Merck’s Investigational Medicine Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure and Treatment-Naïve Adult Patients with Chronic Hepatitis C Genotype 1 Compared to Control

BOSTON, - Merck reported today that final results from two pivotal Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, demonstrated significantly higher sustained virologic response (SVR)1 rates in adult patients who previously failed treatment (treatment-failure; HCV RESPOND-2) and in adult patients who were new to treatment (treatment-naïve; HCV SPRINT-2) for chronic hepatitis C virus (HCV) genotype 1 compared to control, the primary objective of the studies. The results for the primary endpoints of these studies, which were first reported in a news release in August 20102, and a broad range of further data analyses from these studies are being presented in oral and poster presentations at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).3,4,5

“We are excited by the results of these pivotal studies,” said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. “In these studies, boceprevir substantially increased success rates compared to standard therapy, both for patients who received 48 weeks of treatment and for patients treated with the response-guided therapy approach, many of whom were able to be treated for 28 to 36 weeks,” he added. “Based on these data, Merck has initiated the submission of a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration (FDA) on a rolling basis, and we expect to complete regulatory submissions in the U.S. and E.U. in 2010.”

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir administered in combination with PEGINTRON® (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) (Peg/riba) to assess whether the addition of boceprevir could improve SVR rates and potentially shorten overall treatment duration compared to the use of Peg/riba alone for 48 weeks, which is the current standard duration of therapy. In each study, patients were randomized to three groups:

* Response-guided therapy (RGT), in which total treatment duration was based on certain early response criteria. Treatment-failure patients with undetectable virus (HCV-RNA) at week 8 were eligible to stop all treatment at 36 weeks. Treatment-naïve patients with undetectable virus (HCV-RNA) during weeks 8 through 24 were eligible to stop all treatment at 28 weeks.
* 48 weeks of treatment, in which patients received a 4-week Peg/riba lead-in followed by the addition of boceprevir for 44 weeks.
* Control, in which patients received Peg/riba for 48 weeks.


In both studies, all patients were treated with a 4-week lead-in of PEGINTRON (1.5 mcg/kg/week) and an investigational dose of REBETOL (600-1,400 mg/day), followed by the addition of boceprevir (800 mg three times a day).

In primary results, addition of boceprevir significantly increased SVR rates compared to control
HCV RESPOND-2, which was conducted at U.S. and international sites, included 403 adult patients who had failed prior therapy, including patients who relapsed or were non-responders to prior treatment with peginterferon and ribavirin. HCV SPRINT-2 was conducted in 1,097 treatment-naïve adult patients at U.S. and international sites who were enrolled in two separate cohorts, one with 938 non-African-American/non-Black patients and the other with 159 African-American/Black patients.

As previously reported, the primary results of these two studies were as follows: In treatment-failure patients in HCV RESPOND-2, boceprevir increased SVR rates to 59 percent for the RGT arm (95/162) and 66 percent for the 48-week treatment arm (107/161) compared to 21 percent for control (17/80). In treatment-naïve patients in HCV SPRINT-2, boceprevir increased SVR rates to 63 percent for the RGT arm (233/368) and 66 percent for the 48-week treatment arm (242/366), compared to 38 percent for control (137/363).

Researchers present new analyses on boceprevir response-guided therapy
In secondary analyses presented for the first time at AASLD, researchers reported that nearly half of all patients in the boceprevir RGT arms met early response criteria and received a shorter total duration of therapy:

* In the RGT arm of the treatment-failure study, 46 percent (74/162) of patients met the early response criteria and were eligible to stop all treatment at 36 weeks, which is 12 weeks shorter than current standard therapy. In these patients, the SVR rate was 86 percent (64/74).
* In the RGT arm of the treatment-naïve study, 44 percent of patients (162/368) met the early response criteria and were eligible to stop all treatment at 28 weeks, which is 20 weeks shorter than current standard therapy. In these patients, the SVR rates were 97 percent (143/147) in non-African-American/non-Black treatment-naïve patients and 87 percent (13/15) in African-American/Black treatment-naïve patients.


For the corresponding patients in the boceprevir 48-week treatment arms of these studies, the SVR rates were 88 percent (74/84) in treatment-failure patients, 96 percent (137/142) in non-African-American/non-Black treatment-naïve patients and 95 percent (18/19) in African-American/Black treatment-naïve patients.

