HCV-Targeting Therapy Shows More Promise

By Michael Smith, North American Correspondent, MedPage Today

Published: April 23, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse

AMSTERDAM – An investigational drug that acts directly against the hepatitis C virus (HCV) works quickly and effectively, according to new reports.

Each report on the oral nucleotide analogue sofosbuvir, appearing in the New England Journal of Medicine, focuses on different patient populations, but, with one exception, they suggest that the drug can deliver high cure rates and an acceptable safety profile with 12 weeks of therapy.

In contrast, the current standard of care – involving pegylated interferon and ribavirin -- can take up to 48 weeks.

All of the findings will be presented this week at the Internal Liver Congress sponsored by the European Association for the Study of the Liver.

The data suggest that "a radical change in clinical practice is imminent," according to Joost P.H. Drenth, MD, PhD, of Radboud University Nijmegen Medical Center in Nijmegen, the Netherlands.

In an accompanying NEJM editorial, Drenth argued that the arrival of new agents that act directly against the virus is "unprecedented" and raises the hope that clinicians will be able to do away with interferon, which is regarded as hard to take and dangerous to use.

In particular, it has been just 3 years between the publication of the chemical structure of the compound and the current phase III trials.

In many ways, Drenth noted, treatment of HCV today is a matter of managing the adverse effects of the standard treatments and many researchers are eyeing the demise of interferon therapy.

But since ribavirin is still in the game – playing an important role in all four of these studies – "it may be premature to start dismantling the dedicated [treatment] centers now that interferon is in retreat," he wrote.

In one industry-sponsored phase III trial – dubbed NEUTRINO -- Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand, and colleagues investigated the effect of sofosbuvir in 327 patients mainly with HCV genotype 1, although a handful of patients had genotypes 4, 5, and 6.

They were treated with the drug, plus pegylated interferon and ribavirin, for 12 weeks in a single-arm, open-label study. For genotype 1 patients, the current standard of care is one of two approved protease inhibitors for 12 to 32 weeks combined with 24 to 48 weeks of peginterferon and ribavirin.

The primary endpoint of the study was the so-called sustained virologic response 12 weeks after the end of therapy (SVR₁₂), where SVR was defined as a viral load too low to quantify.

Gane and colleagues noted that regulatory authorities had agreed that a comparator arm using the standard of care was not needed, owing to the "expectation of high response rates, improved safety, and shorter treatment duration."

In fact, they found that 90% of the patients reached an SVR₁₂, compared with an adjusted historical response rate of 60%. There were no major differences in response rates by genotype -- 89% for the 291 patients with HCV genotype 1 and 96% for the 28 genotype 4 patients, while all six patients with genotype 6 and the lone genotype 5 patient reached SVR₁₂.

In the second industry-sponsored phase III study called FISSION, Gane and colleagues studied the effect of 12 weeks of sofosbuvir and ribavirin in 499 patients with viral genotypes 2 and 3, compared with 24 weeks of pegylated interferon and ribavirin, which is the standard of care for such patients.

The study was designed to shown noninferiority of the all-oral sofosbuvir/ribavirin regimen to the standard regimen, in which interferon is given intravenously.

Gane and colleagues reported that SVR₁₂ rates for the two regimens were identical at 67%, showing the all-oral regimen was not inferior to standard care.

In both studies, the most common adverse events were fatigue, headache, nausea, and insomnia.

Patients with HCV genotypes 2 and 3 were the target of the two other industry-sponsored phase III studies, reported by Ira Jacobson, MD, of Weill Cornell Medical College in New York City, and colleagues in NEJM.

The POSITRON trial looked at 278 patients for whom treatment with peginterferon was not an option, because of other health issues such as psychiatric or autoimmune disorders.

They were randomly assigned in roughly a 3:1 fashion to get either oral sofosbuvir and ribavirin or placebo for 12 weeks. Jacobson and colleagues reported that the SVR₁₂ rate was 78% among those treated with sofosbuvir and ribavirin versus 0% in the placebo group (P<0.001).

The second trial by Jacobson's group studied 201 patients who had not responded to previous therapy with interferon and ribavirin and were randomly assigned to receive sofosbuvir and ribavirin for either 12 or 16 weeks.

Jacobson and colleagues found that half the patients who got the 12 weeks of therapy achieved an SVR₁₂, compared with 73% among those treated for 16 weeks. The 23-percentage point difference was significant (P<0.001).

