Thursday, April 19, 2012

EASL-All Oral Combo Daclatasvir and GS-7977=100% SVR Geno 1 and 91% SVR Geno 2 and 3 "SVR=4 weeks after-treatment"

What is SVR?
"Sustained virologic response," or sustained response is defined by no detectable hepatitis C virus six months after stopping therapy.

In the press release the participants in the clinical trial reached "SVR4" defined as no detectable hepatitis C virus four weeks after stopping therapy.

What is a  rapid and sustained viral response?
(RVR)-Rapid Viral Response; Is an undetectable viral load four weeks into treatment. In standard therapy if you have an RVR your chance of cure is better than 78% and 92%

In the clinical trial overall 100% of patients with genotype 1, 2, or 3 HCV achieved a rapid viral response-RVR.

**SVR12 has been highly correlated with SVR24, which is a recognized indicator of viral cure.

Press Release--
April 19, 2012 05:00 AM Eastern Daylight Time

All-Oral Combination of Investigational Hepatitis C (HCV) Compounds Daclatasvir and GS-7977 Achieved Sustained Virologic Response (SVR4) in 100% of Genotype 1 and 91% of Genotype 2 and 3 Treatment-Naïve Patients in Phase II Study

  • First demonstration of 100% SVR with once-daily, interferon- and ribavirin-free regimen in treatment-naïve genotype 1 HCV patients
  • First report of a study designed to assess antiviral efficacy of a NS5A replication complex inhibitor and a NS5B nucleotide polymerase inhibitor as potential combination HCV therapy
  • All-oral investigational treatment regimen suppressed viral load through 4 weeks post-treatment (SVR4) in genotypes 1, 2 and 3, with or without ribavirin
  • Data presented at The International Liver Congress in Barcelona

PRINCETON, N.J.--()--Bristol-Myers Squibb Company (NYSE: BMY) announced today interim results from a Phase II open-label study of daclatasvir, Bristol-Myers Squibb’s NS5A replication complex inhibitor, and GS-7977, a nucleotide NS5B polymerase inhibitor, in treatment-naïve patients with hepatitis C genotypes 1, 2 and 3. In this interim analysis, a combination of the two oral, once-daily investigational compounds taken for 24 weeks, with or without ribavirin, achieved a rapid and sustained viral response. Overall, 100% of patients with genotype 1, 2, or 3 HCV achieved viral load below the lower limit of quantification at Week 4 on treatment. In the genotype 1 HCV treatment groups, 100% of patients achieved sustained virologic response through four weeks off-treatment (SVR4). In the genotypes 2 and 3 treatment groups, 91% (40/44) of patients achieved SVR4. The data were presented today at the International Liver Congress (ILC), the 47th annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain.

The most frequent (≥25% overall) adverse events (AE) on treatment, based upon the most recent 12-week interim safety analysis, were fatigue, headache and nausea. Drug-related AEs were generally mild and did not lead to treatment discontinuation. Grade 3-4 laboratory abnormalities occurring in patients in the ribavirin treatment groups included anemia, elevated glucose, elevated fasting glucose, lymphopenia and low serum phosphorus, and the grade 3-4 laboratory abnormalities reported in the ribavirin-sparing treatment groups were low phosphorus and elevated cholesterol.

“The achievement of high SVR rates with a once-daily, pan-genotypic oral combination regimen has emerged as a key goal in HCV research,” said Mark Sulkowski, MD, Professor of Medicine, Medical Director, Viral Hepatitis Center, Johns Hopkins University School of Medicine. “The interim results of this study indicate that combining the potent antiviral activity of daclatasvir with a nucleotide analogue polymerase inhibitor has the potential to address this goal for the treatment of HCV genotypes 1, 2 and 3, and warrants further study to more fully evaluate this combination.”
Daclatasvir has demonstrated potent antiviral activity against HCV genotypes 1, 2, 3, and 4 in vitro.

