermore, telaprevir and boceprevir have been licensed by the US Food and Drug Administration only for treating HCV genotype 1 infection. As Pawlotsky says, “What we are seeing now is just the first step into the era of direct-acting antivirals. It will cause a real shift, but it's not a full revolution.”

Covering every angle

More than 50 other drugs are, however, in the research and development pipeline (see 'Drug candidates for treating HCV infection 2011'). Many of these are in new classes — that is, they target different mechanisms — and can be combined to create antiviral cocktails, limiting the emergence of drug resistance. With so many new agents snapping at their heels, boceprevir and telaprevir might have a very limited time as the dominant new drugs, says Zeuzem.

Two other first-generation protease inhibitors are in phase III trials: TMC435, from Tibotec Pharmaceuticals, in Beerse, Belgium, and pharmaceutical company Medivir in Huddinge, Sweden; and BI201335, from pharmaceutical company Boehringer Ingelheim, headquartered in Ingelheim am Rhein, Germany. Both are taken once daily instead of three times, seem to cause fewer side effects and might even be more potent than boceprevir and telaprevir.

The second generation of protease inhibitors is expected to be led by Merck's MK-5172, a compound that does not seem to have cross-resistance issues with other drugs of this class and might be effective across multiple genotypes. “We want to see if the resistance profile is robust enough that we can treat people who are failures from earlier generations of protease inhibitors,” says Keith Gottesdiener, vice president for hepatitis C clinical development at Merck. “That would be exciting if it was proven in the clinic.”

The pharmaceutical company F. Hoffmann-La Roche, headquartered in Basel, is about to start phase III trials of mericitabine, which blocks the activity of HCV's polymerase enzyme, NS5B. By mimicking the building blocks of RNA, mericitabine is incorporated into newly formed viral RNA but prematurely terminates it, halting the life cycle.

Another protein generating immense interest as a drug target is NS5A. Its precise function is mysterious, but it seems to be involved in the replication, assembly and release of HCV. BMS-790052, from biopharmaceutical company Bristol-Myers Squibb, headquartered in New York, was the first inhibitor in this class and is now in phase II trials. The pipeline is rapidly filling with others.

Cyclophilin A inhibitors block a host protein that is essential for viral replication. Candidates include alisporivir (DEB025), from drug company Novartis, headquartered in Basel, Switzerland, which is in phase III trials. In theory, targeting a human protein that HCV needs will render the virus' genotype or mutation status irrelevant and make it much less likely that resistant strains of HCV will emerge.

Free from interferon

There is also hope for patients who are not responsive to — or cannot tolerate — the backbone of triple therapy: interferon. This April at the International Liver Congress, Anna Lok, a hepatologist at the University of Michigan in Ann Arbor, presented data from a small phase IIa study of an interferon-free regimen in null responders. The study comprised patients on double therapy consisting of two classes of direct-acting antiviral: Bristol-Myers Squibb's BMS-650032 (a protease inhibitor) and BMS-790052 (an NS5A inhibitor). These patients were compared with a cohort taking quadruple therapy, consisting of these two antivirals plus interferon-α and ribavirin. The quadruple therapy suppressed HCV in 10 out of 10 patients for at least 12 weeks after treatment, whereas the interferon-free double therapy suppressed HCV in 4 out of 11 patients, with 6 being null or partial responders.

The numbers might not seem great, but they are a start. “The potential for an interferon-free regimen is some of the most exciting news this year,” says Thursz. Without interferon-α and ribavirin, the virus was expected to rebound after treatment, but this occurred in only one case. “There is still a lot of work to be done. But this was a group of very difficult-to-treat patients with excellent outcomes. Although the numbers are small, I think this is the direction we can expect to go in the future.”

Indeed, this possibility has energized hepatitis C researchers. “People would have laughed at you if you suggested something like this five years ago,” says Zeuzem. “Now, we know that such a therapy might be available in another five to ten years.”