As in the other studies, the most common adverse events were headache, fatigue, nausea, and insomnia. Overall, only 1% to 2% rate of patients stopped using sofosbuvir.

Both studies were supported by Gilead Sciences. Gane reported financial links with Gilead, Janssen-Zilag, Novartis, AbbVie, Roche, and Vertex. Jacobson reported financial links with Abbott, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta, Gilead Sciences, GlaxoSmithKline, Idenix, Kadmon, Novartis, Presidio, Roche–Genentech, Schering-Plough (now part of Merck), Tibotec, and Vertex Pharmaceuticals.

Primary source: New England Journal of Medicine
Source reference:
Lawitz E, et al "Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection" N Engl J Med 2013; DOI: 10.1056/NEJMoa1214853.

Additional source: New England Journal of Medicine
Source reference:
Jacobson IM, et al "Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options" N Engl J Med 2013; DOI: 10.1056/NEJMoa1214854.

Additional source: New England Journal of Medicine
Source reference:
Drenth JP "HCV Treatment -- No More Room for Interferonologists?" N Engl J Med 2013; DOI: 10.1056/NEJMe1303818.

Source

Also See: Data from Phase 3 Studies of Gilead’s Sofosbuvir for Hepatitis C To Be Presented at 48th Annual EASL Meeting; Findings Published Online Today in The New England Journal of Medicine

Horse race heats up to find the next best thing in hepatitis C treatment

Purification of potential hepatitis C treatment at Gilead Sciences lab

April 23, 2013, 4:41 PM

By Russ Britt

(Corrected to note AbbVie is in phase 3 of trials.)

With an international conference as a backdrop, the four-company horse race to get the next best thing for treating hepatitis C — an oral medication — heated up Tuesday as all four got the word out on progress developing their weapons against the liver ailment.

Bristol-Myers Squibb Co. /quotes/zigman/220498/quotes/nls/bmyBMY+1.07%, AbbVie Inc. /quotes/zigman/13067932/quotes/nls/abbvABBV+0.02%, Merck & Co. /quotes/zigman/574389/quotes/nls/mrkMRK-0.21% and Gilead Sciences Inc. /quotes/zigman/72849/quotes/nls/gildGILD-0.62% all were vying for investors’ affection — and getting it in some cases in Tuesday trading. The European Association for the Study of the Liver conference in Amsterdam was the setting for an onslaught of presentations by the various companies hoping to get the upper hand in getting their treatments to market.

A paper released in the New England Journal of Medicine Tuesday seemed to give Gilead the edge, though it was hard to tell from the company’s stock price. Shares were down 1.3% to $53.33 at the close.

Gilead’s phase 3 testing showed that a combination of the company’s sofosbuvir along with ribavirin wiped out the disease in all patients after a 12-week treatment program, noting that 97% to 99% of the virus was eliminated in patients within four weeks.

Gilead is considered the furthest along and is expected to seek marketing approval next year. But AbbVie released findings on Tuesday that showed its treatment, a combination of five oral drugs, cured 88% of patients after eight weeks and 99% after 12 weeks. AbbVie’s results were done in November, during phase 2 of testing, and it has since moved on to phase 3. It was rewarded by investors at first as shares jumped more than 4% at one point. Shares settled back for a 2% gain to $45.14 by session’s end.

Bristol-Myers jumped on the bandwagon by noting that phase 2 tests of its three-drug medication achieved high rates of success in 94% of patients anywhere between four to 36 weeks. The company plans to start phase 3 testing later this year. Shares were up marginally to $42.30.

And Merck let it be known that its hepatitis C solution, a concoction of three medications, would be presented later this week at the Amsterdam gathering. Phase 2 testing showed continued response for up to 92% patients after 24 weeks. Shares closed higher by 1.5% to $48.63.

Current hepatitis C treatments can take up to a year and generally come in injected forms. The market is considered lucrative because the disease affects 170 million people worldwide.

Stay tuned……

Follow Russ Britt on Twitter @russbrittmktw

Follow Health Exchange on Twitter @MWHealthBlog

Source

Hepatitis C drug nears approval

Nature News Blog

23 Apr 2013 | 11:01 BST | Posted by Lauren Morello | Category: Drug discovery

Posted on behalf of Beth Mole.

A highly anticipated new drug for treating hepatitis C has sailed through its first phase III clinical trials, according to two papers published today in the New England Journal of Medicine.

