Pill Burden a Key Concern With New Chronic Hepatitis C Drugs

Only Kadmon Pharmaceuticals' RIBASPHERE^® RIBAPAK^® Offers a Reduction in Ribavirin Pill Burden Designed to Increase Treatment Adherence
NEW YORK, NY--(Marketwire - May 18, 2011) - This past Friday, the U.S. Food and Drug Administration (FDA) approved the first of a new generation of chronic hepatitis C drugs, known as protease inhibitors. The drug, VICTRELIS® (boceprevir), from Merck & Co., has been shown to increase the rate of sustained viral response and shorten treatment times when used in combination with the current standard of care, ribavirin and pegylated alpha interferon, in the treatment of chronic hepatitis C. Vertex Pharmaceuticals is seeking approval to market a similar drug, INCIVEK® (telaprevir).

The addition of protease inhibitors to the current standard of care puts a new and significantly greater treatment burden on the patient. Under most treatment regimens, pegylated alpha-interferon is injected once a week, and ribavirin is taken twice a day, for a total of five or six pills when prescribed in generic form. VICTRELIS is taken three times a day, for a total of 12 pills. INCIVEK is also taken three times a day, for a total of 6 pills. A treatment cycle lasting 48 weeks could mean that the patient is responsible for taking over 5,700 pills on schedule for the entire regimen. If the patient does not adhere to the prescribed regimen, the risk of treatment failure or relapse is increased (Reddy KR, Shiffman ML, Morgan TR, et al. Clin Gastroenterol Hepatol. 2007;5:124-129). Furthermore, because of the direct antiviral mechanism of protease inhibitors, missed doses of a protease inhibitor could lead to viral resistance (Weiss, et al. Aliment Pharmacol Ther 2009; 30:14-27).

Kadmon Pharmaceuticals' proprietary RIBASPHERE® RIBAPAK® (ribavirin, USP) is the only ribavirin available in a daily, two-pill compliance package designed to enhance therapy adherence. With RIBASPHERE RIBAPAK, the patient takes only two pills each day -- one in the morning and one at night -- reducing the total ribavirin pill burden by up to 66 percent over a 48 week course of treatment. RIBASPHERE RIBAPAK packaging is clearly marked for seven days of AM and PM dosing, and the completion of a compliance pack reminds the patient to administer their accompanying weekly interferon therapy. Kadmon is also offering patients a daily therapy diary to help keep track of their treatment schedule.

"Maintaining treatment adherence under the burden of a triple therapy combination will require significantly greater vigilance from the patient," said Bruce R. Bacon, M.D., professor of internal medicine at the Saint Louis University School of Medicine, and a clinical investigator for VICTRELIS. "With only one chance at success with this therapeutic approach, RIBASPHERE RIBAPAK represents an invaluable insurance policy for a treatment combination which could transform the enormous public health risks of hepatitis C."

About Hepatitis C

Hepatitis C is a liver disease that results from infection with the hepatitis C virus. It can range in severity from a mild illness lasting a few weeks to a serious, lifelong illness. Hepatitis C virus can be either "acute" or "chronic." Acute hepatitis C virus infection is a short-term illness that occurs within the first 6 months after someone is exposed to the hepatitis C virus. Seventy-five - 85% of acute HCV infections become chronic HCV infections. Chronic hepatitis C virus is a serious disease than can result in long-term health problems, such as serious liver disease, including cirrhosis and liver cancer, or even death. An estimated 3.2 million Americans have a chronic infection of the hepatitis C virus.

About RIBASPHERE® RIBAPAK® (ribavirin, USP)

INDICATION

RIBASPHERE® (ribavirin, USP) in combination with peginterferon alfa-2a is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha.

IMPORTANT SAFETY INFORMATION

RIBASPHERE (ribavirin, USP) monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication (see WARNINGS). The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6 month post treatment follow-up period.

CONTRAINDICATIONS

RIBASPHERE (ribavirin, USP) is contraindicated in:

• Patients with known hypersensitivity to RIBASPHERE (ribavirin, USP) or to any component of the tablet.
• Women who are pregnant.
• Men whose female partners are pregnant, plan to become pregnant, or are not using contraception.
• Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
• In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a combination therapy is contraindicated in patients with:

• Autoimmune hepatitis.
• Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment.
• Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment.

WARNINGS AND PRECAUTIONS

Treatment with RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a should be administered under the guidance of a qualified physician and may lead to moderate to severe adverse experiences requiring dose reduction, temporary dose cessation or discontinuation of therapy.

RIBASPHERE (ribavirin, USP) must not be used alone because ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection.

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a should be discontinued in patients who develop evidence of hepatic decompensation during treatment.

There are significant adverse events caused by ribavirin/peginterferon alfa-2a therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes. The peginterferon alfa-2a package insert and medication guide should be reviewed in their entirety prior to initiation of combination treatment for additional safety information.

Pregnancy: Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.

Anemia: The primary toxicity of ribavirin is hemolytic anemia (hemoglobin < 10 g/dL), which was observed in approximately 13% of all ribavirin and peginterferon alfa-2a treated patients in clinical trials.

Hepatic Failure: Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART.

Hypersensitivity: Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy.

Renal Impairment: RIBASPHERE (ribavirin, USP) should not be used in patients with creatinine clearance < 50 mL/min.

Pulmonary: Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, pneumonia, and occasional cases of fatal pneumonia, have been reported during therapy with ribavirin and interferon. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported.

Bone Marrow Suppression: Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine.

Pancreatitis: RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

Laboratory Tests: Before beginning peginterferon alfa-2a/RIBASPHERE (ribavirin, USP) combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients.

Drug Interactions: Nucleoside Analogues: NRTIs: In clinical trials, cases of hepatic decompensation (some fatal) were observed among the CHC/HIV coinfected cirrhotic patients receiving NRTIs. Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment associated toxicities.

ADVERSE REACTIONS

Peginterferon alfa-2a in combination with ribavirin causes a broad variety of serious adverse reactions. The most common serious or life-threatening adverse reactions induced or aggravated by peginterferon alfa-2a and ribavirin include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of < 1%. Hepatic decompensation occurred in 2% of CHC/HIV patients. Nearly all patients in clinical trials experienced one or more adverse events.

For more information please see the accompanying RIBASPHERE RIBAPAK (ribavirin, USP) Tablets Full Prescribing Information. The peginterferon alfa-2a Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.

About Kadmon Pharmaceuticals
Kadmon Pharmaceuticals LLC is a privately held, New York City-based biopharmaceutical company founded on its expertise in novel science. The company explores new understandings in molecular biology to develop therapies that target the metabolomic or signaling pathways associated with disease, including novel anti hepatitis C therapies. Collaborating with academic centers and private enterprise at the forefront of innovation, Kadmon is focused on pioneering medicines in the areas of oncology, infectious diseases and immunology. For more information, visit www.kadmon.com.

Source 

FDA approves Victrelis (Boceprevir) for Hepatitis C

FDA NEWS RELEASE

For Immediate Release: May 13, 2011
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA approves Victrelis for Hepatitis C

The U.S. Food and Drug Administration today approved Victrelis (boceprevir) to treat certain adults with chronic hepatitis C. Victrelis is used for patients who still have some liver function, and who either have not been previously treated with drug therapy for their hepatitis C or who have failed such treatment. Victrelis is approved for use in combination with peginterferon alfa and ribavirin.

The safety and effectiveness of Victrelis was evaluated in two phase 3 clinical trials with 1,500 adult patients. In both trials, two-thirds of patients receiving Victrelis in combination with pegylated interferon and ribavirin experienced a significantly increased sustained virologic response (i.e., the hepatitis C virus was no longer detected in the blood 24 weeks after stopping treatment), compared to pegylated interferon and ribavirin alone, the current standard of care.

When a person sustains a virologic response after completing treatment, this suggests that HCV infection has been cured.

Sustained virologic response can result in decreased cirrhosis and complications of liver disease, decreased rates of liver cancer (hepatocelluar carcinoma), and decreased mortality.

