More on Tyzeka as monotherapy and for co~infection:
FDA Approves New Treatment for Chronic Hepatitis B in Adults The Food and Drug Administration (FDA) today approved Tyzeka (telbivudine) for the treatment of adults with chronic hepatitis B (HBV), a serious viral infection that attacks the liver and can cause lifelong infection, scarring of the liver (cirrhosis), and eventually liver cancer, liver failure, and death. Tyzeka is a new molecular entity, which is a term used by the FDA to describe a medication containing an active substance that has never before been approved for marketing in any form in the United States. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01498.html
"In a typical year, an estimated 70,000 Americans become infected with chronic HBV, and some 5,000 of them will die of the complications caused by the disease," said Dr. Steven Galson, Director of the Center for Drug Evaluation and Research. "Tyzeka offers prescribers another option for treating these patients."
Tyzeka was studied in a year-long international clinical trial in 1,367 patients with chronic HBV. Three-quarters of the trial participants were male, and all were 16 years of age or older. The trial produced evidence of antiviral effectiveness, including the suppression of hepatitis B virus, and improvement in liver inflammation comparable to Epivir-HBV (lamivudine), one of five other medications approved to treat patients with chronic HBV.
HBV is spread when blood from an infected person enters the body of a person who is not infected, sometimes by sexual contact or blood contamination. Tyzeka is not a cure for hepatitis B, and long-term treatment benefits of this drug are not known. Use of Tyzeka has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
In clinical studies Tyzeka was generally well tolerated, and most reported adverse events were mild to moderate. The most common side effects were elevated CPK (creatinine phosphokinase, an enzyme that is present in muscle tissue and is a marker for breakdown of muscle tissue), upper respiratory tract infection, fatigue, headache, abdominal pain and cough.
Also, after several weeks to months of Tyzeka use, some patients developed symptoms ranging from transient muscle pain to muscle weakness. Those who developed muscle weakness experienced significant improvement in their symptoms when Tyzeka was discontinued.
Patients should only stop Tyzeka after a careful discussion with their doctor. As has happened with other forms of treatment for hepatitis B, some patients who discontinued Tyzeka experienced a sudden and severe worsening of their hepatitis B. Therefore, patients who discontinue Tyzeka should be closely monitored by their doctor for at least several months.
Among drugs in the same class as Tyzeka, some cases of lactic acidosis (too much acid in the body due to buildup of lactic acid) and severe enlargement and accumulation of fat in the liver, including fatal cases, have been reported.
Tyzeka is manufactured by Novartis Pharma Stein AG, Stein, Switzerland and marketed and distributed by Idenix Pharmaceuticals, Inc., Cambridge, MA.
Tyzeka Approved to Treat Chronic Hepatitis B WEDNESDAY, Oct. 25 (HealthDay News) -- The Novartis Pharma drug Tyzeka (telbivudine) was approved Wednesday by the U.S. Food and Drug Administration to treat chronic hepatitis B (HBV), a serious liver infection. The drug contains a new molecular entity that hadn't been previously approved for marketing in the United States, the FDA said.
Some 70,000 Americans are infected with HBV each year. It can cause scarring of the liver (cirrhosis), possibly leading to liver cancer, liver failure, and death. In a year-long trial of Tyzeka involving 1,367 patients, the drug outperformed lamivudine, one of five other medications approved to treat chronic HBV, the agency said.
HBV is typically spread via sexual contact or contaminated blood. Tyzeka is not a cure for the disease, nor has it been shown to reduce the risk of transmission, the FDA said. The long-term benefits of treatment with Tyzeka aren't known, the agency added.
After several weeks of use, some clinical trial participants developed muscle problems ranging from weakness to pain. Symptoms in many of these patients improved once the drug was discontinued.