Many of the other drugs in the pipeline, such as the NS5B inhibitors, could also be candidates for an interferon-free regimen, says Paul Pockros, co-director of clinical research at the Scripps Translational Science Institute in La Jolla, California, who is involved in phase II studies of mericitabine. Although mericitabine is slightly less effective than the protease inhibitors, it seems to be a safe drug with a high barrier to resistance. “This one would be a good partner for a protease inhibitor,” says Pockros.

With all the excitement about new drugs, one would be forgiven for thinking that interferon has had its day. But there is also development on this front. Bristol-Myers Squibb has developed a variant called pegylated interferon-λ, which is designed to be more potent and safer than interferon-α. Interferon-λ docks with different receptors that are less common than the receptors for interferon-α. This interferon circumvents the bone marrow and therefore avoids anaemia and flu-like symptoms, so it might be a good partner for direct-acting antivirals. “This would help a lot of people who cannot tolerate the current interferon,” says Zeuzem, who is involved in clinical trials of this drug.

With interferon-free regimens on the horizon, the question is whether a new interferon will be needed. But there are many potential pitfalls on the way to the clinic, and HCV is a very difficult virus to target. Researchers need as many options at their disposal as possible, says Zeuzem, “just in case.”

Source

June 20, 2011

Novel Pegylated Interferon Safer, More Effective Than Current Treatment, Study Shows

Gastroenterology and Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by David Wild

Berlin—A novel variant of pegylated interferon (PegIFN) called PegIFN-lambda is significantly more effective than PegIFN-alfa-2a (Pegasys, Genentech) at suppressing viral loads in patients with certain genotypes of hepatitis C virus (HCV), according to preliminary findings from an ongoing randomized trial. Patients also experienced fewer adverse events on the novel PegIFN.

“If the superior virological response rates and minimal adverse events are sustained through the completion of this study and replicated in other research, this form of interferon will represent a major advance in the treatment of chronic hepatitis C,” said Emmet Keeffe, MD, professor emeritus of medicine, Stanford University Medical Center, Palo Alto, Calif., who was not involved in the study.

An estimated 20% of patients stop treatment for HCV because of side effects associated with PegIFN-alfa-2a. PegIFN-lambda attaches to fewer cellular receptors than PegIFN-alpha-2a and thus may be a safer and equally effective alternative.

In this study, lead researcher Stefan Zeuzem, MD, and colleagues at 39 international centers randomly assigned individuals with chronic HCV to receive ribavirin in combination with PegIFN-alfa-2a 180 mcg (n=132), PegIFN-lambda 120 mcg (n=130), PegIFN-lambda 180 mcg (n=131) or PegIFN-lambda 240 mcg (n=133). The study is ongoing, but the current efficacy and safety findings are based on 12 weeks of double-blinded treatment.

The data showed that 14.7% and 16.5% of those with HCV genotypes 1 and 4 who received 180 and 240 mcg of PegIFN-lambda, respectively, experienced a rapid virologic response (RVR) to the novel drug compared with 5.8% of patients with the same HCV genotypes who took PegIFN-alfa-2a (P<0.05). The RVR rate among individuals with genotypes 1 and 4 who received 120 mcg of PegIFN-lambda was 6%.

Complete early virologic response rates were 55%, 55.9% and 56.3% among those with HCV genotypes 1 and 4 who received 120, 180 and 240 mcg of PegIFN-lambda compared with 37.9% among PegIFN-alfa-2a recipients (P<0.05). Response rates among those with HCV genotypes 2 and 3 did not differ significantly between the treatment groups, the researchers reported.

Patients administered PegIFN-lambda also experienced fewer flu-like and musculoskeletal symptoms as well as fewer cytopenias (Table). However, aspartate and alanine transaminase levels rose to more than five times the upper limit of normal in 17.4% of those receiving the highest dose of PegIFN-lambda, and direct bilirubin concentration exceeded 1.2 mg/dL in 7.6% of patients in the same group. These adverse events resolved with dose reduction or drug discontinuation.