“Victrelis is an important new advance for patients with hepatitis C,” said Edward Cox, M.D., M.P.H, director, Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research. “This new medication provides an effective treatment for a serious disease, and offers a greater chance of cure for some patients’ hepatitis C infection compared to currently available therapy.”

According to the U.S. Centers for Disease Control and Prevention, about 3.2 million people in the United States have chronic hepatitis C, a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure.

Most people with hepatitis have no symptoms of the disease until liver damage occurs, which may take several years.

Most liver transplants performed in the United States are due to progressive liver disease caused by hepatitis C virus infection. After the initial infection with hepatitis C virus (HCV), most people develop chronic hepatitis C. Some will develop cirrhosis of the liver over many years. Cirrhosis can lead to liver damage with complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in abdomen, infections, or liver cancer.

People can get the hepatitis C virus in a number of ways, including: exposure to blood that is infected with the virus; being born to a mother with HCV; sharing a needle; having sex with an infected person; sharing personal items such as a razor, toothbrush with someone who is infected with the virus, or from unsterilized tattoo or piercing tools.

Victrelis is a pill taken three times a day with food. The therapy is part of a class of drugs referred to as protease inhibitors, which work by binding to the virus and preventing it from multiplying.

The most commonly reported side effects in patients receiving Victrelis in combination with pegylated interferon and ribavirin include fatigue, low red blood cell count (anemia), nausea, headache and taste distortion (dysgeusia).

Victrelis is marketed by Whitehouse Station, N.J.-based Merck.

For more information:
FDA: Approved Drugs: Questions and Answers
FDA: What’s New at FDA in Hepatitis
FDA: Hepatitis C Tests
CDC: Hepatitis C Information for the Public

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source

FDA Approves Merck's VICTRELIS™ (boceprevir), First-in-Class Oral Hepatitis C Virus (HCV) Protease Inhibitor

WHITEHOUSE STATION, N.J., May 13, 2011 – Merck (NYSE:MRK) (known as MSD outside the United States and Canada) announced today that the U.S. Food and Drug Administration (FDA) has approved VICTRELIS^™ (boceprevir), the company's innovative new medicine for the treatment of chronic hepatitis C (CHC). VICTRELIS is approved for the treatment of CHC genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years of age and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

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

• VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
• VICTRELIS efficacy 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.
• VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log HCV-RNA decline by treatment week 12) to peginterferon alfa and ribavirin therapy.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR)¹ , and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin.

VICTRELIS is the first in a new class of medicines approved to treat chronic hepatitis C
VICTRELIS is the first in a new class of medicines known as hepatitis C virus (HCV) protease inhibitors approved for use in combination with peginterferon alfa and ribavirin, which is the current standard therapy, for the treatment of chronic hepatitis C.

“This is an exciting day for physicians and patients because VICTRELIS is the first major advancement for the treatment of chronic hepatitis C approved in a decade,” said Bruce Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and a clinical investigator for VICTRELIS. “Compared to current standard therapy, VICTRELIS can significantly increase a patient’s chance of achieving undetectable levels of the virus, thereby obtaining an SVR. For many patients, VICTRELIS may allow for a shorter total duration of treatment.”

“Merck is deeply committed to innovation in bringing forward new medicines that significantly address unmet medical needs, and VICTRELIS is a shining example of our commitment being realized," said Kenneth C. Frazier, president and chief executive officer, Merck. "We look forward to building on our legacy in the fight against infectious diseases, and to being a part of this exciting new era in the treatment of chronic hepatitis C."

Merck will begin shipping VICTRELIS to pharmacies within a week so that patients will have access to this new medication as soon as possible. In addition, the company is expanding its support of public awareness and education programs for chronic hepatitis C. Resources include coupons to help eligible patients with their medication cost, reimbursement support to help patients understand their insurance coverage for VICTRELIS, and 24/7 nurse phone support.

Separately, Merck will also add VICTRELIS to its patient assistance program through which eligible patients may be able to receive product free of charge.

Current standard therapy for HCV works to strengthen the body’s natural immune response to the virus, but only about 40 percent of patients with chronic HCV genotype 1 infection are able to achieve SVR. VICTRELIS is a Direct Acting Antiviral (DAA) agent that interferes with the ability of the hepatitis C virus to replicate by inhibiting a key viral enzyme (NS3/4A serine protease).

The FDA approval of VICTRELIS is based on the efficacy and safety results from two large Phase III clinical studies that evaluated approximately 1,500 adult patients with chronic HCV genotype 1 infection. Both studies included two treatment arms with VICTRELIS: a response-guided therapy (RGT) arm, in which patients with undetectable virus (HCV-RNA) at treatment week 8 were eligible for a shorter duration of therapy, as well as a 48-week treatment arm. All patients receiving VICTRELIS in these studies were first treated with peginterferon alfa-2b and ribavirin (P/R) in a 4-week lead-in phase, followed by the addition of VICTRELIS after week 4. The studies also included a control arm in which patients received 48 weeks of treatment with P/R alone. Historical null responders were not enrolled.

Adding VICTRELIS to P/R achieved a significant increase in SVR rates compared to P/R alone Primary results from the two pivotal studies: Treatment-failure patients: the addition of VICTRELIS to P/R resulted in nearly a three-fold increase in SVR rates to 59 percent (96/162) for the RGT arm and 66 percent (106/161) for the 48-week treatment arm, compared to 23 percent (18/80) for control. Relapse rates were 14 percent (16/111) for the RGT arm and 12 percent (14/121) for the 48-week treatment arm, compared to 28 percent (7/25) for control. Treatment-naïve patients: the addition of VICTRELIS to P/R resulted in a significant increase (1.7 fold) in SVR rates to 63 percent (232/368) for the RGT arm and 66 percent (242/366) for the 48-week treatment arm, compared to 38 percent (138/363) for control. Relapse rates were 9 percent (24/257) for the RGT arm and 9 percent (24/265) for the 48-week treatment arm, compared to 22 percent (39/176) for control. In a separate, pre-specified cohort of 159 Black treatment-naïve patients, the addition of VICTRELIS to P/R resulted in a significant increase in SVR to 42 percent (22/52) for the RGT arm and 53 percent (29/55) for the 48-week treatment arm, compared to 23 percent (12/52) for control. Relapse rates were 12 percent (3/25) for the RGT arm and 17 percent (6/35) for the 48-week treatment arm, compared to 14 percent (2/14) for control.