Sofosbuvir, a new antiviral developed by Gilead Sciences of Foster City, California, is one of several drugs in the pipeline that could replace hepatitis C treatments that incorporate the immune-boosting drug interferon, which can cause harsh side effects including depression, anaemia and severe flu-like symptoms. Up to 170 million people worldwide are infected with blood-borne hepatitis C virus (HCV), including as many as 4 million people in the United States. Long-term exposure to the virus can cause chronic liver disease and cancer. Current therapies that combine the antiviral drug ribavirin and interferon cure up to 75% of those treated, but take as long as a year to do so.

Facing a lengthy drug regimen that can produce debilitating side effects, many patients — who may not develop liver damage for years — delay or refuse treatment. And with the promise of better drugs on the way, some doctors approve waiting.

The two papers published today suggest that the wait for improved hepatitis C treatment regimens may be coming to an end. Researchers led by Ira Jacobson of Weill-Cornell Medical College in New York report that a combination of sofosbuvir and ribavirin cured up to 78% of trial participants infected with two types of HCV — genotypes 2 and 3 — in as few as three months, without the need for interferon. That result is similar to outcomes from earlier phase II trials. Another team, led by Eric Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio, showed that a combination of sofosbuvir, ribavirin and interferon cured up to 90% of patients with HCV genotype 1, the most common variety.

“The results are certainly a step forward,” says David Thomas, a hepatitis C expert at the Johns Hopkins Center for Global Health in Baltimore, Maryland. But he adds that most physicians will be more excited to see results from an ongoing trial that is testing the effectiveness of treating HCV genotype 1 patients with sofosbuvir without interferon.

In the meantime, Gilead is seeking approval to market sofosbuvir in the United States. The company submitted an application for new drug approval to the US Food and Drug Administration (FDA) on 8 April.

Thomas says this first set of phase III trials puts sofosbuvir well on the path towards FDA approval. “This starts the clock,” he says, adding that he has already scheduled one of his HCV genotype 1 patients to come in for an interferon-free treatment regimen in December.

Source

Also See: Data from Phase 3 Studies of Gilead’s Sofosbuvir for Hepatitis C To Be Presented at 48th Annual EASL Meeting; Findings Published Online Today in The New England Journal of Medicine

Boehringer Ingelheim’s Faldaprevir-Based Treatment Regimen Achieved Viral Cure in up to 80 Percent of Patients with Hepatitis C in Phase 3 Pivotal Trial

April 23, 2013

- STARTVerso™1 data presented in treatment-naïve patients with genotype-1 hepatitis C treated with investigational faldaprevir and pegylated interferon/ribavirin
- Statistically significant viral cure rates achieved versus placebo plus PegIFN/RBV with similar rates of treatment discontinuation
- The majority of patients qualified for shorter treatment duration of 12 weeks faldaprevir/24 weeks PegIFN/RBV and achieved viral cure (SVR12)

For U.S. Media Only

Ridgefield, CT, April 23, 2013 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from the pivotal Phase 3 STARTVerso™1 trial of faldaprevir (BI 201335) in combination with pegylated interferon and ribavirin (PegIFN/RBV). In previously untreated patients with genotype-1 hepatitis C virus (HCV) who received once-daily faldaprevir plus PegIFN/RBV, 79% and 80% in the 120mg and 240mg arms, respectively, achieved viral cure when measured 12 weeks after treatment was completed (SVR12). This is compared with 52% of patients receiving PegIFN/RBV plus placebo (p<0.0001).

In addition, protocol-defined early treatment success (ETS)* was achieved by 87% and 89% of patients treated with the faldaprevir-based regimen (120mg or 240mg, respectively), meaning they were eligible for an overall shorter treatment duration of 12 weeks faldaprevir/24 weeks PegIFN/RBV. Of those patients who completed treatment early, 86% and 89% (120mg, or 240mg, respectively) went on to achieve viral cure (SVR12). This demonstrates that an overall treatment regimen of 24 weeks was sufficient to achieve viral cure in most patients, cutting treatment duration in half when compared to treatment with PegIFN/RBV alone (48 weeks). A goal in HCV treatment innovation is to reduce the amount of time patients are exposed to treatment with interferon.

STARTVerso™1 included a diverse range of genotype-1a and 1b patients, including patients with compensated cirrhosis (a condition where the liver is heavily scarred but still able to function), who are challenging to treat and cure. The results will be presented tomorrow at EASL’s International Liver Conference™ (ILC) as part of the official press conference and by Professor Peter Ferenci as a late-breaking oral presentation on April 27 (abstract #3281).