Table. Adverse Events in Patients Receiving PegIFN-lambdaa For Hepatitis C Virus Infection
	PegIFN-alfa-2a 180 mcg (n=132)	PegIFN-lambda 240 mcg (n=133)	PegIFN-lambda 180 mcg (n=131)	PegIFN-lambda 120 mcg (n=130)
Flu-like symptoms	42.9%	9.7%	9.9%	12.5%
Musculoskeletal symptoms	46.6%	14.2%	14.5%	18%
Hemoglobin <10 g/dL	44%	12.9%	15.4%	20.5%
Neutrophils <750/mm³	15.2%	–	0.8%	–
Platelets <50,000/mm³	14.4%	–	–	–
PegIFN, pegylated interferon ^a All patients also received ribavirin.

“This is indeed a promising new drug,” said Dr. Zeuzem, professor and chair, Department of Medicine, Johann-Wolfgang Goethe University Hospital, Frankfurt/Main, Germany, who presented his group’s findings at the 46th annual meeting of the European Association for the Study of the Liver (Abstract 1360).

“Now we need to assess longer-term sustained virological responses and to accumulate more safety data,” he said.

Source

April 6, 2011

EASL: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

Public release date: 2-Apr-2011

Contact: Cristi Barnett
cristi.barnett@bms.com
609-252-6028
TogoRun

(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) in genotypes 1, 2, 3, and 4, and complete early virologic response (cEVR) in genotypes 1 and 4 than the standard regimen of PEG-Interferon alfa and ribavirin in treatment-naïve patients chronically infected with hepatitis C (HCV). In this study, there were fewer flu-like and musculoskeletal symptoms and cytopenia, 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 µg: 56.3% (n=103), lambda 180 µg: 55.9% (n=102), lambda 120 µg: 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 µg: 16.5%, lambda 180 µg: 14.7%, lambda 120µg: 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 µg: 83.3% (n=30), lambda 180 µg: 96.6% (n=29), lambda 120 µg: 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 µg: 66.7%, lambda 180 µg: 75.9%, lambda 120 µg: 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 µg: 9.7%; lambda 180 µg: 9.9%; lambda 120 µg: 12.5%; alfa: 42.9%), musculoskeletal symptoms (lambda 240 µg: 14.2%; lambda 180 µg: 14.5%; lambda 120 µg: 18.0%; alfa: 46.6%), neutropenia < 750/mm³ (lambda 240 µg: 0.0%; lambda 180 µg: 0.8%; lambda 120 µg: 0.0%; alfa: 15.2%), anemia with hemoglobin < 10 g/dL (lambda 240 µg: 12.9%; lambda 180 µg: 15.4%; lambda 120 µg: 20.5%; alfa: 43.9%.) and thrombocytopenia < 50K/mm³ (lambda 240 µg: 0.0%; lambda 180 µg: 0.0%; lambda 120 µg: 0.0%; alfa: 14.4%).

The proportion of patients that required interferon dose reductions were: lambda 240 µg: 12.7%; lambda 180 µg: 3.8%; lambda 120 µg: 0.8%; alfa: 18.8%, and the proportion of patients that withheld and/or reduced ribavirin were: lambda 240 µg: 11.2%; lambda 180 µg: 4.6%; lambda 120 µg: 10.2%; alfa: 20.3%. The proportion of patients who required ribavirin dose reductions for anemia were: lambda 240 µg: 0.7%; lambda 180 µg: 1.5%; lambda 120 µg: 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 µg: 17.4%; lambda 180 µg: 2.3%; lambda 120 µg: 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 µg: 7.6%; lambda 180 µg: 3.9%; lambda 120 µg: 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-naïve 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 µg (n=134), PEG-Interferon lambda 180 µg (n=131), PEG-Interferon lambda 120 µg (n=128) and PEG-Interferon alfa 180 µg (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 Hepatitis C1

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with blood. An estimated 170 million people worldwide are infected with hepatitis C. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, 20 percent will progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a curable disease.

###

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.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the compound described in this release will move from exploratory development into full product development, that clinical trials of this compound will support a regulatory filing, or that the compound will receive regulatory approval or become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2010, in our Quarterly Reports on Form 10-Q, and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

Contacts:
Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com
Investors: John Elicker, 609-252-4611, john.elicker@bms.com

References
1 World Health Organization. Hepatitis C. Available at: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index1.html. Accessed March 9, 2011.