Study Results
In the study, 88 treatment-naïve patients were divided into six treatment groups. The proportions of patients achieving viral load below the lower limit of quantification (HCV RNA <25 IU/mL) were:
Week 4
Week 12
Week 24
Week 4
Post-Treatment (SVR4)a
7-day lead-in dose of GS-7977, then
DCV + GS-7977 for 23 weeks
GT 1 100%
GT 2/3 100%
DCV + GS-7977 for 24 weeks GT 1 100%
GT 2/3 100%
DCV + GS-7977 + ribavirin for 24 weeks GT 1 100%
GT 2/3 100%
a In this study, SVR4 was defined as viral load below the lower limit of quantification. All but one patient who achieved SVR4 also had undetectable viral load (HCV RNA <10 IU/mL); this patient had undetectable viral load when retested eight days later.
b One patient experienced viral relapse and one patient experienced viral breakthrough.
c Two patients were lost to follow-up.
Safety data from this ongoing study are available through 12 weeks on-treatment. The most frequent (≥25% overall) adverse events (AEs) on treatment were fatigue, headache and nausea. AEs were generally mild to moderate intensity and did not lead to treatment discontinuation. Grade 3-4 laboratory abnormalities included anemia, elevated glucose, elevated fasting glucose, lymphopenia and low serum phosphorus– all of which occurred in patients who received ribavirin. Grade 3-4 laboratory abnormalities reported in the ribavirin-sparing treatment groups were low phosphorus and elevated cholesterol. Two patients discontinued treatment for non-drug related AEs and both achieved SVR4. An additional two patients with genotype 2 who received daclatasvir, GS-7977 and ribavirin discontinued the study for non-AE-related reasons and were lost to follow-up. No patients discontinued therapy due to treatment-related AEs. Of the 88 patients treated, one patient with genotype 3 HCV who received GS-7977 and daclatasvir without ribavirin experienced viral relapse, and one patient met the protocol definition of viral breakthrough – HCV RNA below the lower limit of quantification on or after Week 8, confirmed by immediate retesting. This definition of viral breakthrough is not widely accepted and has since been removed from the protocol.

About the Study
This Phase II study (AI444-040) was designed to evaluate the potential to achieve sustained virologic response with an oral, pan-genotypic, once-daily treatment regimen combining daclatasvir (DCV) and Gilead Sciences Inc.’s GS-7977, with or without ribavirin, in patients chronically infected with HCV genotypes 1, 2 and 3. In the initial phase of this study, patients were randomized into six groups, evaluating three different dosing schedules in patients with HCV genotype 1 (n=44) and in patients with HCV genotype 2 or 3 (n=44).
  • GS-7977 400 mg QD for 7 days then DCV 60 mg QD + GS-7977 400 mg QD for 23 weeks
  • DCV 60 mg QD + GS-7977 400 mg QD for 24 weeks
  • DCV 60 mg QD + GS-7977 400 mg QD + ribavirin for 24 weeks
The study was subsequently expanded to include four new treatment arms that evaluate HCV genotype 1 patients who have previously failed telaprevir or boceprevir treatment, and shorter duration of therapy in treatment-naïve HCV genotype 1 patients. These treatment groups are currently under study.

The primary endpoint of the study is sustained virologic response 12 weeks post-treatment (SVR12). An interim analysis for safety and antiviral activity was conducted at 12 weeks on-treatment. An additional interim analysis for antiviral efficacy was conducted four weeks post-treatment. Final study results will be presented at a future medical meeting.

About Hepatitis C
Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

About Bristol-Myers Squibb
Bristol-Myers Squibb is studying a portfolio of compounds that aim to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes a portfolio of compounds with different mechanisms of action, pursuing both biologics as well as small molecule antivirals. These compounds are being studied as part of multiple novel treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies. Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials and is currently in Phase III development.
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 or follow us on Twitter at

Bristol-Myers Squibb Forward Looking Statement
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 the clinical trials of this compound will support regulatory filings, or that the compound will receive regulatory approvals or, if approved, that the compound will 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, 2011, 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.

Bristol-Myers Squibb:
Sonia Choi, 609-252-5132
John Elicker, 609-252-4611

In The News

Gilead, Bristol Put Profits Ahead of Best Care for Hep C Patients

By Adam Feuerstein

BARCELONA (TheStreet) -- The most effective new therapy for hepatitis C -- two pills that could cure nearly every patient treated -- may never see the light of day because the developers of these new medicines, Bristol-Myers Squibb(BMY) and Gilead Sciences(GILD), seem unable to work together.