Patients in the boceprevir RGT arms of these studies who did not meet the early response criteria and were treated for up to 48 weeks also achieved substantially higher SVR rates compared to control. In these patients, the SVR rates were 40 percent (29/72) in treatment-failure patients, 74 percent (52/70) in non-African-American/non-Black treatment-naïve patients and 58 percent (7/12) in African-American/Black treatment-naïve patients.

“In the study of patients who failed prior treatment, boceprevir combination therapy helped the majority of patients achieve sustained virologic response, the goal of treatment,” said Bruce Bacon, M.D., professor of Internal Medicine, Saint Louis University School of Medicine and co-principal investigator of HCV RESPOND-2. “This is the only study to evaluate a strategy for shorter treatment in these difficult-to-treat patients. We observed that many patients in the boceprevir response-guided therapy arm were able to have their treatment duration reduced by three months compared to current standard duration of treatment.”

“In these studies, boceprevir response-guided therapy provided physicians flexibility in the management of their patients’ HCV therapy, which enabled them to adapt treatment duration based on individual patient response,” said Fred Poordad, M.D., chief of hepatology in the division of gastroenterology at Cedars-Sinai Medical Center, associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles (UCLA), and co-principal investigator of the HCV SPRINT-2 study. “These studies were designed with a four-week lead-in strategy that was intended to help physicians identify their patients’ responsiveness to interferon prior to the addition of a protease inhibitor, which provided an early indication of the likelihood of treatment success.”

Tolerability profile in treatment-failure patients
The five most common treatment-related adverse events in the HCV RESPOND-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (54, 57, and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39 and 38 percent), chills (35, 30 and 30 percent) and influenza-like illness (23, 23 and 25 percent). Anemia was reported in 43, 46 and 20 percent of patients in the study arms, respectively. Serious adverse events were reported in 10, 14 and 5 percent of patients in the study arms, respectively.

Treatment discontinuations due to adverse events over the total course of all treatment were 8 percent and 12 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 3 percent for control. Treatment discontinuations due to anemia were 0 percent and 3 percent for the boceprevir arms, respectively, compared to 0 percent for control. Erythropoietin (EPO) for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 41 and 46 percent of patients in the boceprevir RGT and 48-week treatment arms, respectively, compared to 21 percent for control.

Tolerability profile in treatment-naïve patients
The five most common treatment-related adverse events in the HCV SPRINT-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (52, 57 and 59 percent), headache (45, 43 and 42 percent), nausea (46, 42 and 40 percent), anemia (49, 49 and 29 percent) and dysgeusia (bad taste) (37, 43 and 18 percent). Serious adverse events were reported in 11, 12 and 9 percent of patients in the study arms, respectively.

Treatment discontinuations due to adverse events over the total course of all treatment were 12 percent and 16 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 16 percent for control. Treatment discontinuations due to anemia were 2 percent for each of the boceprevir treatment arms compared to 1 percent for control. EPO for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 43 percent of patients in each of the boceprevir treatment arms compared to 24 percent for control.

The HCV RESPOND-2 and HCV SPRINT-2 studies each employed futility or “stopping” rules, whereby patients in any treatment arm who had detectable virus at week 12 in the HCV RESPOND-2 study or at week 24 in the HCV SPRINT-2 study were considered treatment failures and discontinued all treatment. These stopping rules allowed for patients in the studies who did not respond to treatment to have their therapy stopped early, thereby avoiding unnecessary treatment.

Merck’s global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to viral hepatitis care.

About PEGINTRON
PEGINTRON is indicated for use in combination with REBETOL (ribavirin) for the treatment of chronic hepatitis C in patients three years of age and older with compensated liver disease.

The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (1) These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.

PEGINTRON is also indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.

The following points should be considered when initiating therapy with PEGINTRON alone: Combination therapy with REBETOL is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, REBETOL. Combination therapy provides substantially better response rates than monotherapy.

Selected Safety Information on PEGINTRON WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

Alpha interferons, including PEGINTRON, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PEGINTRON therapy.

Use with Ribavirin: Ribavirin may cause birth defects and death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.


Contraindications
PEGINTRON is contraindicated in patients with known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis to interferon alpha or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment. PEGINTRON/REBETOL combination therapy is additionally contraindicated in women who are pregnant or may become pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), and patients with creatinine clearance less than 50 mL per min.