Source

December 28, 2010

Pegylated Interferon-Lambda for Chronic Hepatitis C Virus Infection

Summary and Comment

In a phase Ib study, PEG-IFN-Lambda showed promise in both treatment-naive and relapsing patients.

The cornerstone for treating patients with hepatitis C virus (HCV) infection is pegylated interferon alfa (PEG-IFN-alpha ) plus ribavirin. However, adverse effects can reduce quality of life, lead to dose reductions, and even prompt discontinuation of therapy, with potential consequences for efficacy. Interferon-Lambda1, also known as interleukin-29, has shown in vitro antiviral activity similar to that of PEG-IFN-apha Unlike the widely distributed IFN-alpha receptors, expression of the IFN-Lambda1 receptor is more restricted, suggesting that a treatment that targets IFN-Lambda1 might be less prone to cause adverse effects.

In an industry-funded, open-label phase-Ib study, investigators tested the efficacy of PEG-IFN-Lambda in HCV genotype 1–infected patients. Twenty-four patients who had relapsed on PEG-IFN-alpha therapy received PEG-IFN-Lambda monotherapy (1.5 µg/kg or 3.0 µg/kg, either weekly or twice weekly), 25 patients who had relapsed on IFN-alpha therapy received PEG-IFN-Lambda (0.50–2.25 µg/kg weekly) plus ribavirin, and 7 treatment-naive patients received PEG-IFN-Lambda (1.5 µg/kg weekly) plus ribavirin. All treatments lasted 4 weeks; antiviral and safety assessments were made for at least another 4 weeks.

In two of the seven treatment-naive patients, HCV became undetectable by week 4. All PEG-IFN-Lambda doses induced virologic response, in a roughly dose-related pattern. Flu-like symptoms were uncommon; hematologic abnormalities were observed only in relation to use of ribavirin. The most commonly reported adverse symptoms were fatigue (29%), nausea (12%), and myalgias (11%). The incidence of adverse events was not dose related.

Comment: Current and future HCV therapies are likely to use interferon as the backbone. In this study, PEG-IFN-Lambda had strong antiviral activity with minimal adverse effects. If later-phase trials confirm the virologic response and low incidence of adverse effects, PEG-IFN-Lambda could become the foundation of future treatment regimens. Both treatment-naive and relapsing patients might then have treatment options that are more effective, better tolerated, and less likely to be discontinued than currently available therapies.

— David A. Johnson, MD

Published in Journal Watch Gastroenterology December 22, 2010

Citation(s):
Muir AJ et al. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology 2010 Sep; 52:822.

Medline abstract (Free)

October 31, 2010

BMS posts data update on investigational compound PEG-IFN lambda for hepatitis C, Data presented at AASLD today

Pipeline Asset Update for PEG-Interferon Lambda

Pipeline Asset: PEG-Interferon lambda, a novel and potential first-in-class interferon in development for the treatment of hepatitis C virus (HCV) infection

Current Phase of Development: Phase II

Meeting or Publication: American Association for the Study of Liver Diseases (AASLD) 2010

Study Title: Pegylated Interferon Lambda (PEG-IFN-Lambda) Phase II Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naïve HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12

Abstract Number: 821

Date/Time of Presentation: Sunday, October 31, 2010 from 8:00 a.m. – 5:30 p.m. EDT

Media Embargo: Per AASLD press guidelines, these data are no longer under embargo.

Study Objective: To assess the safety and antiviral activity of four fixed doses of PEG-IFN-lambda in treatment-naïve patients with HCV genotypes 1, 2, 3, and 4

Study Conclusion: At PEG-IFN-lambda’s three highest dosing levels (120 mcg, 180 mcg, 240 mcg), virologic response at 4 and 12 weeks was similar to or greater than that observed and reported with standard interferons (PEG-IFN-alpha).

Adverse events were mild to moderate in severity and led to few treatment discontinuations.