Apparently, profits are more important than best patient care.The new Hep C therapy at issue here combines Bristol's daclatasvir with Gilead's GS-7977. Each is a single pill administered once a day. The results from this new therapy are nothing short of spectacular -- an early cure rate of 100% for genotype 1 patients and 91% of genotype 2/3 patients, according to data from a mid-stage study announced Thursday at the European Association for the Study of Liver Disease (EASL) meeting.

A 100% cure rate for genotype 1 patients! Obviously, results can't get better than that.
You'd think there'd be a rush to move the combination regimen of daclatasvir and GS-7977 into a larger, confirmatory phase III trial, but you'd be mistaken. Amazingly, this most promising new treatment for hepatitis C patients may actually be discontinued because Bristol and Gilead can't work together.

Good luck understanding why Bristol and Gilead can't come together to help Hep C patients. The companies can't even agree on the fact that the two companies are not agreeing.

"Given the strong SVR4 [early cure] data from the combo trial of daclatasvir (DCV) + GS-7977, and in the interest of advancing the science and for the benefit of patients, we were interested in a Phase III collaboration. Unfortunately Gilead was not interested," said Bristol spokeswoman Cristi Barnett.
Gilead spokeswoman Amy Flood responded, "That's not the case. There are a number of new data sets at EASL and we need to evaluate and understand all of them. We're going to do that, and look at the best option or options for proceeding as quickly as possible to advance the best all-oral regimen."
Gilead may have $11 billion worth of reasons for not wanting to hook up with Bristol, as in the money spent by the company to acquire Pharmasset this year and gain control of GS-7977. Gilead spent outrageously to buy Pharmasset in an attempt to dominate the future of Hep C treatment in much the same way it already dominates the HIV market.

Gilead needs to justify that $11 billion and deliver profits and returns to its shareholders. Collaborating with Bristol would more than likely dilute Gilead's Hep C profits, which helps explain why Gilead isn't exactly thrilled to push ahead with the daclatasvir GS-7977 combination.

Instead, Gilead would prefer to combine GS-7977 with GS-5885, another drug it owns 100% that belongs to the same NS5A inhibitor class as daclatasvir. But a lot of work remains to be done on GS-5885; it may not be as safe or as effective as daclatasvir. It could also take longer for this all-Gilead combination to reach the market, which means Hep C patients in need of treatment will suffer.

Bristol is in a similar situation. Without access to GS-7977, the company is likely to move ahead with a combination of daclatasvir and INX-189, which belongs to the same nucleoside, or "nuc" class of drugs as GS-7977. Bristol acquired INX-189 when it bought Inhibitex for $2 billion earlier this year.
Bristol still has a lot of work to do with the daclatasvir-INX-189 combination before it can move into phase III studies, which also potentially means Hep C patients will be waiting longer.

Idenix Pharmaceuticals(IDIX_) is also working on a regimen combining an NS5A inhibitor with a nuc, but those clinical studies are well behind Bristol and Gilead.

Regardless of who's to blame in this Bristol-Gilead spat, Hep C patients in need of convenient and potent new cures are being hurt. It remains to be seen if leading Hep C doctors, patient advocacy groups or medical societies like EASL will object and pressure the companies to move daclatasvir and GS-7977 into phase III studies as soon as possible.
Drug companies always say patients come before profits, but that feels like nothing more than an empty slogan today.
--Written by Adam Feuerstein in Boston.

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UPDATE: Gilead, Bristol's Hepatitis C Drugs Show Promise In Study
Source - News: Dow Jones

--Gilead/Bristol combination had 100% viral suppression in most common type of hepatitis C
--Gilead reports positive results for GS-7977 in separate study--Results bolster prospects for interferon-free, all-oral regimens
(Adds details of Gilead study, analyst reaction and stock prices.)
By Peter Loftus
A regimen combining experimental drugs from Gilead Sciences Inc. (GILD) and Bristol-Myers Squibb Co. (BMY) suppressed the hepatitis C virus in most patients four weeks after completing treatment, according to a new study.

In a separate study, Gilead said a combination of its drug, GS-7977, with an older drug, ribavirin, suppressed the liver-disease-causing virus in most patients four weeks after treatment.
The results bolster the prospects for an all-oral regimen for hepatitis C that eliminates an injectable drug used in the current standard treatment, interferon, which can be difficult for patients to tolerate.
Bristol-Myers, Gilead and others including Abbott Laboratories (ABT) are racing to bring an all-oral hepatitis C regimen to market, hoping to tap what is expected to be a multibillion-dollar market for such a therapy.