Pregnancy
REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for six months after completion of therapy. If this drug is used during pregnancy, or if a patient becomes pregnant, the patient should be apprised of the potential hazard to a fetus. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Patients with the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:

* Hemolytic anemia with ribavirin
* Neuropsychiatric events
* History of significant or unstable cardiac disease
* Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication
* New or worsening ophthalmologic disorders
* Ischemic and hemorrhagic cerebrovascular events
* Severe decreases in neutrophil or platelet counts
* History of autoimmune disorders
* Pancreatitis and ulcerative or hemorrhagic/ischemic colitis and pancreatitis
* Pulmonary infiltrates or pulmonary function impairment
* Child-Pugh score greater than 6 (Class B and C)
* Increased creatinine levels in patients with renal insufficiency
* Serious, acute hypersensitivity reactions and cutaneous eruptions
* Dental/periodontal disorders reported with combination therapy
* Hypertriglyceridemia may result in pancreatitis (e.g., triglycerides greater than 1000 mg/dL)
* Weight loss and growth inhibition reported with combination therapy in pediatric patients.



Life-threatening or fatal neuropsychiatric events, including suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior, sometimes directed towards others, have occurred in patients with and without a previous psychiatric disorder during PEGINTRON treatment and follow-up.

Adverse events
Serious adverse reactions have occurred in approximately 12 percent of subjects in clinical trials. The most common serious events occurring in subjects treated with PEGINTRON and REBETOL were depression and suicidal ideation, each occurring at a frequency of less than 1 percent. The most common fatal events occurring in subjects treated with PEGINTRON and REBETOL were cardiac arrest, suicidal ideation, and suicide attempt, all occurring in less than 1 percent of subjects.

The incidence of serious adverse reactions was comparable between PEGINTRON monotherapy (about 12 percent) and PEGINTRON/REBETOL combination therapy weight-based (12 percent) or flat-dose (17 percent). In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In a study with PEGINTRON/REBETOL (weight-based) combination therapy in adult patients, anemia with weight-based dosing occurred at an increased rate (29 percent vs. 19 percent); however, the majority of these cases were mild and responded to dose reductions. The incidence of serious adverse reactions reported for the weight-based REBETOL group was 12 percent. There were 31 deaths in clinical trials which occurred during treatment or during follow-up. Of the deaths, 19 were patients on either PEGINTRON or PEGINTRON/REBETOL combination therapy and three occurred during the follow-up period but had been on PEGINTRON/REBETOL combination therapy.

Additional serious adverse reactions seen in clinical trials at a frequency of equal to or less than 1 percent included psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection site necrosis, vasculitis, and phototoxicity.

Greater than 96 percent of all subjects in clinical trials experienced one or more adverse events. Most common adverse reactions (greater than 40 percent) in adult patients receiving either PEGINTRON or PEGINTRON/REBETOL are injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability.

The adverse reaction profile was similar between weight-based and flat-dose PEGINTRON/REBETOL therapies. Weight-based PEGINTRON/REBETOL dosing resulted in increased rates of anemia. Most common adverse reactions with PEGINTRON/REBETOL (weight-based) therapy were psychiatric, which occurred among 68-69 percent of patients and included depression, irritability, and insomnia, each reported by approximately 30-40 percent of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2 percent of all patients during treatment or during follow-up after treatment cessation. Other common reactions included injection site reactions, fatigue/ asthenia, headache, rigors, fever, nausea, myalgia, anxiety/emotional lability/irritability. The severity of some of these systemic symptoms tends to decrease as treatment continues.

Subjects receiving PEGINTRON/REBETOL as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to previous treatment-naïve patients receiving this regimen.

In general, the adverse reaction profile in the pediatric population was similar to that observed in adults. Most common adverse reactions (greater than 25 percent) in pediatric patients receiving PEGINTRON/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, abdominal pain, and vomiting.

Please see full prescribing information at http://www.spfiles.com/pipeg-intron.pdf and at http://www.spfiles.com/pirebetol.pdf.

About Merck
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1 SVR, the protocol specified primary efficacy endpoint of the 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.
2 Merck news release: In Pivotal Phase III Studies, Merck’s Investigational Medicine Boceprevir Helped Majority of Patients with Chronic Hepatitis C Genotype 1 Infection Achieve Sustained Virologic Response, the Primary Endpoint of the Studies. Available at: http://www.merck.com/newsroom/news-release-archive/home.html. Aug. 4, 2010.
3 B.R. Bacon et al. HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin. Abstract 216.
4 F. Poordad et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. Abstract LB-4.
5 J. Bronowicki et al. Response-Guided Therapy (RGT) with Boceprevir (BOC) + Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1 Was Similar to a 48-Wk Fixed-Duration Regimen with BOC + P/R in SPRINT-2. Abstract LB-15.