Efficacy Results: The proportion of patients in each dosing arm that achieved undetectable viral load varied by patient genotype. In this study, undetectable viral load was defined as HCV RNA <25 IU/mL.

Proportion of patients with HCV genotypes 2 or 3 who achieved undetectable viral load:

Dose                                Week 4     Week 12

PEG-IFN-lambda 80 μg      60%          80%

PEG-IFN-lambda 120 μg    100%        100%

PEG-IFN-lambda 180 μg    80%          80%

PEG-IFN-lambda 240 μg   100%        100%

PEG-IFN-alfa-2a 180 μg    100%        100%

Proportion of patients with HCV genotypes 1 or 4 who achieved undetectable viral load:

Dose                               Week 4    Week 12

PEG-IFN-lambda 80 μg        14%          14%

PEG-IFN-lambda 120 μg      43%          71%

PEG-IFN-lambda 180 μg      67%          67%

PEG-IFN-lambda 240 μg      43%          43%

PEG-IFN-alfa-2a 180 μg      40%          40%

Adverse Events: The rate of treatment-related serious adverse events (SAEs) through Week 12 was:

-- All doses of PEG-IFN-lambda: 4% (2/45)
-- PEG-IFN-alfa-2a: 10% (1/10)

The rate of discontinuations due to treatment-related adverse events (AEs) through Week 12 was:

-- All doses of PEG-IFN-lambda: 4% (2/45)
-- PEG-IFN-alfa-2a: 10% (1/10)

Adverse Event   PEG-IFN-alfa-2a           All doses of PEG-IFN-
                                 (n=10)                                 lambda
                                                                             (n=45)

Myalgia                      4 (40%)                              6 (13.3%)

Fatigue                       3 (30%)                            10 (22.2%)

Headache                  3 (30%)                            10 (22.2%)

Nausea                        3 (30%)                            10 (22.2%)

Injection site reaction  3 (30%)                              9 (20%)

Depression                  2 (20%)                              6 (13.3%)

Pruritus                       1 (10%)                              5 (11.1%)

Vomiting                     1 (10%)                              5 (11.1%)

Irritability                    1 (10%)                            11 (24.4%)

Insomnia                      0                                      11 (24.4%)

The majority of PEG-IFN-lambda adverse events were mild to moderate in severity. No apparent dose relationship was observed.

PEG-IFN-lambda Background: PEG-IFN-lambda is a novel and potential first-in-class interferon in development for the treatment of hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.

PEG-IFN-lambda is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C. The portfolio of investigational compounds, which also includes several small molecule direct-acting antivirals, fits into the company’s overall R&D focus on diseases where there is major unmet medical need.

Study Background: The EMERGE study is a two-part, randomized, controlled, multicenter phase II, phase II study of PEG-IFN lambda in treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4.

These data are from the first part of the EMERGE study. In this ongoing, open-label Phase IIa study, 55 patients were randomized to receive PEG-IFN-lambda at one of four dose levels (80, 120, 180 or 240 mg) or PEG-IFN-alpha at 180 μg. Patients received PEG-IFN lambda and PEG-IFN alpha administered subcutaneously on a weekly basis, as well as ribavirin on a daily basis, dosed according to HCV genotype and body weight. Patients with HCV genotype 2 or 3 were studied for up to 24 weeks; patients with genotype 1 or 4 were studied for up to 48 weeks.

Inclusion Criteria:
-- 18 to 70 years of age
-- HCV genotype 1, 2, 3, or 4 with HCV RNA ≥100,000 IU/mL at screening
-- Naïve to prior IFN therapy
-- ALT, AST ≤5.0x ULN; INR ≤1.2; bilirubin ≤1.5 mg/dL; albumin ≤ULN
-- No evidence of decompensated liver disease or cirrhosis

Exclusion Criteria:
-- Mixed genotype HCV infection
-- History of decompensated liver disease
-- Co-infection with HIV or hepatitis B virus
-- Active substance abuse

ClinicalTrials.gov Identifier: NCT01001754

Request for More Information and Media Interviews: Invest
ors: John Elicker, 609-252-4611, john.elicker@bms.com

Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com

Supporting information: The abstract can be viewed on the AASLD website.