Gilead shares rose 14% to $52.95 in premarket trading. The company appears to be leading the race of new oral hepatitis C treatments, as it hopes to bring a GS-7977-based therapy to market late next year or in 2014. Bristol was up 2.2% at $34.30.

UBS analyst Matthew Roden said the data released Thursday puts Gilead "squarely in the driver's seat" in developing the next-generation hepatitis C regimen. He noted that Gilead was developing another drug that could be substituted for the Bristol-Myers drug in further development.
Hepatitis C is a viral disease that attacks the liver, and is believed to afflict about 180 million world-wide, with more than 4 million in the U.S., according to the National Institute of Allergy and Infectious Diseases. One research firm has estimated that the world-wide hepatitis C market could reach $16 billion in 2015, up from $1.7 billion in 2010.

The Gilead and Bristol data were among several new studies of hepatitis C therapies released Thursday at the annual scientific meeting of the European Association for the Study of the Liver, or EASL, in Barcelona.

The study tested Gilead's GS-7977, which it acquired in its $11 billion purchase of Pharmasset earlier this year, and Bristol-Myers' daclatasvir. Each works by a different mechanism to attack hepatitis C, which can cause inflammation of the liver.

The Gilead compound, GS-7977, is a so-called nucleotide inhibitor, or "nuke," which Gilead believes could be the cornerstone of the first all-oral regimen for hepatitis C. Bristol's daclatasvir is known as an NS5A replication complex inhibitor.

The companies studied three regimens in 88 hepatitis C patients who hadn't received prior therapy. In one arm, patients were assigned to take GS-7977 for seven days, then a combination of GS-7977 and daclatasvir for 23 weeks. The second group was assigned to take both drugs for 24 weeks, and the third group took both drugs plus an older drug, ribavirin, for 24 weeks.
Each of three regimens had patients divided into two groups: those with genotype 1 hepatitis C--the most common form of the disease in the U.S. and one that is difficult to treat--and a group combining genotypes 2 and 3.

At four weeks following completion of treatment, 100% of the genotype 1 patients across all three treatment regimens had achieved a sustained virologic response, or SVR 4, according to Bristol-Myers. A sustained virologic response that holds up over time is considered by many doctors to be a cure.

Among the genotype 2/3 patients, 91% achieved SVR 4. The breakdown was 100% in the group that received GS-7977 and daclatasvir for 24 weeks; 88% in the group receiving the seven-day lead-in with GS-7977; and 86% for the group that received ribavirin in addition to the experimental drugs.
Adverse events included fatigue, headache and nausea, and were generally mild to moderate.
Bristol and Gilead are awaiting additional data on whether the liver-disease-causing virus remains suppressed over a longer follow-up period. They are also studying whether halving the course of treatment to 12 weeks will achieve the same results.

The results "clearly put this combination into a leading position," said Douglas J. Manion, a senior vice president in Bristol's research-and-development division.

However, Manion said Gilead hasn't agreed to move the combination regimen into a late-stage, or Phase 3, study that could generate data to support a filing for regulatory approval. It's possible Gilead would seek to further develop GS- 7977 with its own NS5A inhibitor, rather than Bristol's.
"There are a lot of encouraging data sets here at EASL, including for our own NS5A and non-nucleoside, to consider," said John McHutchison, Gilead's senior vice president of liver disease therapeutics. "We're going to look at everything presented here and be scientific in our approach as we consider the best option for proceeding as quickly and efficiently toward a safe, simple, all-oral regimen."

Bristol-Myers recently obtained another so-called "nuke" drug with its $2.5 billion acquisition of Inhibitex.

In a separate study, Gilead tested GS-7977 plus ribavirin in treatment-naive patients with genotype 1 hepatitis C. Of the 25 patients who completed 12 weeks of treatment, 88% achieved SVR 4, Gilead said.

Adverse events included fatigue, dizziness and headache.

In a press release, the lead investigator of the Gilead study said 12 weeks of GS-7977 and ribavirin may be enough to cure hepatitis C in many genotype 1 patients.

-By Peter Loftus, Dow Jones Newswires; +1-215-982-5581;

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