Many patients receiving VICTRELIS in combination therapy were early responders at treatment week 8 Secondary analyses from the two pivotal studies were as follows: Treatment-failure patients: 46 percent (74/162) of patients in the RGT arm and 52 percent (84/161) of patients in the 48-week treatment arm receiving VICTRELIS had undetectable virus (HCV-RNA) at treatment week 8 and were considered early responders, compared to 9 percent (7/80) for control. The SVR rate for these early responders was 88 percent (65/74) in the RGT arm and 88 percent (74/84) in the 48-week treatment arm, compared to 100 percent (7/7) for control. Early responders in the RGT arm were eligible to stop all treatment at week 36. Treatment-naïve patients: 57 percent (208/368) of patients in the RGT arm and 56 percent (204/366) of patients in the 48-week treatment arm receiving VICTRELIS had undetectable virus (HCV-RNA) at treatment week 8 and were considered early responders, compared to 17 percent (60/363) for control. The SVR rate for these early responders was 88 percent (184/208) in the RGT arm and 90 percent (184/204) in the 48-week treatment arm, compared to 85 percent (51/60) for control. Early responders in the RGT arm were eligible to stop all treatment at week 28. SVR achieved with VICTRELIS in combination therapy in late responders Treatment-failure patients: Patients who had detectable virus (HCV-RNA) at treatment week 8, but undetectable virus (HCV-RNA) at treatment week 12, and completed at least 36 weeks of treatment, were considered late responders. The SVR rate for these late responders was 79 percent (27/34) in the RGT arm and 72 percent (29/40) in the 48-week treatment arm. Late responders in the RGT arm stopped VICTRELIS at week 36 and continued P/R alone for an additional 12 weeks (48 weeks total). Treatment-naïve patients: Patients who had detectable virus (HCV-RNA) at treatment week 8, but undetectable virus (HCV-RNA) at treatment week 24, and completed at least 28 weeks of treatment, were considered late responders. The SVR rate for these late responders was 66 percent (45/68) in the RGT arm and 75 percent (55/73) in the 48-week treatment arm. Late responders in the RGT arm stopped VICTRELIS at week 28 and continued P/R alone for an additional 20 weeks (48 weeks total). VICTRELIS in combination therapy increased SVR rates in specific patient populations The addition of VICTRELIS to P/R in treatment-failure patients with less than a 1 log decline in virus (HCV-RNA) during the 4-week lead-in resulted in an increase in SVR rates to 33 percent (15/46) for the RGT arm and 34 percent (15/44) for the 48-week treatment arm, compared to 0 percent (0/12) for control. In treatment-failure patients with cirrhosis at baseline, 77 percent (17/22) achieved SVR with the addition of 44 weeks of VICTRELIS to P/R, compared to 35 percent (6/17) for those who received RGT. In treatment-naïve patients with cirrhosis at baseline, 42 percent (10/24) achieved SVR with the addition of 44 weeks of VICTRELIS to P/R, compared to 31 percent (5/16) for those who received RGT. Safety and tolerability profile of VICTRELIS in 2,095 patients in Phase II and III studies Serious adverse events were reported in 11 percent of patients receiving VICTRELIS in combination with P/R, compared to 8 percent of patients receiving P/R alone. During the entire course of treatment, the proportion of patients who discontinued treatment due to adverse reactions was 13 percent for patients receiving VICTRELIS in combination with P/R, compared to 12 percent for patients receiving P/R alone. Events resulting in discontinuation were similar to those seen in previous studies with P/R alone. Adverse reactions that led to dose modifications of any drug (primarily P/R) occurred in 39 percent of patients receiving the combination of VICTRELIS with P/R compared to 24 percent of patients receiving P/R alone. The most common reason for dose reduction was anemia, which occurred more frequently in patients receiving the combination of VICTRELIS with P/R than in patients receiving P/R alone. The proportion of patients who experienced anemia was higher in patients receiving VICTRELIS in combination with P/R than in those treated with P/R alone. With management of anemia, the average additional decrease of hemoglobin was approximately 1 g/dL. Dose modifications (generally of P/R) due to anemia occurred more often in patients treated with VICTRELIS in combination with P/R (26 percent), compared to those treated with P/R alone (13 percent). Treatment discontinuations due to anemia were similar for patients receiving VICTRELIS in combination with P/R (1 percent) compared to those treated with P/R alone (1 percent). Erythropoietin (EPO) with or without ribavirin dose reduction for management of anemia was allowed at the discretion of the investigator per the study protocol. In pivotal clinical studies, the 4-week lead-in provided important clinical insights Interferon-responsiveness (equal to or greater than a 1 log decline in virus (HCV-RNA) at treatment week 4) was predictive of SVR. Patients receiving VICTRELIS who demonstrated interferon-responsiveness at treatment week 4 achieved higher SVR rates than those with poor interferon-responsiveness (less than a 1 log decline in virus (HCV-RNA) at treatment week 4). During the four-week lead-in period with P/R in the treatment arms containing VICTRELIS, 2 percent (28/1263) of patients experienced adverse reactions leading to discontinuation of treatment. Background on the pivotal Phase III studies for VICTRELIS The HCV RESPOND-2 study (treatment-failure patients) and the HCV SPRINT-2 study (treatment-naïve patients) each evaluated two treatment strategies with VICTRELIS added to P/R to assess the ability of VICTRELIS to improve SVR rates and potentially shorten overall treatment duration, compared to the use of P/R alone for 48 weeks, which is the current standard duration of therapy. In both studies, all patients receiving VICTRELIS were treated with a 4-week lead-in of peginterferon alfa-2b (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (800 mg three times a day) after week 4. In each study, patients were randomized to three groups: Response-guided therapy (RGT), in which patients with undetectable virus (HCV-RNA) at treatment week 8 were considered early responders and were eligible for a shorter duration of therapy. Treatment-naïve patients with undetectable HCV-RNA during weeks 8 through 24 were eligible to stop all treatment at week 28. Treatment-failure patients with undetectable HCV-RNA at treatment weeks 8 and 12 were eligible to stop all treatment at week 36. 48 weeks of treatment, in which patients received a 4-week lead-in with P/R followed by 44 weeks of VICTRELIS in combination with P/R. Control, in which patients received P/R for 48 weeks.  In the HCV RESPOND-2 study, all patients with detectable virus (HCV-RNA) at treatment week 12 were discontinued from treatment. In the HCV SPRINT-2 study, all patients with detectable virus (HCV-RNA) at treatment week 24 were discontinued from treatment. The HCV RESPOND-2 study was conducted at U.S. and international sites, and included 403 adult patients who had failed prior treatment, including patients who relapsed or were partial responders to prior treatment with standard therapy. Historical null responders were not enrolled. Patients were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV genotype (1a or 1b). The HCV SPRINT-2 study was conducted at U.S. and international sites in 1,097 adult patients who were new to treatment. Patients were randomized in a 1:1:1 ratio within two separate cohorts (938 non-Black patients and 159 Black patients) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (less than or equal to 400,000 IU/mL vs. greater than 400,000 IU/mL). Black patients with chronic HCV historically have been shown to be harder to treat successfully. Final results of the HCV RESPOND-2 and HCV SPRINT-2 studies were published in the New England Journal of Medicine on March 31, 2011. Important safety information about VICTRELIS All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin 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 two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin. 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 also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced boceprevir 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, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and midazolam (orally administered).  Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. The addition of VICTRELIS may result in a worsening of neutropenia associated with peginterferon alfa and ribavirin alone. Complete blood counts should be obtained pretreatment, and at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate. If a patient has a serious adverse reaction potentially related to peginterferon alfa and ribavirin therapy, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin. The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients that were treated with VICTRELIS combination therapy compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent), dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previously untreated patients that were treated with VICTRELIS combination therapy compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea(43 vs. 38 percent), dysgeusia (44 vs. 11 percent), 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 prescribing information Dosing and administration VICTRELIS must be administered in combination with peginterferon alfa and ribavirin. Therapy is initiated with peginterferon alfa and ribavirin for 4 weeks. Beginning in treatment week 5, VICTRELIS is added at a dose of 800 mg (four 200 mg capsules) orally three times daily (every 7-9 hours) with food (a meal or light snack). Based on the patient's virus (HCV-RNA) levels at treatment weeks 8, 12 and 24, dosing is adjusted using the following response-guided therapy guidelines. Treatment-naive patients: Patients who are undetectable at treatment weeks 8 and 24 complete all therapy at treatment week 28. Patients who are detectable at treatment week 8, but undetectable at treatment week 24, complete VICTRELIS at treatment week 36 and continue on peginterferon alfa and ribavirin alone until treatment week 48. Treatment-failure patients: Patients (previous partial responders or relapsers) who are undetectable at treatment weeks 8 and 24 complete all therapy at treatment week 36. Patients who are detectable at treatment week 8, but undetectable at treatment week 24, complete VICTRELIS at treatment week 36 and continue on peginterferon alfa and ribavirin alone until treatment week 48. Response-guided therapy was not studied in treatment-failure patients who had less than a 2 log decrease in virus (HCV-RNA) at treatment week 12 of prior treatment (null responders). If treated, these patients should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS in combination with peginterferon alfa and ribavirin. Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS in combination with peginterferon alfa and ribavirin. Patients who have HCV-RNA results greater than or equal to 100 IU/mL at treatment week 12 discontinue the three-medicine regimen. Patients who have confirmed detectable HCV-RNA at treatment week 24 discontinue the three-medicine regimen. The wholesale acquisition cost (WAC) of VICTRELIS per week is $1,100. About Merck Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside 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. 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. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements. The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to 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 2010 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). Please see attached Prescribing Information and Medication Guide for VICTRELIS. VICTRELIS™ is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA. Revatio® and Adcirca® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA. 1SVR, the protocol specified primary efficacy endpoint of the pivotal studies, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient’s 12-week post-treatment assessment was utilized. Source