But the agency warned that no one should stop using Tyzeka without consulting a doctor, since some people who discontinued the drug had a sudden and severe worsening of hepatitis B symptoms. http://www.medicinenet.com/script/main/art.asp?articlekey=77132
And off label use of Tyzeka for HIV/HBV co~infection:
The U.S. Food and Drug Administration (FDA) granted approval on Wednesday to Tyzeka™ (telbivudine), a new treatment for chronic hepatitis B virus (HBV) infection. While the new agent, developed by Switzerland's Novartis Pharma and being sold in the U.S. by Idenix Pharmaceuticals, has not been specifically approved for HIV-positive people with hepatitis B, it can still be prescribed by doctors treating patients with both infections.
The number of new hepatitis B infections in the U.S. has declined from about 260,000 a year in the 1980s to approximately 73,000 in 2003, with the greatest decline occurring in children and adolescents due to routine HBV vaccination. However, roughly 1.25 million people in the U.S. are living with chronic HBV infection, and 350 million are believed to be living with the virus worldwide.
Every year, approximately 5,000 people in the U.S. die of liver disease attributed to HBV infection in the U.S.
HBV is very similar to HIV in the ways it is transmitted, notably blood-to-blood contact and through sexual activity. In turn, many people living with HIV have also been exposed to HBV. What's more, HIV-positive people who are exposed to HBV are less likely to clear the infection within six months, ultimately leading to long-term (chronic) infection and an increased risk of severe liver damage and death.
Tyzeka was studied in a year-long international clinical trial involving 1,367 HIV-negative patients with chronic HBV. Three-quarters of the trial participants were male, and all were 16 years of age or older. The trial produced evidence of antiviral effectiveness, including the suppression of HBV, and improvement in liver inflammation comparable to Epivir®.
Unlike other treatments active against HBV, such as Epivir, Hepsera®, Viread® (tenofovir), and Emtriva® (emtricitabine), Tyzeka does not have any activity against HIV. This is actually good news, as it might be used as a treatment for HBV before HIV treatment is needed. Tyzeka may be used as monotherapy in this situation without the risk of HIV becoming resistant to the drug and, as a result, becoming cross resistant to other nucleoside reverse transcriptase inhibitors (NRTIs) used to treat HIV infection.
In clinical studies, none of which included HIV-positive people, Tyzeka was generally well tolerated, and most reported adverse events were mild to moderate. The most common side effects were elevated CPK (creatinine phosphokinase, a marker for breakdown of muscle tissue), upper respiratory tract infection, fatigue, headache, abdominal pain and cough.
Also, after several weeks to months of Tyzeka use, some patients developed muscle pain and muscle weakness. Those who developed these symptoms often experienced significant improvement after Tyzeka was discontinued.
Patients should only stop Tyzeka after a careful discussion with their doctor. As has happened with other forms of treatment for hepatitis B, some patients who discontinued Tyzeka experienced a sudden and severe worsening of their hepatitis B. Therefore, patients who discontinue Tyzeka should be closely monitored by their doctor for at least several months.
By Neil Osterweil, Senior Associate Editor, MedPage Today Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine October 30, 2006
Additional AASLD Coverage
BOSTON, Oct. 30 -- Tyzeka (telbivudine) was superior to Epivir (lamivudine) at reducing hepatitis B virus (HBV) to undetectable levels after two years, reported investigators here. Action Points
Explain to interested patients that in the study described, significantly more patients with hepatitis B viral infections, with and without the HBeAg, who were treated with Tyzeka (telbivudine) had undetectable viral levels at two years compared with patients treated with Epivir (lamivudine).
This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication. In the multicenter international GLOBE trial, significantly more HBe-antigen negative (HBeAg-) and antigen-positive (HBeAg+) patients treated with Tyzeka had undetectable levels of HBV RNA in serum than similar patients treated with Epivir, according to Ching-Lung Lai, M.D., of the University of Hong Kong, and colleagues.
The FDA last week approved Tyzeka, a nucleoside inhibitor, as a once-daily oral antiviral therapy for chronic HBV infections. Results of the GLOBE trial, which was the pivotal registration study for Tyzeka, were presented by Dr. Lai at the American Association for the Study of Liver diseases meeting here.