Source

October 2, 2010

ZymoGenetics and Bristol-Myers Squibb to Present PEG-Interferon Lambda Phase 2a Interim Clinical Trial Results at AASLD 2010

SEATTLE & PRINCETON, N.J.--(BUSINESS WIRE)--Oct 1, 2010 - ZymoGenetics, Inc. (NASDAQ: ZGEN) and Bristol-Myers Squibb Company (NYSE: BMY) announced that interim results from Phase 2a of the EMERGE clinical trial of PEG-Interferon lambda administered with ribavirin in treatment-naïve hepatitis C virus patients, will be presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting in Boston, October 29 – November 2, 2010. PEG-Interferon lambda abstracts, including clinical, pharmacokinetic and viral kinetic data along with in vitro data in combination with direct-acting antiviral agents, were published today and are available on the AASLD website at http://www.aasld.org/.

AASLD 2010 PEG-Interferon lambda Poster Presentations

Title: Pegylated Interferon Lambda (PEG-IFN-Î») Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naïve HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12

Abstract: 821
Presenter: A.J. Muir
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM

Title: Pharmacokinetics of PEG-Interferon lambda (PEG-IFN-Î») Following Fixed Dosing in Treatment-Naïve Hepatitis C Subjects (Single Dose Interim Data from a Dose-Ranging Phase 2A Study)
Abstract: 830
Presenter: K.A. Byrnes-Blake
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM

Title: The Effect of Treatment Group, HCV Genotype, and IL28B Genotype on Early HCV Viral Kinetics in a Phase 2A Study of PEG-Interferon lambda (PEG-IFN-Î») in Hepatitis C Patients
Abstract: 831
Presenter: J.A. Freeman
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM

Title: In vitro activity of the combination of pegylated interferon lambda (PEG-IFN-Î») with direct-acting antivirals in the HCV replicon model
Abstract: 1854
Presenter: F. McPhee
Date: Tuesday, November 2, 2010
Time: 7:00 AM - 12:00 PM
About PEG-Interferon lambda

PEG-Interferon lambda (IL-29) is a novel and first in class interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.

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.

About ZymoGenetics

ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company developed and is marketing RECOTHROM® Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics' discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit http://www.zymogenetics.com/.

Bristol-Myers Squibb Forward-Looking Statements

This press release contains "forward-looking statements" relating to the acquisition of ZymoGenetics by Bristol-Myers Squibb. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the acquisition will be completed, or if it is completed, that it will close within the anticipated time period. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2009, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

Except for the historical information presented herein, matters discussed herein may constitute forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from any future results, performance or achievements expressed or implied by such statements. Statements that are not historical facts, including statements preceded by, followed by, or that include the words “future”; “anticipate”; “potential”; “believe”; or similar statements are forward-looking statements. Risks and uncertainties include uncertainties as to the timing of the tender offer and merger; uncertainties as to how many of the ZymoGenetics shareholders will tender their shares in the offer; the risk that competing offers will be made; the possibility that various closing conditions for the transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transaction; the effects of disruption from the transaction making it more difficult to maintain relationships with employees, licensees, other business partners or governmental entities; as well as risks detailed from time to time in ZymoGenetics' public disclosure filings with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009, subsequent quarterly filings on Form 10-Q and the Solicitation/Recommendation Statement filed in connection with the tender offer. The information contained in this release is as of September 28, 2010.

This press release is neither an offer to purchase nor a solicitation of an offer to sell shares of ZymoGenetics. Bristol-Myers Squibb Company and Zeus Acquisition Corporation have filed a tender offer statement with the SEC, and have mailed an offer to purchase, forms of letter or transmittal and related documents to ZymoGenetics shareholders. ZymoGenetics has filed with the SEC, and has mailed to ZymoGenetics shareholders a solicitation/recommendation statement on Schedule 14D-9. These documents contain important information about the tender offer and stockholders of ZymoGenetics are urged to read them carefully when they become available.