EASL: HCV Drug Resistance

This is an excellant article written by Jules Levin of NATAP

from Jules: This is a controversial issue & was at this just completed EASL. Where a number of researchers said flatly 'we will be able to re-use HCV protease inhibitors after patients develop resistance if we wait 2 years for the mutations to disappear & this was pretty much said with regards to telaprevir following the oral presentation by Sullivan of Vertex reporting that mutations mostly disappear after 1.5 years following stopping telaprevir therapy'. This may end up being true but right now this is just a theory without any evidence, no data to support this supposition, it cannot be considered true until a study or real clinical evidence supports this. Until we have data on this question one cannot say flatly patients will be able to re-use a HCV protease after resistance and receive viral load reductions from the drug. Will such a study ever be done, I don't know. There are many other classes of HCV drugs in development so in the future patients ought to be able to switch to a regimen of 2-4 oral drugs with or without peg/rbv without a protease, so the question may be moot. Still I think we need to clarify this. One issue is that the Sullivan study did not use ultra-deep sequencing, which in this study below shows mutations missed by clonal sequencing are picked up by UDS. At baseline before therapy mutations pre-exist, so 2 years later you would expect these same pre-existing mutations to be present but HCV multi-drug therapy suppresses these mutations and SVR still has been achieved evidenced by the studies with telaprevir & boceprevir, but the question is will these mutations be further enriched after failing therapy, will mutations accumulate to a significant degree if a patient remains on failing therapy, will compensatory mutations accumulate, and will these situations persist & affect re-treatment with a PI, I don't know the answer to these questions and I don't think anyone does. Perhaps the prediction that this will not be a problem is correct but we don't know & we have not studied this adequately.

AASLD: Ultra-Deep Sequencing of the NS3 and NS5B Regions Detects Pre-Existing Resistant Variants to Direct Acting Antivirals (DAA) in HCV Genotype 1 Treatment-Naïve Infected Patients - (11/29/10)

"Minority variants resistant to PI or NNI were detected in 3 and 10 subjects respectively at frequencies that ranged from 0.6 to 14%. Concordance between UDPS and molecular clonal sequencing was 87% for MVs detected (by either method) at a level >10%; 68% for MVs detected at a level of 5% to 10%; and 26% for MVs detected at a level of 1% to 5%."

ULTRA-DEEP SEQUENCING OF THE NS3 AND NS5B REGIONS DETECTS PRE-EXISTING RESISTANT VARI- ANTS TO DIRECT ACTING ANTIVIRALS (DAA) IN HCV GENOTYPE 1 INFECTED PATIENTS NAïVE

AASLD ABSTRACT 2010 October

Severine Margeridon4, Sophie Le Pogam2, Tommy F. Liu4, Bozena Hanczaruk3, Todd E. Arnold3, Birgitte B. Simen3, Nancy Shulman1, Robert W. Shafer4, Isabel Najera2; 1Virology - Pharma Research Early Development, Roche Pharmaceuticals, Palo Alto, CA; 2Virol- ogy - Discovery, Roche Pharmaceuticals, Palo Alto, CA; 3454 Life- sciences, a Roche Company, Branford, CT; 4Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, CA

Background: Naturally occurring HCV drug-resistance minority variants (MVs) that are not detectable by standard consensus sequencing may have an impact on the effectiveness of HCV inhibitors. We used ultradeep pyrosequencing (UDPS) and molecular clonal sequencing to assess the prevalence of HCV drug-resistant minority variants to protease (PI), nucleoside ana- log (NA), and nonnucleoside polymerase inhibitors (NNI) in serum samples from DAA-naïve HCV infected subjects.

Methods: Samples were obtained from 39 DAA treatment naive HCV-infected subjects (27 genotype 1a and 12 genotype 1b). Molecular clonal sequencing and UDPS were performed span- ning those regions of the NS3 protease,and of the NS5B poly- merase including amino acid residues known to confer resistance to PIs, NAs and NNIs. The median viral load was 6.6 log10 IU/ml (range 5.1 - 7.6). UDPS was performed using the GS FLX Titanium platform (454 / Roche Life Sciences) at a median coverage per base of ~3,500. MVs for the UDPS were defined as mutations present in ≥0.5% of UDPS reads..whereas for the clonal sequencing analysis, MVs were defined as muta- tions present in ≥1 molecular clone.

Results: Plasmid control experiments identified a UDPS error rate of 0.1% - resulting from a combination of PCR and pyrosequencing error. No NA resistance mutation was detected by UDPS nor through molecular clonal sequencing. Minority variants resistant to PI or NNI were detected in 3 and 10 subjects respectively at frequencies that ranged from 0.6 to 14%. Concordance between UDPS and molecular clonal sequencing was 87% for MVs detected (by either method) at a level >10%; 68% for MVs detected at a level of 5% to 10%; and 26% for MVs detected at a level of 1% to 5%.

Conclusions: UDPS is a powerful technique for detecting minority variants within viral quasispecies. Optimization of a number of factors such as amplification error rate, input viral load, and the refining the sensitivity of the technique is ongoing. Comparison of results from molecular cloning and UDPS showed that no nucleoside analogs DRM as detected through either technique. Both techniques, however, detected the most prevalent NNI-DRMs with relative high concordance for MVs present at levels > 5%.

Source

IL28B-Genotype Testing Now and in the Era of Direct-Acting Antiviral Agents

Clinical Gastroenterology and Hepatology
Volume 9, Issue 4 , Pages 293-294, April 2011

Timothy R. Morgan, MD
Thomas R. O'Brien, MD, MPH

published online 24 December 2010.

Full Text

Peginterferon alpha and ribavirin treatment for 48 weeks leads to a sustained virological response (SVR) in 40%–50% of subjects infected with hepatitis C virus (HCV) genotype 1 or 4 (G1/4) while treatment for 24 weeks produces SVR in 70%–80% of patients infected with HCV genotype 2 or 3. The variability in response to treatment, especially between patients of different racial groups, suggested that human genetic variability might explain differences in treatment response and led to investigations of the role of host genetics in achieving an SVR.

Genome-wide association studies which examine the association between >500,000 single nucleotide polymorphisms (SNPs) and a disease of interest, have been exceptionally successful in finding SNPs associated with response to hepatitis C treatment. In 2009, 3 groups reported that SNPs located near the gene for interleukin-28B (IL28B) were strongly associated with the likelihood of achieving an SVR with peginterferon + ribavirin treatment.1, 2, 3 IL28B encodes a protein that is also known as interferon lambda-3 (IFN-λ3), a type III interferon. The receptors for interferon alpha, a type I interferon, differ from those for IFN-λ3, but both IFN-λ and IFN-α activate the same intracellular pathway (Jak/STAT), which results in expression of many interferon stimulated genes.4, 5, 6

SNPs rs12979860 and rs8099917, respectively located 3 and 8 kb upstream of IL28B, were the variants most strongly associated with treatment response in these studies. Among treatment naive G1-infected subjects of European ancestry who were enrolled in the IDEAL study, approximately 69% of those who carried 2 C alleles (C/C) at rs12979860 achieved an SVR compared with 33% of those with the C/T genotype and 27% with genotype T/T.7 Consistent findings were reported for rs8099917 among Japanese, Australian, and European populations.2, 3 These studies demonstrated that carriage of 2 IL28B favorable alleles strongly, but not fully, predicted SVR, while carriage of 1 or 2 unfavorable alleles did not completely predict failure to respond to treatment. It appears that rs12979860 is more predictive of SVR than rs8099917, especially among people of African ancestry in whom rs8099917 is less polymorphic than rs12979860.1