“In the STARTVerso™1 study, faldaprevir has shown efficacy in a range of genotype-1a and 1b HCV patients with and without cirrhosis,” said Principal Investigator Professor Peter Ferenci of the Medical University Vienna. “The viral cure rates and potential for shorter treatment duration seen in STARTVerso™ 1 are very encouraging for the many patients currently facing a year of interferon-based treatment.”

Serious adverse events were experienced by 6% (n=8) of placebo patients, 7% (n=17) of patients receiving 120mg faldaprevir and 7% (n=17) of patients receiving 240mg faldaprevir. Anemia (11%, 13%, 12%), rash (6%, 8%, 9%) and gastrointestinal issues (3%, 7%, 12%) were the most common Grade 2-4 adverse events in placebo, faldaprevir 120mg and faldaprevir 240mg arms, respectively. No rash events were life-threatening; 1% of patients discontinued treatment in each study arm due to rash. Adverse events led to discontinuation of study medications in 4% (n=5), 4% (n=10) and 5% (n=14) in the placebo, faldaprevir 120mg and faldaprevir 240mg arms, respectively.

“With the results of the first of our pivotal faldaprevir trials, STARTVerso™1, now available, Boehringer Ingelheim is making strides toward our short-term goal of providing a treatment option with a shorter duration for HCV patients eligible for interferon-based regimens,” said Peter Piliero, MD, vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “We are developing faldaprevir as a potential foundation for both interferon-based and interferon-free treatment regimens. We are optimistic that ongoing studies with our pipeline compounds will lead to faldaprevir-based interferon-free regimens for patients with HCV.”

In separate abstracts at EASL’s ILC meeting, sub-analyses from Boehringer Ingelheim’s interferon-free Phase 2b SOUND-C2 study are also being presented. These include data regarding viral response rates by level of fibrosis (abstract #1227), predictors of anemia (abstract #1186) and pharmacokinetic modeling of the relationship between virologic response and the level of faldaprevir or BI 207127 found in the blood (abstract #1212). The SOUND-C2 trial evaluated the interferon-free combination of faldaprevir and BI 207127, an investigational non-nucleoside NS5B polymerase inhibitor, plus ribavirin.

Presentation abstracts can be accessed through the congress website.

About STARTVerso™1

STARTVerso™1 is a double-blind, placebo-controlled Phase 3 trial of faldaprevir in combination with PegIFN/RBV. The study enrolled and treated 652 treatment-naïve patients from Europe and Japan who were infected with chronic genotype-1 HCV. Patients were randomized to receive PegIFN/RBV in combination with a once-daily dose of 120mg faldaprevir, 240mg faldaprevir or placebo. Treatment duration depended on whether patients met criteria for ETS, protocol-defined early treatment success (week 4 below limit of quantification [BLQ] and week 8 below limit of detection [BLD]).

• Group 1: All patients received 24 weeks of placebo with PegIFN/RBV followed by 24 weeks of PegIFN/RBV (48 weeks total treatment).
• Group 2: All patients received 12 weeks of 120mg faldaprevir with PegIFN/RBV. Patients who met ETS criteria received an additional 12 weeks of PegIFN/RBV (24 weeks total treatment). Patients who did not meet ETS criteria received an additional 12 weeks of 120mg faldaprevir with PegIFN/RBV followed by 24 weeks of PegIFN/RBV (48 weeks total treatment).
• Group 3: All patients received 12 weeks 240mg faldaprevir with PegIFN/RBV followed by 12 weeks of PegIFN/RBV. Patients who met ETS criteria stopped treatment after 24 weeks total treatment. Patients who did not meet ETS criteria received an additional 24 weeks of PegIFN/RBV (48 weeks total treatment).

About Boehringer Ingelheim in Hepatitis C Virus (HCV)

In partnership with the scientific community, our clinical trial program is rigorously designed to find answers to the challenges that HCV patients face, including those who are the most difficult to treat. Our pivotal HCV clinical trials for faldaprevir and BI 207127 are comprised of two multi-trial programs, STARTVerso™ and HCVerso™.

