FDA Approves Telbivudine for Treatment of Chronic Hepatitis B

On October 26, the U.S. Food and Drug Administration approved the new hepatitis B virus (HBV) nucleoside analog polymerase inhibitor, telbivudine, which will be marketed in the U.S. under the brand name Tyzeka.

The new drug is indicated as a once-daily oral therapy, to be taken with or without food, for the treatment of chronic hepatitis B. Telbivudine is approved for adult chronic hepatitis B patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active liver disease.

Recent studies have demonstrated that telbivudine rapidly and profoundly suppresses HBV replication; it is arguably the most potent anti-HBV drug now available. Other approved monotherapies for HBV are lamivudine (Epivir-HB), adefovir (Hepsera), entecavir (Baraclude), interferon alfa-2b (Intron A), and peginterferon alfa-2a (Pegasys).

Approval was based in large part on data from the pivotal Phase III GLOBE study, which compared telbivudine to lamivudine in 1367 patients. In HBeAg-positive patients, therapeutic response was 75% among patients treated with telbivudine, compared with 67% for those treated with lamivudine. For HBeAg-negative patients after 1 year, the respective response rates were 75% and 77%. Patients who achieved undetectable HBV DNA levels at 24 weeks were more likely to undergo "e" antigen seroconversion, achieve sustained undetectable HBV DNA, experience ALT normalization, and minimize resistance at 1 year.

In clinical trials to date, telbivudine was generally well tolerated, with most side effects classified as mild or moderate in severity. The most commonly reported adverse events were upper respiratory infections (14%), fatigue/malaise (12%), abdominal pain (12%), sore throat (nasopharyngitis, 11%), and headache (11%).

Following are excerpts from the approval announcement released by Idenix, which has co-developed and will co-market telbivudine with Novartis Pharma AG under a collaborative development and commercialization agreement:

"Profound suppression of the hepatitis B virus is associated with improved outcomes and is a primary treatment goal," said Adrian M. Di Bisceglie, MD, Professor of Medicine and Chief of Hepatology, Division of Gastroenterology and Hepatology, at Saint Louis University, and Co-Director, Saint Louis University Liver Center. "Tyzeka's ability to provide rapid viral suppression in the first 24 weeks of treatment, along with its safety and tolerability profile, make it a promising treatment option for appropriate patients."

"The FDA approval of Tyzeka is a major milestone for Idenix as it is the first Idenix drug to receive U.S. approval," said Jean-Pierre Sommadossi, PhD, chairman and chief executive officer at Idenix Pharmaceuticals, Inc. "Receiving approval just six years after Tyzeka entered clinical development is a tremendous accomplishment and demonstrates Idenix's commitment to discovering and developing new treatment options for patients affected by devastating viral diseases."

"The approval of Tyzeka is based primarily on the efficacy and safety data from the GLOBE study, the largest worldwide registration trial ever conducted to date in patients with chronic hepatitis B," said Nathaniel Brown, MD, chief medical officer of Idenix Pharmaceuticals, Inc. "We believe that Tyzeka will be an important new treatment option for patients with hepatitis B."

HIV and Hepatitis.com Articles on Telbivudine (Tyzeka)

Telbivudine Demonstrates Greater Antiviral Efficacy than Adefovir at 24 Weeks- 5/30/06

Phase III Comparison of Telbivudine vs Lamivudine in Patients with Chronic Hepatitis B:  Response at 1 Year -5-23-06

Telbivudine Provides Greater Antiviral and Clinical Efficacy Compared to Lamivudine in Patients with Chronic Hepatitis B - 3/31/06

Maximal Early HBV Suppression is Predictive of Optimal Virologic and Clinical Efficacy in Nucleoside-Treated Hepatitis B Patients: The GLOBE Study - 11/18/05

Better HBV Suppression with Telbivudine Compared to Lamivudine after 2 Years of Therapy - 6/01/05

Clinical Pharmacokinetics of Telbivudine in Patients with Abnormal Liver or Kidney Function - 11/19/04

Cross-resistance Testing of Adefovir, Lamivudine, Telbivudine, Entecavir, and Other Anti-HBV Compounds Against 4 Major Mutational Patterns of Lamivudine-resistant
HBV 11/01/04

About Tyzeka

Tyzeka is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on virologic, serologic, biochemical and histologic responses after one year of treatment in nucleoside-treatment-naïve adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease.

Already approved in Switzerland, telbivudine will be marketed as Sebivo outside the United States. Applications for approval were filed with the European Medicines Agency (EMEA) and the Chinese health authority in the first quarter of 2006.

Important Safety Information About Tyzeka

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Tyzeka. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Cases of myopathy have been reported with Tyzeka use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Physicians considering concomitant treatment with these or other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor and advise patients to report any signs or symptoms of unexplained muscle pain, tenderness or weakness, particularly during periods of upward dosage titration. Tyzeka therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is diagnosed.

Because Tyzeka is eliminated primarily by renal excretion, co-administration of Tyzeka with drugs that affect renal function may alter plasma concentrations of Tyzeka and/or the co-administered drug. Dose interval adjustment is recommended in patients with creatinine clearance < 50 mL/min.

The safety and efficacy of Tyzeka in liver transplant recipients are unknown. If Tyzeka treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function should be monitored both before and during treatment with Tyzeka.

Patients should be advised that treatment with Tyzeka has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.

Safety and effectiveness of Tyzeka in pediatric patients under the age of 16 years have not been established.

Selected treatment-emergent clinical adverse events of moderate to severe intensity (Grade 2-4) reported in the GLOBE study with Tyzeka were: muscle-related symptoms 2%; fatigue/malaise 1%; headache 1%; pyrexia 1%; abdominal pain <1%; arthralgia <1%; cough <1%; diarrhea <1%; gastritis <1%.

Creatine kinase (CK) elevations were more frequent among subjects on telbivudine treatment. Grade 3/4 CK elevations occurred in 9% of telbivudine-treated patients and 3% of lamivudine-treated patients.

The optimal duration of treatment with Tyzeka has not been established. The relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis are unknown.

About Hepatitis B

Approximately 1.25 million people in the United States are living with chronic hepatitis B (CHB) caused by the hepatitis B virus, which infects the liver and is 50 to 100 times more infectious than HIV. CHB globally affects approximately 350 million people.

Idenix/Novartis Collaboration

Idenix is co-promoting its hepatitis B product, Tyzeka, and developing its hepatitis B and hepatitis C clinical product candidates, (valtorcitabine and valopicitabine, respectively), in collaboration with Novartis Pharma AG under a development and commercialization agreement established in May 2003. Under this agreement, Novartis and Idenix will co-promote Tyzeka, and if successfully developed, valtorcitabine and valopicitabine, in the United States, France, Germany, Italy, Spain and the United Kingdom. Novartis has the exclusive right to commercialize licensed approved products in the rest of the world.
About Idenix

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, MA, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and human immunodeficiency virus (HIV). For further information about Idenix, please refer to http://www.idenix.com.

10/27/06

Source
Idenix Pharmaceuticals. Tyzeka (telbivudine) Approved by U.S. Food and Drug Administration (FDA) as a New Treatment for Patients with Chronic hepatitis B. Press Release. October 26, 2006.