In the current issue of Clinical Gastroenterology and Hepatology, Stättermayer and colleagues performed IL28B genotype testing for rs12979860 and rs8099917 in 682 Austrian subjects (G1 = 372; G2/3 = 208; G4 = 102) who completed treatment with peginterferon and ribavirin and agreed to return for genetic testing.8 They found that subjects infected with G1/4 who carried 2 C alleles at rs12979860 (ie, the most favorable genotype) had a greater decline in HCV ribonucleic acid (RNA) 24 hours after the first injection of interferon than did G1/4-infected subjects who carried a T allele (either C/T or T/T). Similarly, subjects infected with G1/4 who carried rs12979860 C/C were more likely to achieve a rapid virological response (RVR; G1: 38% vs 12%) and SVR (G1: 79% vs 43%) as compared with carriers of the T allele. Among subjects infected with G2/3, rs12979860 C/C carriers had a higher likelihood of RVR (75% vs 53%), but the difference for SVR (81% vs 72%) did not reach statistical significance. IL28B rs12979860 genotype was the strongest pretreatment predictor of SVR, but when the initial response to peginterferon and ribavirin was considered, RVR rather than IL28B genotype was the strongest predictor of SVR in this population. The authors concluded that IL28B genotype influenced the rate of initial viral decline with peginterferon/ribavirin treatment and that IL28B genotype, in conjunction with RVR, might be useful parameters in predicting SVR in G1/4 subjects.

The findings of Stättermayer and coworkers confirm prior reports of IL28B genotype testing among subjects treated with peginterferon + ribavirin. Several investigators have reported that subjects with rs12979860 C/C have a greater initial decline in HCV RNA level and a higher likelihood of achieving RVR and SVR.1, 7, 9 Thompson reported that IL28B genotype is the most important pretreatment variable to predict SVR, but IL28B genotype loses importance as a predictor of SVR when RVR is included in a multivariate analysis.7 Stättermayer confirmed that rs12979860 is more informative than rs8099917 as a pretreatment predictor of SVR among those of European ancestry.1 In total, studies from Stättermayer and others show a strong association of IL28B genotype with virological response to peginterferon + ribavirin treatment, including the rate of early viral decline and the likelihood of achieving RVR and SVR.

The human genome project promised to introduce an era of personalized medicine, in which genetic testing would be used to predict the likelihood of clinical outcomes, including response to drugs, in individual patients.10 In 2010 several clinical laboratories announced assays for IL28B rs12979860 genotype. Gastroenterologists now must decide whether to obtain IL28B genotype for their HCV-infected patients and, if so, how to incorporate these results into decisions regarding hepatitis C treatment. IL28B genotype joins a considerable list of pretreatment factors that have been shown to predict the probability of SVR, including HCV genotype, HCV RNA level, severity of liver fibrosis, and racial ancestry. Information on each of these factors can help inform the physician and patient of the likelihood of achieving an SVR, however, none alone is sufficient to guarantee or preclude the possibility of achieving an SVR. Although IL28B genotype alone is insufficient for deciding whether or not a patient is likely to respond to peginterferon and ribavirin, we believe that mathematical clinical prediction models based on IL28B genotype and clinical characteristics may prove useful for predicting SVR. Indeed, among interferon nonresponders who were re-treated with peginterferon + ribavirin in the HALT-C Trial, we have presented “proof of concept” that a model that includes IL28B plus some commonly measured clinical variables (HCV viral load, liver fibrosis score and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio) has good discrimination and predictive ability for the probability of SVR (O'Brien et al, Hepatology 2010;52:382A [abstract]). If validated, such a model could be used to calculate individually tailored probabilities of achieving an SVR for patients. Clinical prediction models may also be useful for on-treatment predictions of SVR.

The availability of IL28B genotype testing to help predict SVR coincides with another major advance in the treatment of chronic hepatitis C, the introduction of direct-acting antiviral agents (DAAs) that specifically target enzymes critical to HCV replication. At this writing, it appears likely that 2 HCV-specific protease inhibitors, boceprevir and telaprevir, will be approved by the Food and Drug Administration (FDA) in 2011. Data from clinical trials suggest that adding a protease inhibitor to the peginterferon + ribavirin regimen increases the overall SVR rate among treatment naive G1-infected patients to 65%–75% (Bacon et al, Hepatology 2010;52:216 [abstract]; Jacobson et al, Hepatology 2010;52:211 [abstract]). However, adding a viral protease inhibitor to current standard of care is not without additional risks. Patients taking these agents are subject to several potential adverse effects, including anemia and skin rash. Furthermore, patients who fail to achieve SVR on a regimen that includes a protease inhibitor will likely harbor resistant viruses that limit future use of protease inhibitors in that patient. Initial studies suggest that IL28B genotype may be predictive of response to treatment with protease inhibitors, too. Among Japanese patients who received telaprevir + peginterferon + ribavirin, Akuta and colleagues reported an SVR rate of 83% for subjects carrying rs12979860 C/C as compared with 32% among subjects who carried a T allele.11 If confirmed in other populations, these data suggest that carriers of the less favorable IL28B genotypes will be less likely to respond to triple therapy that includes protease inhibitors and raise the possibility that IL28B genotype-based models may be useful for predicting the likelihood of SVR in response to treatment with peginterferon + ribavirin + protease inhibitors.

Until now, the outcome of treatment for chronic hepatitis C could be broadly classified as either successful (SVR) or futile (nonresponse). The advent of the direct-acting antiviral agent (DAA) era promises to increase the number of patients for whom treatment is successful, but also introduce a third outcome—patients who not only fail treatment, but also harbor resistant viral strains that may compromise future treatment options. Thoughtful incorporation of IL28B genotyping into treatment decision-making may serve to increase the number of patients for whom treatment is successful while minimizing those in whom it is deleterious.

Acknowledgments

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

References

1.Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401

2.Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–1104

3.Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–1109

4.O'Brien TR. Interferon-alfa, interferon-lambda and hepatitis C. Nat Genet. 2009;41:1048–1050

5.Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77

6.Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–68

7.Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139:120–129e18

8.Stättermayer A, Stauber R, Hofer H, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2011;9:344–350

9.McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology. 2010;138:2307–2314

10.Feero WG, Guttmacher AE, Collins FS. Genomic medicine--an updated primer. N Engl J Med. 2010;362:2001–2011

11.Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatol. 2010;52:421–429

Conflicts of interest The authors disclose the following: Timothy R. Morgan has received research support from Genentech, Vertex, Merck, and WAKO Diagnostics. Thomas R. O'Brien discloses no conflicts.

Funding This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.

PII: S1542-3565(10)01278-4
doi:10.1016/j.cgh.2010.12.014
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

Long-Term Consistent Use of HIV Therapy Protects the Liver

April 6, 2011

People with HIV who aren’t also infected with viral hepatitis are at significant risk of developing liver disease, but long-term consistent use of antiretroviral (ARV) therapy appears to be protective, according to a study published in the May 9 issue of Clinical Infectious Diseases.

Liver disease is now the No. 1 cause of death in people with HIV. While the vast majority of people with HIV who have liver disease are also infected with either hepatitis C virus (HCV) or hepatitis B virus (HBV), people with HIV who don’t have hepatitis are also at significantly increased risk for liver failure.

Two of the challenges of monitoring for liver disease in people who don’t otherwise have major risk factors are predicting who is most at risk and determining the best method to monitor for the disease. The gold standard for assessing a person’s liver condition is a liver biopsy, but that can be quite painful and it carries some health risks—plus, most providers would not perform a biopsy on someone who doesn’t have risks or signs of liver disease.

To help determine the risk of liver disease progression, and to validate the use of non-invasive methods for monitoring liver disease, Monia Mendeni, MD, from the University of Brescia School of Medicine, in Brescia, Italy, and her colleagues followed 1,112 HIV-positive people enrolled in the Italian Hepatotoxicity of Different Kinds of Antiretrovirals study.

