Basel, November 14, 2005 - Results from the GLOBE study, a Phase III trial in patients with chronic hepatitis B, showed that treatment of patients after one year with telbivudine (LDT600) provided superior response on all evaluated virologic markers compared to lamivudine, the current standard of care. The results were announced today at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.
Patients treated with telbivudine, a specific and selective oral once-daily nucleoside, achieved a significantly greater reduction of hepatitis B virus (HBV) DNA, which resulted in more patients achieving clearance of detectable virus compared to lamivudine-treated patients. Profound reduction of virus in the blood (viral suppression) decreases the risk of disease progression and is a primary treatment goal in chronic hepatitis B.
The GLOBE study, which compares telbivudine with lamivudine in 1,367 patients from 20 countries, is the largest study ever conducted in both HBeAg-positive and HBeAg-negative chronic hepatitis B patients. HBeAg-positive patients test positive for the 'hepatitis B e antigen' whereas HBeAg-negative patients do not; HBeAg-negative disease generally occurs as a result of a mutation of the virus, and these patients tend to have more advanced liver damage. This study is also the first global chronic hepatitis B registration trial to include patients from China, where the disease is highly prevalent.
"Despite recent advances in the treatment of chronic hepatitis B, there remains a need for new safe and effective treatment options," said Dr. Ching-Lung Lai, Professor of Medicine and Chief of the Gastroenterology and Hepatology Division at the University of Hong Kong, and lead investigator of the GLOBE study. "The potent viral suppression achieved with telbivudine has the potential to reduce the serious complications associated with chronic hepatitis B and telbivudine's favorable safety and convenience profile in trials to date also make it a promising treatment option for patients, including those requiring long-term therapy."
Chronic hepatitis B is the tenth leading cause of death worldwide1 with more than 350 million people chronically infected (lifelong infection)2. Additionally, chronic hepatitis B is the second leading cause of cancer after smoking, responsible for up to 80 percent of the world's primary liver cancer3. Approximately 1.2 million individuals are estimated to die annually from hepatitis B-related chronic liver disease4. Current unmet medical needs in chronic hepatitis B treatment include improved response rates, better long-term efficacy, reduced rates of drug resistance, improved safety and tolerability and more patient-friendly dosing regimens.
"We are pleased with the positive one-year GLOBE results that we will include in key global regulatory submissions currently anticipated to be made by the end of the first quarter 2006 and look forward to obtaining the two-year data from GLOBE to evaluate the longer-term efficacy and safety of telbivudine," said Dr. James Shannon, Global Head of Development, Novartis Pharma AG.
Results from GLOBE indicate that telbivudine produces significantly faster and more profound viral suppression compared to lamivudine after one year of treatment. Telbivudine patients achieved significantly greater HBV DNA reductions after 52 weeks in both hepatitis B e antigen (HBeAg)-positive patients (-6.5 log10 vs. -5.5 log10 with lamivudine; p<0.01) and HBeAg-negative patients (-5.2 log10, vs. -4.4 log10 with lamivudine; p<0.01).
Similarly, after 52 weeks of treatment, significantly more patients receiving telbivudine achieved clearance of detectable HBV DNA and became PCR negative. In HBeAg-positive patients, telbivudine treatment led to loss of detectable HBV DNA in 60 percent of patients compared to 40 percent with lamivudine treatment (p<0.01). In HBeAg-negative patients, telbivudine treatment reduced HBV DNA to below detectable levels in 88 percent of patients compared to 71 percent with lamivudine treatment (p<0.01).
Analyses of the one-year GLOBE data demonstrated that, regardless of treatment, achieving profound viral suppression early in the course of therapy results in better efficacy outcomes at one year, including non-detectable virus levels (PCR negativity), liver enzyme (ALT) normalization, HBeAg seroconversion and decreased incidence of viral resistance. The majority of telbivudine-treated patients achieved PCR negativity in the first 24 weeks of treatment, and 95 percent of those patients remained PCR negative at one year.
The primary efficacy endpoint of the GLOBE study was therapeutic response, a composite endpoint coupling viral suppression (serum HBV DNA suppression below 100,000 copies/mL) with either improved liver disease markers (ALT normalization) or loss of detectable hepatitis B e-antigen (HBeAg). The study successfully reached this endpoint, which was designed to assess if telbivudine was at least as effective as lamivudine in both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patients, therapeutic response was significantly higher among patients treated with telbivudine (75 percent) compared to patients treated with lamivudine (67 percent) (p<0.05), while the response after one year was similar for HBeAg-negative patients taking either treatment (75 percent versus 77 percent, respectively).
