Valeant Pharmaceuticals International (NYSE:VRX) today previewed its 24-week data from the Infergen® (Consensus Interferon) DIRECT trial through an abstract submitted to and accepted by the American Association for the Study of Liver Diseases (AASLD). Additional data, including 48 week data, will be presented as a late-breaker poster at the upcoming AASLD meeting in Boston on October 30, 2006.
The DIRECT trial is evaluating the daily use of Infergen in combination with ribavirin for the treatment of hepatitis C in patients who were non-responsive to previous pegylated interferon and ribavirin therapy. The screening criteria for this trial were very strict, which resulted in more than 75 percent of patients having evidence of advanced fibrosis/cirrhosis (stage 3 and 4). Patients also were especially heavy, with an average weight of 89 kg (196 lbs.) and also had been off therapy (washed out) for a median of 395 days in the 9 µg group and 492 days in the 15 µg group. No patients in the study received growth factors for treatment of neutropenia or anemia.
Early virologic response rates (≥2 log10 decline in HCV RNA or undetectable HCV RNA) in the trial for the Infergen 9 µg and 15 µg groups were 46 percent and 54 percent, respectively (TMA assay). The percent of patients who were virus negative at week 24 were 14 percent and 20 percent for the Infergen 9 µg and 15 µg groups, respectively (TMA assay). Response rates at 24 weeks using the bDNA assay were 26 percent and 32 percent for the Infergen 9 µg and 15 µg groups, respectively.
Non-cirrhotic patients, including patients with bridging fibrosis, receiving Infergen 15 µg daily experienced 25 percent viral negativity at 24 weeks (36 percent by bDNA). Of the non-cirrhotic patients who maintained at least 80 percent of their Infergen and ribavirin doses, the response rate was 33 percent (47 percent by bDNA).
The washout period (days from completion of at least 12 weeks of compliant pegylated interferon and ribavirin therapy to the first dose of Infergen in the DIRECT trial) had a significant impact on viral response as well. Patients receiving Infergen 15 µg daily with a washout period less than the 492 median days were twice as likely to be virus free at week 24 (26 percent vs. 13 percent by TMA). The company plans to perform further analyses of these data and will present them at the AASLD meeting, including the 48 week results in the analysis as well.
“These early results from the DIRECT trial are promising. The high percentage of patients with advanced disease and the long washout period make this a challenging population to treat. These patients had not previously responded to pegylated interferon and ribavirin, and it is encouraging that companies are developing new treatment options with the potential to help many of these patients achieve a sustained virologic response,†commented Bruce R. Bacon, M.D., the DIRECT trial lead investigator and Director of the Division of Gastroenterology and Hepatology at Saint Louis University.
“To date, there is no approved therapy to treat the growing number of pegylated interferon and ribavirin non-responders. Pending the final sustained virologic response rates, Valeant plans to seek FDA approval for the daily use of Infergen and ribavirin for the treatment of pegylated interferon non-responders,†said Wesley P. Wheeler, Valeant's President of North America and Global Product Development.
About DIRECT
The DIRECT (Daily-Dose Consensus Interferon and Ribavirin:Efficacy of CombinedTherapy) trial is a Phase 3 open-label multi-center U.S.-based study enrolling patients who were previous non-responders and compliant with at least 12 weeks of pegylated interferon and ribavirin therapy. The 343 genotype non-2, 3 patients enrolled were randomized to receive either Infergen 9 µg/day plus ribavirin (1.0-1.2 g/day) or Infergen 15 µg/day plus ribavirin (1.0-1.2 g/day) for 48 weeks. The patients enrolled were required to have less than a 2 log10 decline in viral load while undergoing at least 12 weeks of previous pegylated interferon and ribavirin therapy or have detectable HCV RNA at the end of treatment, after completing at least 24 weeks of pegylated interferon and ribavirin.
Patient demographics in the trial include patients with a mean age of 50 years, 70 percent male, 67 percent high viral load (> 2 million copies/ml), 92 percent genotype 1, a mean weight of 89kg, 20 percent African Americans, 65 percent Caucasians, and 77 percent with evidence of liver disease, including bridging fibrosis or cirrhosis on biopsy. The median washout period was 395 days for the Infergen 9 µg cohort and 492 days for the Infergen 15 µg group.
The most common adverse events were fatigue, flu like symptoms, nausea, headache and insomnia and were similar between groups. The percent of patients modifying their Infergen dose due to adverse events were 24 percent in the Infergen 9 µg cohort and 39 percent in the Infergen 15 µg group. Neutropenia was the most comment adverse event leading to dose modification and occurred in 12 percent in the Infergen 9 µg cohort and 21 percent in the Infergen 15 µg group. Growth factors were not used in the study.
About Infergen
Infergen or consensus interferon is a bio-optimized, selective and highly potent type 1 interferon alpha originally developed by Amgen and launched in the United States in 1997. It is currently indicated as monotherapy for the treatment of adult patients suffering from chronic hepatitis C viral infections with compensated liver disease and is dosed three times per week. Infergen is the only interferon with data in the label regarding use in patients following relapse or non-response to certain previous treatments.
Infergen is being studied in ongoing clinical trials to evaluate its potential for daily use with ribavirin. Enrollment in the Phase 3 IHRC-001 (DIRECT) trial was completed in mid-2005 with 514 patients at 40 sites in the United States. The DIRECT trial, which should be completed in 2007, is evaluating the safety and efficacy of both 9 µg and 15 µg doses of daily Infergen in combination with ribavirin in non-responders.