To be eligible for the analysis, people needed to have enrolled in the study between 1996 and 2006. They also could not have either HBV or HCV, and they could not have been diagnosed with cirrhosis. The average length of follow-up in the study was six years. More than two thirds of the study participants were male, and the average age was 36. The majority of the participants did not have liver damage (fibrosis) at the beginning of the study.

Mendeni’s team used two methods for assessing the conditions of the participants’ livers. One is called an FIB-4 score, which is based on a calculation of a person’s age, alanine transaminase (ALT) levels and the ratio of aspartate transaminase (AST) levels to platelet count. A second method, called APRI, calculates only the AST to platelet ratio.

The team found that liver fibrosis progression was common, even in the absence of viral hepatitis. Using the FIB-4 scoring method, 259 (24 percent) of the participants progressed to a greater degree of liver fibrosis over the course of the study, with 89 of them being confirmed by liver biopsy to have fibrosis. Using the APRI scoring, 356 (31 percent) people had progression of liver fibrosis, which was confirmed by biopsy in 126 of them. Regardless of the scoring method, most people who initially showed progression reverted back to a healthier score without any sort of treatment intervention.

Mendeni and her colleagues found that the FIB-4 and the APRI scoring methods differed in their predictive value, particularly in people with the mildest fibrosis. Both methods, however, had a much higher degree of accuracy when predicting fibrosis in people with more advanced liver disease.

Overall, the team found that older age increased the likelihood of having liver fibrosis more than any other factor. Having a low CD4 count also increased the chance of having liver disease progression.

Of note, Mendeni’s team found—for the first time in any study—that longer-term use of ARV medication had a protective affect against liver disease progression. The effect was small, but present. The team also found that people who took Videx (didanosine), Zerit (stavudine) or Hivid (zalcitabine) were more likely to have fibrosis progression, confirming previous studies showing that these drugs may have a negative impact on the liver.

The authors acknowledge that FIB-4 and APRI are not gold-standard methods for assessing liver fibrosis, and thus may not have provided the most accurate measure of liver damage. They note, however, that performing proactive liver biopsies in people without significant risk factors is unethical. They also acknowledge that excessive alcohol use might also have influenced the study results, but point out that they tried to control for this by measuring gamma-GT levels.

“This study demonstrated that HIV-[positive people who aren’t also infected with HCV or HBV] display significant risk of [liver fibrosis] liv liver progression,” state the authors. “Although formal validations are necessary, in the meantime, FIB-4 and APRI should be used to identify those patients who are most at risk and who need further clinical work-up (such as liver biopsy) and more-proactive counseling to modify dangerous behaviors (such as alcohol abuse).”

“Lastly,” they conclude, “our results suggest the benefit of earlier [ARV] initiation for liver disease fibrosis in HIV-monoinfected patients, provided that the most dangerous drugs [e.g. Zerit, Videx and Hivid] are avoided.”

Source

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.

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Breakthrough: Non-Interferon/Ribavirin Regimen Can Cure Hep C

April 4, 2011
by Tim Horn

In what is being heralded as a hepatitis C virus (HCV) treatment research breakthrough, a clinical trial evaluating two oral medications being developed by Bristol-Myers Squibb (BMS) suggests that at least some cases of chronic HCV infection can be cured without the use of either pegylated interferon or ribavirin (IFN/RBV).

The same study, reported Saturday, April 2, at the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, also appeared to cure 10 people living with HCV treated with a quadruple regimen, consisting of BMS’s BMS-650032 and BMS-790052 in combination with IFN/RBV.

Though a combination of IFN/RBV has long been the standard treatment for chronic HCV infection, both drugs are associated with side effects and neither drug works directly against the virus. The high rate of toxicities, compounded by their indirect mechanisms of action, help explain why current treatment isn’t highly effective in a proportion of people living with HCV, particularly those with hard-to-treat genotype 1 infection.

Direct-acting antivirals (DAAs), drugs that directly target HCV, have been in development for several years. Not only can they potentially maximize treatment responses and reduce the amount of time someone needs to be treated for HCV, but they also have been eyed as a way of treating hepatitis C without the need for either IFN or RBV.

Numerous studies at EASL suggest that DAAs, including protease inhibitors, NS5A inhibitors and polymerase inhibitors, can substantially increase rates of sustained virologic responses (SVRs)—maintaining an undetectable HCV viral load for six months after stopping treatment, or a viral cure—when used in combination with IFN/RBV. Not only did a clinical trial evaluating BMS’s protease inhibitor (BMS-790052) and NS5A inhibitor (650032) add to the encouraging news, but it also demonstrated that two DAAs used together, without IFN/RBV, can cure HCV in some patients.

The Phase II study looked at a cohort of 21 HCV genotype 1 null responders—patients who had very limited responses to previous treatment with IFN/RBV—of whom 19 had an unfavorable IL28B genotype, which predisposes HCV patients to treatment failure. The cohort was divided into two groups: Group A involved 11 patients treated with BMS-790052 plus BMS-650032 without IFN/RB for 24 weeks; Group B involved 10 patients treated with both BMS drugs plus IFN/RBV for 24 weeks.

Nine of the 10 patients treated with quadruple therapy had an SVR after 24 weeks (SVR24), reported Anna Lok, MD, of the University of Michigan Medical Center at Ann Arbor and her colleagues. The one patient who didn’t have an SVR24 was tested again 35 days later and found to have an undetectable HCV viral load, suggesting a possible cure rate of 100 percent in the small number of individuals who received four-drug treatment.

Of particular interest are the results among those treated with the DAAs without IFN/RBV. Four of the 11 patients had an SVR24—among the first individuals in a clinical trial to be successfully cured of HCV without today’s standard-of-care drugs.

In the six patients who saw their HCV viral loads rebound during treatment with the DAAs, IFN/RBV was promptly added. Four of the patients then went on to achieve undetectable HCV viral loads. HCV resistance to both BMS-790052 and BMS-650032 was documented in all six patients who did not respond favorably to DAA therapy alone, though it is not clear what the implications of resistance are for those who potentially require retreatment with these or similar agents.

Many side effects were similar in both groups, including diarrhea, fatigue, headache, fever and difficulty sleeping. Most side effects, however, were mild to moderate in severity, and there were no discontinuations from the study due to adverse events. Moderate-to-severe drops in neutrophils, a type of white blood cell, was documented in six patients in the quadruple-therapy group, compared with no patients in the dual-DAA group.

Lok concluded that quadruple therapy can result in a high rate of cure in this difficult-to-treat population and that, based on the encouraging dual-DAA study results, that HCV infection can be cured without IFN or RBV.

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Also See:
EASL: Quadruple therapy shows 100 percent SVR for HCV patients previously unresponsive to treatment

In-vitro model systems to study Hepatitis C Virus

Published on: 2011-04-06

Hepatitis C virus (HCV) is a major cause of chronic liver diseases including steatosis, cirrhosis and hepatocellular carcinoma. Currently, there is no vaccine available for prevention of HCV infection due to high degree of strain variation.

The current treatment of care, Pegylated interferon alpha in combination with ribavirin is costly, has significant side effects and fails to cure about half of all infections. The development of in-vitro models such as HCV infection system, HCV sub-genomic replicon, HCV producing pseudoparticles (HCVpp) and infectious HCV virion provide an important tool to develop new antiviral drugs of different targets against HCV.

These models also play an important role to study virus lifecycle such as virus entry, endocytosis, replication and release and HCV induced pathogenesis. This review summarizes the most important in-vitro models currently used to study future HCV research as well as drug design.

Author: Usman AshfaqShaheen KhanZafar NawazSheikh Riazuddin

Credits/Source: Genetic Vaccines and Therapy 2011, 9:7

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Scientific Breakthrough: New Non-Invasive Oral HIV Rapid Test by OraWell Delivers Reliable Results in Just 10 Minutes

OraWell USA announces its revolutionary at-home oral HIV test, an AIDS test that now delivers accurate results in just 10 minutes!