Faldaprevir, also known as BI 201335, is an investigational, oral protease inhibitor that is specifically designed to target viral replication in the liver. Boehringer Ingelheim is developing faldaprevir as a core component of both interferon-based and interferon-free hepatitis C treatment regimens. STARTVerso™1 is the first of an ongoing multi-study Phase 3 trial program that is evaluating faldaprevir combined with PegIFN/RBV. Three additional trials in treatment-naïve, treatment-experienced and HIV co-infected patients with chronic genotype-1 HCV are near clinical completion. BI 207127 is an investigational NS5B non-nucleoside polymerase inhibitor that has shown the potential to eliminate interferon from HCV treatment when combined in a regimen with faldaprevir and RBV. Phase 2 trials of this interferon-free regimen have been completed and Phase 3 HCVerso^TM trials investigating this regimen are now underway. As part of our long-term commitment to HCV, the company is exploring other combinations of investigational HCV compounds that work in complementary ways. The recent collaboration of Boehringer Ingelheim with Presidio Pharmaceuticals, Inc. for a Phase 2 clinical study investigating an interferon-free, all-oral combination is part of the company’s continued commitment to discover and develop innovative options for the treatment of HCV.

Faldaprevir and BI 207127 are investigational compounds and not approved by the FDA. Their safety and efficacy have not been established.

Hepatitis C is a blood-born infectious disease and a leading cause of chronic liver disease, transplant and failure that affects as many as 150 million people globally. In the United States, an estimated 4.1 million Americans have been infected with HCV, of which approximately 3.2 million have chronic HCV infection. Since 1999 there has been a significant increase in deaths due to chronic HCV, which accounts for 10,000 - 12,000 deaths in the United States per year.

About Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

*ETS = protocol-defined early treatment success (week 4 below limit of quantification [BLQ] and week 8 below limit of detection [BLD])

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High Rates of SVR Demonstrated in Phase II Study with Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 in Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C Infection

• This all-oral treatment regimen is being studied as an interferon-free and ribavirin-free option
• Investigational regimen involves three different classes of direct-acting antivirals (DAAs) - an NS5A replication complex inhibitor, an NS3 protease inhibitor and an NS5B non-nucleoside polymerase inhibitor
• Phase III development as a fixed-dose combination is anticipated to begin by late 2013

Tuesday, April 23, 2013 6:01 am EDT

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced additional, interim Phase II data demonstrating that 12- and 24-week Triple DAA treatment regimens of daclatasvir (DCV), asunaprevir (ASV) and BMS-791325 (’325) achieved high rates of sustained virologic response (SVR) of up to 94%, in treatment-naïve, genotype 1 chronic hepatitis C patients, at time points ranging from 4 to 36 weeks post-treatment depending on the treatment group. These data support the continued development of this interferon alfa-, ribavirin (RBV)- and ritonavir (RTV)-free regimen, with Phase III initiation anticipated to begin by late 2013.

The study results will be presented this week at the International Liver Congress, the 48^th annual meeting of the European Association for the Study of the Liver (EASL), in Amsterdam.

Two serious adverse events (2/66), renal calculus and cerebral vasoconstriction, were reported in this study. The renal calculus was determined by the investigator to be unrelated to study drug. The cerebral vasoconstriction was associated with treatment intensification with peginterferon alfa and ribavirin following viral breakthrough in one patient. Headache was the most common adverse event in the study (27.3%, 18/66).

“The diversity of the hepatitis C patient population requires multiple treatment options that can enable a personalized approach to therapy. Effective and well-tolerated oral treatment regimens that are ribavirin-free remain an important unmet medical need in hepatitis C,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “These data, which demonstrate comparable efficacy among the 12- and 24-week Triple DAA treatment groups, support the rapid Phase III development of this investigational Triple DAA regimen and provide further data on daclatasvir as an important component of DAA-based therapy.”

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an oral, NS3 protease inhibitor in Phase III development with daclatasvir. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase II development for hepatitis C as a component of daclatasvir-based treatment regimens.

Study Design and Results

This open-label, two-part Phase II study is designed to evaluate the safety and antiviral activity of the investigational hepatitis C treatment regimen of DCV, ASV and ‘325 in treatment-naïve patients with genotype 1a and 1b chronic hepatitis C infection. The primary endpoint of the study is viral load below the lower limit of quantitation (LLOQ; HCV RNA <25 IU/mL) at 12 weeks post-treatment (SVR₁₂).

Part 1 of the study evaluated a treatment regimen of DCV 60 mg QD, ASV 200 mg BID and ‘325 75 mg BID for 24 or 12 weeks (Groups 1 and 2, respectively). Part 2 of the study evaluated the same DAA regimen for 24 or 12 weeks, with ‘325 dosed at 150 mg BID (Groups 3 and 4, respectively).