About Hepatitis C
According to the Centers for Disease Control and Prevention, an estimated 3.9 million Americans (1.8 percent) have been infected with the hepatitis C virus (HCV). HCV causes an estimated 10,000 to 12,000 deaths annually in the United States and is the leading cause of the need for liver transplants. The prevalence of HCV is increasing and approximately half of all patients with compensated liver disease do not respond to first-line treatment. There are approximately 250,000 of these non-responder patients currently in the U.S. and the number is growing by an estimated 50,000 each year.
Important Safety Information
Alpha interferons, including Interferon alfacon-1, 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 symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping Interferon alfacon-1 therapy.
INFERGEN® is contraindicated in patients with known hypersensitivity to alpha interferons or to any component of the product, in patients with decompensated hepatic disease and autoimmune hepatitis. Development of or exacerbation of autoimmune disorders (e.g. autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis) have been reported in patients receiving alpha interferon therapies, including INFERGEN.
Treatment with INFERGEN 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 further therapy.
Severe psychiatric adverse events may manifest in patients receiving therapy with alpha interferons, including INFERGEN. Depression, suicidal ideation, suicide attempt, and suicide may occur. Other prominent psychiatric adverse events may also occur, including psychosis, aggressive behavior, nervousness, anxiety, emotional lability, abnormal thinking, agitation, apathy and relapse of drug addiction. INFERGEN should be used with extreme caution in patients who report a history of depression. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted.
Bone Marrow Toxicity: Alpha interferons suppress bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts be obtained pretreatment and monitored routinely during therapy. Alpha interferon therapy should be discontinued in patients who develop severe decreases in neutrophil (0.5 x 109/L) or platelet counts (<50 x 109/L).
Hypertension, tachycardia, palpitation, and tachyarrythmias have been reported in patients treated with INFERGEN. INFERGEN should be administered with caution to patients with preexisting cardiac disease. Supraventricular arrhythmias, chest pain, and myocardial infarction have been associated with alpha interferon therapies.
Pneumonia and interstitial pneumonitis, some resulting in respiratory failure and/or patient deaths, have been induced or aggravated by alpha interferon therapy, including INFERGEN. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with INFERGEN.
Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when treated with alpha interferons, including INFERGEN. During treatment, patients' clinical status and hepatic function should be closely monitored, and INFERGEN treatment should be immediately discontinued if symptoms of hepatic decompensation, such as jaundice, ascites, coagulopathy, or decreased serum albumin, are observed.
Ophthalmologic Disorders: Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, and papilledema are induced or aggravated by treatment with INFERGEN or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. INFERGEN therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Ischemic and hemorrhagic cerebrovascular events including hemorrhagic stroke have been observed in patients being treated with INFERGEN. In addition, transient ischemic attack has been reported in young patients being treated with INFERGEN without other reported risk factors.
INFERGEN should be discontinued immediately and appropriate medical treatment instituted if hypersensitivity reactions occur. INFERGEN should be administered with caution to patients with a history of endocrine disorders and should be discontinued immediately in patients who develop signs and symptoms of colitis. In addition, INFERGEN should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.
The most common adverse events reported for INFERGEN during clinical studies were headache (82%), fatigue (69%), fever (61%), myalgia (58%), rigors (57%), body pain (54%), arthralgia (51%), nausea (40%), insomnia (39%), pharyngitis (34%), nervousness (31%), infection upper respiratory (31%), diarrhea (29%), depression (26%), anorexia (24%), injection site erythema (23%), granulocytopenia (23%), dizziness (22%), cough (22%), dyspepsia (21%), thrombocytopenia (19%), anxiety (19%), sinusitis (17%), influenza-like symptoms (15%) and leucopenia (15%).
Physicians and patients can obtain additional prescribing information regarding Infergen, including the product's safety profile and the box warning for all interferon alphas regarding neuropsychiatric, autoimmune, ischemic and infectious disorders, by visiting www.infergen.com.
About Valeant
Valeant Pharmaceuticals International (NYSE:VRX) is a global specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of neurology, infectious disease and dermatology. More information about Valeant can be found at www.valeant.com.
Infergen is a registered trademark of Amgen and its related companies. All other trademarks are the trademarks or the registered trademarks of their respective owners.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements, including, but not limited to, statements regarding the company's ability to successfully complete the DIRECT trial and obtain FDA approval for daily use of Infergen with ribavirin, and successfully expand its infectious disease business. These statements are based upon the current expectations and beliefs of Valeant's management and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. These risks and uncertainties include market conditions and other factors beyond Valeant's control, adverse events that would require clinical trials to be prematurely terminated, clinical results that indicate continuing clinical and commercial pursuit of Infergen is not advisable, and the risk factors and other cautionary statements discussed in Valeant's filings with the U.S. Securities and Exchange Commission. Valeant wishes to caution the reader that these factors are among the factors that could cause actual results to differ materially from the expectations described in the forward-looking statements. Valeant also cautions the reader that undue reliance should not be placed on any of the forward-looking statements, which speak only as of the date of this release. The company undertakes no obligation to update any of these forward-looking statements to reflect events or circumstances after the date of this release or to reflect actual outcomes.