Allentown, PA (PRWEB) April 6, 2011

OraWell USA proudly announces its revolutionary, first-of-its kind, at-home oral HIV test, which can deliver reliable results in as little as 10 minutes. Now, it’s easier than ever to have peace of mind and find out the results of an HIV test sooner, without the hassle or inconvenience of having to visit a doctor’s office or clinic. There is no blood draw required for the test, and best of all, the results are completely confidential.

According to the U.S. Centers for Disease Control and Prevention, more than one million people are living with HIV in the United States. More than one in five of those people living with HIV are unaware of their infection. Don’t live your life wondering if you are HIV-positive. Use the OraWell USA Oral HIV Rapid Test to find out the answer – the fast and easy way.

Reliable & Confidential HIV Test Results at Home

The OraWell Oral HIV Rapid Test 1&2 is a fully approved at-home test recommended by doctors and proven to deliver results with more than 99.98% accuracy. The test comes with supplies so patients can collect their own specimen of saliva as well as a panel to place the specimen onto for analysis. It’s as easy as collecting a sample of saliva and placing it on an easy-to-use specimen tray.

In about 10 minutes, patients using the test can learn the results, which are produced with a simple positive or negative response. There is no complicated scientific analysis of the results or confusing medical terminology to understand, so the OraWell Oral HIV Rapid Test is suitable for all users.

HIV and AIDS: Learn the Facts

It has been proven that acquired immunodeficiency syndrome (AIDS) is caused by viruses which are transmitted by sexual contact, blood transfusion, using contaminated blood products, and sharing contaminated needles. HIV-1 and 2 viruses, which may lead to AIDS, deplete T-helper cells in the body, leaving AIDS patients more susceptible to opportunistic infections and developing malignant tumors.

Patients with AIDS or those who are at risk of contracting the disease have a higher incidence of specific antibodies. The OraWell HIV-1&2 Antibody Saliva Rapid Screen Test was designed to detect these antibodies and identify any potential donors who are carrying these antibodies in their saliva.

OraWell At-Home HIV Test: How it Works

The OraWell HIV-1&2 Antibody Saliva Rapid Screen Test is a chromatographic immunoassay for the detection of antibodies to HIV-1&2 in human saliva. HIV-1&2 antibodies with binding protein are precoated onto membrane as capture reagents. During the testing, a specimen is allowed to react with the colloidal gold reagents which have been labeled with HIV- 1&2 specific antigens. If present in the saliva specimen, the antibodies will cause a pink-colored band to develop on the membrane in proportion to the amount of HIV-1&2 antibodies detected. A negative test result is indicated by an absence of this pink colored band in the test. As a procedural control, a pink-colored band will always appear in the control region of the test, regardless of the presence or absence of the antibodies.

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Progress Made on AIDS Vaccine

By Mercer R. Cook, CRIMSON STAFF WRITER
Published: Wednesday, April 06, 2011

A medical breakthrough in HIV prevention could eventually lead to the development of an AIDS vaccine, due to a recent discovery by researchers at the Harvard-affiliated Dana-Farber Cancer Institute.

Scientists took an antibody from an HIV-positive man who had not shown any symptoms of AIDS even after a decade of having HIV and administered it to rhesus monkeys. They then injected the monkeys with a form of the human HIV virus that was mutated so it could spread in monkeys.

Although the virus in the monkeys was a different strain than the original human virus, the antibody still effectively prevented the onset of AIDS symptoms. Monkeys who were administered the antibody remained completely symptom-free, while monkeys without the antibody suffered all of the normal effects of the virus.

This finding is significant because one of the fundamental challenges in the development of an HIV vaccine is accounting for the millions of different strains of the highly-mutable HIV virus. Due to the variance, an effective and practical vaccine must target commonalities between the strains.

“The big problem with so many millions of HIV virus out there is there needs to be a way to target the common theme,” said Harvard Medical School Professor Ruth M. Ruprecht, senior author of the study. “This is a step in the direction of identifying targets for vaccines.”

In this study, researchers were able to discover a similarity between multiple strains of the virus by discerning what part of the virus was targeted by the antibody.

Medical School instructor Nagadenahalli B. Siddappa, one of the lead authors of the study, also stressed the importance of the antibody’s apparently universal protective qualities, noting the difficulty scientists often face when attempting to develop a preventative vaccine for a continually evolving virus.

“[Scientists] always see different viruses,” he said. “This could be very useful.”

While researchers said they were excited about this finding and its potential significance, they also stressed that there is still a long way to go before any type of preventative vaccine is actually ready for use on humans. An active immunization, which could be widely administered to the public, must allow antibodies to be produced on their own by the body.

“The next step is to see if we can focus active immunization on the portion of the [virus] that is conserved,” Ruprecht said. “At the same time, we are trying to find other regions that are conserved” between strains.

Ruprecht also explained that this antibody is not thought to be a cure, though she left the possibility open.

“This is a different clinical situation,” she said. “This is not about the cure.”

—Staff writer Mercer R. Cook can be reached at mcook@college.harvard.edu.

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EASL: Telaprevir Add-On Effective After Initial HCV Therapy Fails

Daniel M. Keller, PhD

April 6, 2011 (Berlin, Germany) — Telaprevir added to standard pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) therapy for hepatitis C virus (HCV) infection was superior to retreatment with peg-IFN/RBV plus placebo in patients for whom standard therapy had failed in the past, researchers announced here at the European Association for the Study of the Liver (EASL) 46th Annual Meeting.

The safety and tolerability of adding telaprevir were similar to results seen in previous trials. Adverse events leading to permanent discontinuation of the drugs consisted mainly of anemia and rash, and were more prevalent in the telaprevir groups than in the control group.

Standard combination therapy with peg-IFN/RBV fails in approximately 60% of patients with HCV genotype 1, which is one of the more difficult genotypes to eradicate, noted Stefan Zeuzem, MD, chief of the Department of Medicine and professor of medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, who presented the study results.

The aim of the Re-Treatment of Patients With Telaprevir-Based Regimen to Optimize Outcomes (REALIZE) trial was to test the addition of telaprevir, a new small-molecule HCV protease inhibitor, to peg-IFN/RBV in 662 patients with HCV genotype 1 for whom peg-IFN/RBV had previously failed to produce sufficient and sustained viral suppression.

The primary objective of this pivotal phase 3 international, multicenter, double-blind, placebo-controlled trial was to compare the proportion of patients achieving a sustained virologic response (SVR) with telaprevir plus peg-IFN/RBV and the proportion achieving an SVR with placebo plus peg-IFN/RBV. All SVRs were below 25 IU HCV RNA (undetectable level).

Patients were divided into 3 categories: null responders did not show at least a 2 log10 drop in serum HCV RNA at week 12 of previous standard therapy; partial responders experienced at least a 2 log10 drop at week 12 of previous therapy but still had detectable HCV RNA in the blood at week 24; and relapsers achieved viral levels below the limit of detection at 42 weeks but then had a recurrence of detectable virus.

The groups were well matched at baseline. Approximately 70% were men, median age was approximately 50 years, 93% were white, HCV RNA was above 800,000 IU/mL in 86% to 89%, and almost 60% were in the advanced stages of disease with bridging fibrosis or cirrhosis (26%). About half were infected with genotype 1a and about half with genotype 1b. About 30% were previous nonresponders, 20% were partial responders, and 50% were previous relapsers.

Patients were randomly assigned to 1 of 3 treatment groups: 266 patients received telaprevir + peg-IFN/RBV for 12 weeks, then placebo + peg-IFN/RBV for 4 weeks (T12/PR48); 264 patients received a lead-in of placebo + peg-IFN/RBV for 4 weeks, then telaprevir + peg-IFN/RBV for 12 weeks (lead-in T12/PR48); and 132 patients received placebo + peg-IFN/RBV for 16 weeks (placebo/PR48).

In these 3 groups, drug doses were as follows: telaprevir 750 mg every 8 hours; peg-IFN 180 µg/week; and RBV 1000 to 1200 mg/day. The groups were followed-up and assessed for SVR at week 72. The primary statistical calculations were on previous relapsers and on previous nonresponders (a combination of previous partial responders and null responders).