The GLOBE study was a randomized double-blind trial comparing oral Tyzeka at 600 mg/day with oral Epivir at 100 mg/day in 1,367 adults with chronic HBV infection at 112 centers in Asia, Oceania, Europe, and North America.
At the time of entry into the two-year study, patients had to be HB e-antigen positive, indicating a high viral load and high risk of infectivity, have HBV DNA levels at more than 6 log10 copies/mL, have alanine aminotransferase levels (ALT) at 1.3 to 10 times the upper limit of normal, and have compensated liver disease.
The primary endpoint was therapeutic response, a composite endpoint comprising viral suppression (serum HBV DNA suppression below 100,000 copies/mL) with either improved liver disease markers (ALT normalization) or loss of detectable HBeAg.
The investigators reported one-year results from the GLOBE study at the 2005 AASLD meeting. At that time, they reported that HBeAg+ patients taking Tyzeka had a mean reduction in HBV DNA of -6.5 log10, compared with -5.5 log10 among patients on Epivir (P<0.01).
Among HBeAg- patients, those taking Tyzeka had a -5.2 log10 HBV DNA reduction, vs. -4.4 log10 with Epivir (P<0.01).
Among HBeAg+ patients, 60% of those on Tyzeka had an e-antigen loss, compared with 40% of those on Epivir (P<0.01).
Among those who were HBeAg-, Tyzeka treatment reduced HBV DNA to below detectable levels in 88%, compared with 71% of those on Epivir.
In an intention-to-treat analysis of two-year follow-up results presented here, 82% of HBe-antigen negative patients treated with Tyzeka had undetectable levels of HBV RNA in serum, compared with 57% of similar patients treated with Epivir.
Among patients with treatment-refractory HBe-antigen positive infections, 56% on Tyzeka had achieved viral clearance at two years, compared with 39% of those on Epivir.
When they looked at the primary endpoint of therapeutic response, the investigators found that the rate was 64% among HBeAg+ patients treated with Tyzeka, compared with 48% for Epivir-treated HBeAg+ patients.
Among HBeAg- patients, the response rates were 78% for Tyzeka, vs. 66% for Epivir.
The authors also found evidence that early PCR negativity was associated with a lower chance for developing viral resistance, defined as HBV DNA return to >5 log10, or to within 1 log of baseline.
Tyzeka-treated patients who achieved PCR negativity at week 24 had a per-protocol rate of resistance at two years of 4% in HBeAg+ patients, and 2% in HBeAg- patients. In comparison, 17.8% of all patients on Tyzeka, and 30.1% of all patients on Epivir had signs of viral resistance in the per-protocol analysis.
Patients with PCR non-detectable HBV DNA at week 24 showed high positive predictive values for achieving all efficacy endpoints at year two. In contrast, negative predictive values for two-year efficacy outcomes were high for patients with HBV DNA more than 4 logs at week 24.
Disease exacerbation was defined as ALT flares, according to AASLD criteria of ALT more than 10 times the upper limit of normal, and more than two times baseline levels. ALT flares occurred in 2.8% of patients on Tyzeka, and 8.4% on Epivir.
Grade 3 or 4 creatine kinase elevations were significantly higher among patients treated with Tyzeka, at 13%, compared with only 4% of patients treated with Epivir.
The studies were funded by Idenix Pharmaceuticals, makers of Tyzeka. Dr. Lai is scientific adviser to the company.
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Primary source: American Association for the Study of Liver Diseases Source reference: Lai C et al. "Two-Year Results from the GLOBE Trial in Patients with Hepatitis B: Greater Clinical and Antiviral Efficacy for Telbivudine (LdT) vs. Lamivudine." Abstract 91, presented Oct. 30.
Additional source: American Association for the Study of Liver Diseases Source reference: DiBisceglie A et al. "Telbivudine GLOBE Trial: Maximal Early HBV Suppression is Predictive of Optimal Two-Year Efficacy in Nucleoside-Treated Hepatitis B Patients." Abstract 112, presented Oct. 30.
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