Interim results for Part 1 of the study were previously reported at the American Association for the Study of the Liver (AASLD) annual meeting in November 2012.

The study was expanded in November 2012, adding eight new treatment groups including the evaluation of this Triple DAA regimen in treatment-naïve patients with HCV genotype 4 and null responders with HCV genotype 1. Results from these treatment groups are not yet available.

Virologic Response

• 100% (28/28) of patients in Groups 1 and 2 (24- and 12-week treatment, ‘325 75 mg) with post-treatment follow-up data achieved SVR₂₄ and/or SVR₃₆. There was no viral breakthrough during treatment and no post-treatment relapse in either group.
• 91% (31/34) of patients overall in Groups 3 and 4 (24- and 12-week treatment, ’325 150 mg) achieved SVR_4. Three out of the 34 patients experienced virologic failure on or after treatment.

Group 1

Group 2

Group 3

Group 4

(n=16)

(n=16)

(n=16)

(n=18)

BMS-791325 Dose

75 mg

75 mg

150 mg

150 mg

Treatment Duration

24 weeks

12 weeks

24 weeks

12 weeks

SVR4

94%a

94%b

94%

89%c,d

(15/16)

(15/16)

(15/16)

(16/18)

SVR12

94%a

94%b

N/A*

89%c,d

(15/16)

(15/16)

(16/18)

SVR24

88%a,b

94%b

N/A

N/A

(14/16)

(15/16)

SVR36

N/A

88%e

N/A

N/A

(14/16)

Viral Breakthrough

0%

0%

6%

6%

(1/16)

(1/18)

Relapse

0%

0%

0%

6%

(1/18)

^a Patient withdrew consent; ^bOne patient missed this visit but had achieved undetectable viral load at end of treatment or SVR at earlier endpoints; ^cOne patient experienced viral breakthrough; ^dOne patient relapsed; ^eTwo patients missed this visit, but had achieved SVR at earlier endpoints
* N/A = data not available at time of analysis

On-Treatment Safety

There were no deaths and no patient discontinuations due to treatment intolerance or adverse events (AEs) related to BMS therapy. Two serious adverse events (SAEs) were reported in the study. One SAE, cerebral vasoconstriction, occurred in Group 3 during treatment intensification with peginterferon alfa and RBV following viral breakthrough and lead to treatment discontinuation; cerebral vasoconstriction is a known side effect of interferon alfa. The remaining SAE reported on-treatment, renal calculus, was observed in Group 2 and was determined by the investigator to be unrelated to study drug.

Most AEs were mild to moderate in severity. The most common AEs (≥10% total) across all study groups were headache (27.3%, 18/66), asthenia (16.7%, 11/66), diarrhea (16.7%, 11/66), and nausea (13.6%, 9/66).

No Grade 3-4 elevations in liver enzymes (ALT/AST) or bilirubin were observed in this study. One grade 3 AE (headache) resolved after seven days with continued study treatment. One grade 3–4 laboratory abnormality was reported in this study. One case of lymphopenia was recorded in Group 2 at a single study visit concomitant with influenza. All other AEs were grade 1 or 2.

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is studying a portfolio of compounds that aims 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 compounds with different mechanisms of action, pursuing both biologics as well as small molecule direct-acting antivirals. These compounds are being studied as part of multiple treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies.

Daclatasvir is an NS5A replication complex inhibitor that is being extensively studied as a key component of potential DAA-based hepatitis C treatment regimens. Studied in more than 4,100 patients to date, daclatasvir is in Phase III development. Asunaprevir is an NS3 protease inhibitor in Phase III development for hepatitis C as a component of daclatasvir-based treatment regimens, and has been studied in more than 2,000 patients to date. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase II development for hepatitis C as a component of daclatasvir-based treatment regimens that has been studied in more than 300 patients to date.

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.

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.

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 clinical trials of these compounds will support regulatory filings, or that the compounds will receive regulatory approvals or, if approved, that they will become commercially successful products. 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, 2012, 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.

Contact:

Bristol-Myers Squibb
Media:
Sonia Choi, 609-213-6015
sonia.choi@bms.com
or
Carrie Fernandez, 215-859-2605
carrie.fernandez@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com
or
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Ryan Asay, 609-252-5020
ryan.asay@bms.com

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5 tips to protect your liver

Cleanses don’t work; here’s what does

A can of soda does the same damage to the liver as a shot of tequila, says nutritionist Theresa Albert.