These documents will be available at no charge at the SEC's website at http://www.sec.gov/. The tender offer statement and the related materials may be obtained for free by directing a request by mail to Georgeson Inc., 199 Water Street, 26th Floor, New York, New York 10038 or by calling toll-free (800) 491-3096. In addition, a copy of the offer to purchase, letter or transmittal and certain other related tender offer documents (once they become available) may also be obtained free of charge from Bristol-Myers Squibb by directing a request to: Public Affairs, Telephone No.: (609) 252-6579; E-Mail: jennifer.mauer@bms.com.

ZymoGenetics Forward-Looking Statement

This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Phrases such as “look forward” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics' current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics' ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics' filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.

PEGASYS® (Peginterferon alfa-2a) is a registered trademark of Hoffmann-La Roche

Contact: Bristol-Myers Squibb

Media
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors
John Elicker, 609-252-4611
john.elicker@bms.com
or
ZymoGenetics
Media and Investors
Susan W. Specht, 206-442-6592
spechts@zymogenetics.com

Source

August 25, 2010

ZymoGenetics Announces Completion of Enrollment in Phase 2b Clinical Trial with PEG-Interferon lambda in Hepatitis C

Aug. 25, 2010, 6:00 a.m. EDT

SEATTLE, Aug 25, 2010 (BUSINESS WIRE) -- ZymoGenetics, Inc. /quotes/comstock/15*!zgen/quotes/nls/zgen (ZGEN 4.85, -0.01, -0.21%) today announced enrollment has been completed in the Phase 2b clinical trial with PEG-Interferon lambda and ribavirin in chronic hepatitis C virus (HCV) infection. ZymoGenetics is investigating PEG-Interferon lambda in collaboration with Bristol-Myers Squibb Company /quotes/comstock/13*!bmy/quotes/nls/bmy (BMY 25.81, -0.21, -0.81%) for the treatment of HCV infection.

"We're very pleased to have completed the enrollment in the Phase 2b PEG-IFN lambda clinical trial in less than three months," said Eleanor L. Ramos, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "The rapid enrollment to this study speaks to the motivation and enthusiasm of the clinical trial investigators to help address the unmet medical need in hepatitis C and also to the outstanding execution by our clinical team. We should now be able to assess the primary endpoint earlier than originally projected, and we look forward to assessing the data and planning for Phase 3."

The Phase 2 EMERGE study is an international, randomized multi-center clinical trial with PEG-Interferon lambda and ribavirin in treatment-naive patients with HCV. The Phase 2b study enrolled 570 patients with genotypes 1, 2, 3 and 4 chronic HCV infection. The study is assessing the safety and antiviral efficacy of three doses of PEG-Interferon lambda (120 mcg, 180 mcg and 240 mcg) compared to PEGASYS(R). Weekly subcutaneous doses of PEG-Interferon lambda or PEGASYS are being administered for 48 weeks in genotype 1 and 4 patients and for 24 weeks in genotype 2 and 3 patients. All patients also receive daily ribavirin. The primary endpoint of the trial is the proportion of patients who achieve undetectable levels of HCV RNA after 12 weeks of therapy (complete Early Virological Response). Achievement of Early Virologic Response will also be assessed by patient IL-28B genotype, which has been shown to be a robust predictor of treatment success with the combination of interferon-alpha and ribavirin.

PEG-Interferon lambda

PEG-Interferon lambda (IL-29) is a novel interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.

About ZymoGenetics

ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company has developed and is marketing RECOTHROM(R) Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus (HCV) infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics' discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit http://www.zymogenetics.com/.

ZymoGenetics Forward-Looking Statements

This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Words such as "believes," "should" and "could" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics' current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics' ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics' filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.

PEGASYS(R) (Peginterferon alfa-2a) is a registered trademark of Hoffman La Roche.

SOURCE: ZymoGenetics, Inc.

ZymoGenetics, Inc
Susan W. Specht 206-442-6592

Source