Dr. Zeuzem reported that among previous relapsers, 83% to 88% achieved an SVR when treated with telaprevir plus peg-IFN/RBV. Less than 10% of them relapsed by week 72. In contrast, only 41% of previous nonresponders achieved an SVR with telaprevir, but this figure was still a 4-fold increase over the proportion with an SVR when retreated with peg-IFN/RBV and placebo. Overall, about 35% of patients in the 2 telaprevir groups failed to achieve an SVR; those failures occurred mainly among previous partial and previous null responders.

Addition of Telaprevir to Peg-IFN/RBV Enhances SVR Rates

Patient Group T12/PR48, % (n/N) Lead-in T12/PR48, % (n/N) Placebo/PR48, % (n/N)

Previous Relapsers
SVRa  83 (121/145)c  88 (124/141)c  24 (16/68)
Relapseb 7 (10/135)  7 (9/138)  65 (30/46)

Previous Nonresponders
SVRa  41 (50/121)c  41 (51/123)c  9 (6/64)
Relapseb  23 (16/69)  25 (18/72)  33 (3/9)

a SVR assessed 24 weeks after planned treatment completion
b Relapse: detectable virus at week 72 in patients with undetectable HCV RNA at end of assigned treatment
c  P < .001, comparison vs placebo/PR48

"The SVR rates tended to be higher in genotype 1b–infected patients, in particular in prior partial responders and prior null responders," Dr. Zeuzem reported. "The lead-in phase [group] showed numerically slightly higher [SVR] rates in the prior relapsers and the prior nonresponders, but there was an opposite trend for the prior partial responders."

When the data were analyzed by the degree of baseline fibrosis, all subgroups of patients responded better to telaprevir than to peg-IFN/RBV plus placebo. For example, among previous relapsers, 86%, 85%, and 84% achieved an SVR with telaprevir if they had no fibrosis, bridging fibrosis, or cirrhosis, respectively, compared with 32%, 13%, and 13%, respectively, with peg-IFN/RBV plus placebo. The addition of telaprevir added little or no benefit over peg-IFN/RBV alone for previous partial or null responders with cirrhosis.

Dr. Zeuzem noted that adverse events, which occurred at least 10% more frequently in the telaprevir groups than in the placebo group, were fatigue, pruritis, rash, anemia, nausea, diarrhea, and anorectal symptoms (described as pruritis, discomfort, or hemorrhoids).

The majority of adverse effects were grade 1 or 2, with some grade 3 rash in the pooled telaprevir groups. Rash was primarily eczematous, which resolved when therapy ended. Anemia was managed with RBV dose reduction when necessary, which occurred in 25% of the telaprevir-treated patients. Per protocol, erythropoiesis-stimulating agents were not permitted. In the telaprevir groups, 11% to 15% discontinued treatment because of adverse events; in the placebo group, 3% did.

Dr. Zeuzem concluded that "telaprevir/peg-interferon-ribavirin triple therapy was clearly superior to the standard peg-interferon/ribavirin treatment alone" in all 3 treatment-experienced populations."

He said a 4-week lead-in phase with peg-IFN/RBV did not reduce virologic failure or relapse rates and did not improve SVR rates. He noted that the safety of telaprevir was similar to that observed in previous studies. Adverse events, mainly anemia and rash, led to permanent discontinuation of study drugs more frequently in the telaprevir groups than in the control group.

Mark Thursz, MD, professor of hepatology at Imperial College, London, United Kingdom, and vice secretary of EASL, said: "I think these are very responsible conclusions . . . and I feel that the data that are coming out on this particularly difficult-to-treat group of patients — those who had previous treatment and failed — these are really exciting results. Overall, something like 60% of patients were successfully treated [and] reached an SVR in the REALIZE trial." He added that "partial responders [did] so-so; null responders, not so good. This is disappointing but not entirely surprising. They are particularly difficult groups to treat."

Dr. Thursz, who was not involved in the REALIZE trial, said that for patients for whom previous therapy has failed, "now we have treatment options to offer them, assuming that the commissioning authorities will pay for [the drugs] for those who don't pay for their own therapy."

In response to a question from the audience about the rashes and the possibility of Stevens–Johnson syndrome, Dr. Zeuzem said that of the several thousand people exposed to telaprevir, "to the very best of my knowledge, there is only 1 case of Stevens–Johnson syndrome described, but this case occurred after telaprevir was already discontinued, so a causal relationship cannot be justified from this single case. But I know that this single case has made many people very nervous."

Although anemia was more frequent in the telaprevir groups, "we have learned to manage anemia in this group of patients," Dr. Thursz said. "Most patients can tolerate more anemia than the pharmaceutical companies can."

Telaprevir is being developed by Vertex Pharmaceuticals. The US Food and Drug Administration has granted the drug priority review, which is expected on May 23.

Dr. Zeuzem reports relationships with Abbott, Achillion, Anadys, BMS, Gilead, iTherX, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, and Vertex. Dr. Thursz has disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) 46th Annual Meeting: Opening session. Presented March 30, 2011.

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Roche Joins in Spanish Research Cooperation for Personalized Treatment of Hepatitis B and C

April 06, 2011 08:00 AM Eastern Daylight Time

PENZBERG, Germany--(BUSINESS WIRE)--Roche Diagnostics (SIX: RO, ROG; OTCQX: RHHBY) is cooperating with the Spanish Vall d’Hebron Institute of Research (VHIR), the Networking Biomedical Research Centre in Liver and Digestive Diseases (CIBEREHD), and the software producer Advanced Biological Laboratories Therapy Edge Spain (ABL) in a study designed to resolve the current limitations that prevent the individualization of anti-HBV and anti-HCV (hepatitis B and C) treatments. The project will utilize Roche’s 454 Sequencing Systems and bioinformatics analysis, together with other genetic and molecular analytical techniques. Ultimately, the research project aims to identify personalized treatment for each individual while minimizing the healthcare costs and side effects experienced by subjects.

Hepatitis C (HCV) infection affects 3% of the world population, representing a chronic disease for nearly 180 million people. Many infected individuals acquire the disease 15-25 years before identification of the virus and the use of diagnostic tests. The infection remains asymptomatic until advanced stages of the disease characterized by complications such as decompensated cirrhosis or hepatocellular carcinoma. While in the early stages resource use for controlling the disease is very limited, in the advanced stages resource consumption is enormous, and a significant percentage of individuals even require liver transplantation – with the resulting increase in direct and indirect costs, loss of quality of life and increased morbidity-mortality.

“The hepatitis C and B viruses exhibit great variability; a person infected with one of these viruses presents a complex population of variants comprising a structure known as ‘quasispecies’. The identification of these variants may be crucial for avoiding the selection of variants resistant to the new antiviral therapies,” explains Dr. Juan Ignacio Esteban-Mur, head of the line in hepatitis C, molecular biology, immune response and treatment of the liver diseases at VHIR. Dr. Esteban-Mur also is the coordinator of the viral hepatitis program of the CIBERHED, which comprises 8 Spanish research groups, specialized in this field.

The use of 454 Sequencing Systems makes it possible to gain a comprehensive profile of the complex viral populations that circulate in individuals, with the fundamental purpose of identifying the presence of viral quasispecies resistant to the existing antiviral treatments. The goal of the study is to apply this massively parallel sequencing approach to personalize the antiviral treatment strategies in individuals with chronic hepatitis C or B.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2010, Roche had over 80’000 employees worldwide and invested over 9 billion Swiss francs in R&D. The Group posted sales of 47.5 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: http://www.roche.com/.

For life science research only. Not for use in diagnostic procedures.

454, 454 LIFE SCIENCES, and 454 SEQUENCING, are trademarks of Roche.

Other brands or product names are trademarks of their respective holders.

Contacts
Roche Diagnostics
Dr. Burkhard Ziebolz
Phone: +49 8856 604830
Email: burkhard.ziebolz@roche.com

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