By:Vanessa MilneToronto Star, Published on Tue Apr 23 2013

The death rate from liver disease in Canada is rising — up 30 per cent between 2000 and 2007, according to a report from the Canadian Liver Foundation.

And judging by the number of cleanses on the market, Canadians’ concerns for their livers is growing as well.

Unfortunately, they don’t work. “There’s nothing you can do for a week that’s going to make up for a year — or 10 — worth of bad habits,” says Toronto nutritionist Theresa Albert, board member of the Canadian Liver Foundation.

She shared her top tips for keeping your liver healthy:

EAT YOUR VEGETABLES

Dark leafy greens, deeply coloured fruits and cruciferous vegetables are particularly good for your liver, as are beans, Albert says. These also aid weight loss, which reduces the risk of fatty liver disease.

DROP THE SUGAR

People often think of alcohol as most harmful to your liver, but in fact, sugar — and sugar-filled drinks like pop — have a similar effect.

“Some of the studies that are coming to the forefront now talk about the impact of sugar on the liver being exactly the same as alcohol,” says Albert. “A can of soda does the same thing as a shot of tequila.”

GET VACCINATED FOR HEPATITIS

Hepatitis A and B are both liver diseases — and both are preventable with a vaccine. “People don’t think about them,” says Albert. Ask your doctor if you need a shot. Also consider getting tested for hepatitis C.

WATCH YOUR MEDS

Tell your doctor everything you’re taking — combining herbal medicine, vitamins, over the counter drugs and prescription medications can be harmful for your liver.

People don’t realize taking too much acetaminophen (Tylenol) can damage your liver, says Albert. During cold and flu season, it’s easy to accidentally take too much by popping an all-purpose pill and taking acetaminophen after.

Combining acetaminophen and alcohol — by taking a pill at night to prevent a morning hangover — is also damaging.

PICK ECO-CLEANING PRODUCTS

Your liver’s job is to process toxins and that includes those in the environment that you breathe in or ingest. “For so long we kind of pooh-poohed it, but now we know with those toxins, they actually have to be filtered out by the liver,” says Albert.

Using eco-friendly products in your home is a simple way to reduce your toxic load. “Go environmentally friendly or DIY as much as possible,” recommends Albert.

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Merck to Present Updated Interim Data from Phase II Trial Evaluating Investigational NS3/4A Protease Inhibitor MK-5172 for Chronic Hepatitis C Virus Genotype 1 Infection at the International Liver Congress™

Tuesday, April 23, 2013 6:39 am EDT

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the presentation of the latest interim data from a Phase II, multi-center, randomized, dose-ranging clinical trial evaluating the safety and antiviral activity of MK-5172, for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. MK-5172 is an investigational, once-daily, oral HCV NS3/4A protease inhibitor that in preclinical evaluations has demonstrated a high barrier to resistance. These data will be presented at the International Liver Congress™ during the 48^th meeting of the European Association for the Study of the Liver being held in Amsterdam on Friday, April 26, from 4-6 p.m. local time. Earlier interim data from this study was previously presented at the American Association for the Study of Liver Diseases Annual Meeting in November 2012.

MK-5172 in combination with peginterferon alfa-2b and ribavirin (PR) was evaluated versus VICTRELIS® (boceprevir), 200 mg Capsules, in combination with PR in treatment-naïve, non-cirrhotic patients with HCV genotype 1. A total of 332 patients were enrolled and randomized to receive MK-5172 at 100, 200, 400 or 800-mg in combination with PR or boceprevir with PR. MK-5172 was administered for 12 weeks with PR, followed by an additional 12 or 36 weeks of PR therapy (depending on the HCV RNA levels at Treatment Week 4). Boceprevir was administered according to the U.S. product circular.

For those patients evaluated to date, the rates of sustained viral response (SVR) at week 24 follow-up (SVR24) were 86 percent (55/64) and 92 percent (61/66) for the MK-5172 100 mg plus PR and MK-5172 200 mg plus PR arms, respectively, versus 54 percent (31/57) in the boceprevir plus PR active control arm. Patients who discontinued the study for reasons other than virologic failure and were either in follow-up or did not return for week 24 follow-up were, per protocol, formally counted as ‘failures’ in the SVR24 analysis, regardless of their HCV RNA status at the last visit on record. An analysis combining such patients with those who were evaluable for the SVR24 endpoint showed that undetectable HCV RNA, (HCV RNA negative), at last visit on record was achieved for 92 percent (61/66), 99 percent (67/68), and 67 percent (44/66) for MK-5172 100 mg plus PR, MK-5172 200 mg plus PR, and boceprevir plus PR groups respectively.

“We continue to build upon our clinical experience of MK-5172 in chronic hepatitis C,” said Eliav Barr, M.D., vice president, Infectious Diseases, Project Leadership and Management, Merck Research Laboratories. “The interim findings from this study provide clear direction for future larger trials designed to evaluate MK-5172 in novel all oral regimens for HCV.”

Following a review of safety data, an increased incidence of elevated liver transaminases (ALT/AST), a marker of liver toxicity, was observed in patients receiving the highest doses (400 mg and 800 mg) of MK-5172 and consequently the dose of MK-5172 was reduced to 100 mg in these patients. In the patients administered higher doses of 400 mg and 800 mg MK-5172, 91 percent (58/64) and 87 percent (52/60) of patients respectively achieved SVR24.

Of the patients evaluated so far in this study, the incidence of bilirubin increase and/or a late transaminase increase in the 100 mg dose of MK-5172 was comparable to control. In 124 patients receiving a higher dose of MK-5172 (67 on 400 mg and 65 on 800 mg), transaminase levels normalized by week 4 on therapy but increased to more than twice the upper limit of normal thereafter; in the majority of these patients levels declined with continued MK-5172 treatment at the 100 mg level and normalized by week 16. Overall, rates of serious adverse events were 9 percent (25/266) and 8 percent (5/66) for MK-5172 plus PR arms and control group respectively. The incidence of rash was 20 percent (54 /266) and 27 percent (18/66) for MK-5172 plus PR arms and control group respectively. Rates of anemia in MK-5172 plus PR arms, 18 percent (48/266), were lower than those observed in the control group, 27 percent (18/66).

In a separate poster, (#403), Merck scientists presented data from the analysis of blood samples from patients in this Phase II study evaluating MK-5172 plus PR. They evaluated the relationship between MK-5172 plasma levels and elevated liver transaminase activity. A dose dependent, non-linear relationship was determined between exposure to high levels of MK-5172 and the probability of liver toxicity. Based on this data and the SVR data with MK-5172, the 100 mg dose level is being evaluated in trials of interferon-containing and interferon-free regimens.

About MK-5172

MK-5172 is an investigational orally available HCV NS3/4A protease inhibitor currently being evaluated in combination with other approved and investigational medications in Phase II clinical trials. This includes an all oral combination with MK-8742, Merck’s investigational orally available HCV NS5A inhibitor.

Indications and Usage for VICTRELIS

VICTRELIS^® (boceprevir) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy, including prior null responders, partial responders, and relapsers.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with PR.
• The efficacy of VICTRELIS has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to PR.

Important Safety Information about VICTRELIS

All contraindications to PR also apply since VICTRELIS must be administered with PR. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use 2 or more forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated.

VICTRELIS is contraindicated in patients with a history of a hypersensitivity reaction to VICTRELIS. VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS is also contraindicated in coadministration with potent CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s Wort (hypericum perforatum), lovastatin, simvastatin, drospirenone, Revatio^® (sildenafil) or Adcirca^®(tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia – The addition of VICTRELIS to PR is associated with an additional decrease in hemoglobin concentrations compared with PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. If peginterferon alfa or ribavirin is permanently discontinued, VICTRELIS must also be discontinued. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of PR.

Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Serious acute hypersensitivity reactions (eg, urticaria, angioedema) have been observed during combination therapy with VICTRELIS and PR. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted.

The most commonly reported adverse reactions (>35%) in clinical trials in adult patients receiving the combination of VICTRELIS with PR were: fatigue, anemia, nausea, headache, and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates ≥5% above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously untreated subjects that were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (58% vs 59%), anemia (50% vs 30%), nausea (46% vs 42%), and dysgeusia (35% vs 16%), respectively. The incidence of these adverse reactions in previous treatment failure patients that were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55% vs 50%), anemia (45% vs 20%), nausea (43% vs 38%), and dysgeusia (44% vs 11%), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Merck's Global Commitment to Development of Hepatitis Therapies

Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies for our marketed and investigational medicines for the treatment of chronic HCV, extensive research efforts are underway to develop additional oral therapies for viral hepatitis treatment.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Merck forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Contact:

Merck
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or
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or
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