Patients receiving telbivudine showed significantly less viral resistance and less treatment failure, compared to patients receiving lamivudine at one year. Telbivudine was associated with significantly fewer and less severe resistance-associated elevations ("flares") of serum ALT levels, a cause of potentially fatal liver failure in chronic hepatitis B patients, compared to lamivudine. In addition, the 52-week GLOBE study results support a favorable overall safety profile for telbivudine. The diverse nature and rate of occurrence of adverse events were similar between telbivudine-treated patients and lamivudine-treated patients.
More about the GLOBE Study
Histological analysis revealed that telbivudine, compared with lamivudine, provided superior improvement in liver histology after one year in HBeAg-positive patients (65 percent versus 56 percent, respectively; P<0.02), which indicates resolution of liver disease associated with HBV infection. In HBeAg-negative patients, histologic responses were similar for telbivudine and lamivudine (67 percent versus 66 percent, respectively). Histologic response was defined as a two-point or greater reduction in the Knodell necroinflammatory score, with no worsening in the Knodell fibrosis score.
The GLOBE trial is ongoing, with a final analysis expected to be available in late 2006 following completion of two years of treatment for all study patients.
About telbivudine
Telbivudine is a specific and selective, oral, once-daily nucleoside analogue that is being developed for the treatment of chronic hepatitis B and appears to be unique in its preferential inhibition of 2nd strand HBV DNA synthesis.
About Hepatitis B
Hepatitis B, a virus that affects the liver, is 50-100 times more infectious than HIV5. HBV can cause life-long infection, cirrhosis (scarring) of the liver as well as liver cancer, liver failure and death6. Elevated viral loads are recognized to be associated with disease progression. Therefore, a primary goal of treatment is to reduce as much as possible the quantity of virus circulating in the blood (viral suppression).
HBV is widespread in Africa and Southeast Asia, with 8-10% of the population considered to be chronically infected7. High rates of chronic HBV infection are also found in the Amazon basin in South America as well as in the southern parts of Eastern and Central Europe8. In these endemic areas, many people become infected when they are infants or young children. Transmission of HBV frequently occurs during the birthing process when the virus is passed on from the mother to her child9. People who are chronically infected with HBV also can pass the virus to others through blood transfusions, sharing or reusing needles for injection or tattoos as well as through unprotected sex10. Many chronic HBV carriers have no symptoms and feel healthy because of its silent transmission and progression,11 making HBV a serious global public health issue.
Idenix/Novartis collaboration
Idenix is developing its hepatitis B clinical product candidates, telbivudine and valtorcitabine, in collaboration with Novartis Pharma AG under a development and commercialization arrangement established in May 2003. The collaboration arrangement further provides that Novartis and Idenix will co-promote the product candidates that Novartis has licensed, including telbivudine and valtorcitabine, in the US, France, Germany, Italy, Spain and the UK. Novartis holds the exclusive license to telbivudine and valtorcitabine in the rest of the world. This collaboration also provides Novartis with an exclusive option to license and collaborate with Idenix in the development and commercialization of other product candidates in Idenix's portfolio, including valopicitabine (NM283), a direct antiviral hepatitis C product candidate.
About Novartis
Novartis AG (NYSE: NVS) is a world leader in pharmaceuticals and consumer health. In 2004, the Group's businesses achieved net sales of USD 28.2 billion and pro forma net income of USD 5.6 billion. The Group invested approximately USD 4.1 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 91,700 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.
The foregoing release contains certain forward-looking statements that can be identified by terminology such as "has the potential to", "promising treatment", "will include", "anticipated", "look forward to", "longer-term", "expected to", or similar expressions, or by express or implied discussions regarding potential therapeutic benefits and successful development of telbivudine and the anticipated regulatory filings required for the registration of telbivudine, or potential future revenues from telbivudine. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with telbivudine to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that telbivudine will be approved for sale in any market or that it will reach any particular level of revenue. Management's expectations regarding telbivudine could be affected by, among other things, uncertainties relating to clinical trials; new clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; Idenix's dependence on its collaboration with Novartis Pharma AG; Idenix's ability to obtain additional funding required to conduct its research, development and commercialization activities; competition in general; government, industry and general public pricing pressures; as well as other risks and factors referred to in the Company's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
References
1 Lavanchy D. J Viral Hepat. 2004 Mar 11 (2): 97-107
2 WHO Hepatitis B Fact Sheet #204
3 World Health Organization. Expanded programme on immunization hepatitis B vaccine - making global progress
4 WHO Hepatitis B Fact Sheet #204
5 WHO Hepatitis B Fact Sheet #204
6 CDC. Available at: www.cdc.gov/ncidod/diseases/hepatitis/b/faqb.htm
7 WHO Hepatitis B Fact Sheet #204
8 WHO Hepatitis B Fact Sheet #204
9 Grob P Vaccine 1995; 13Suppl1: s-14-15
10 CDC. Available at: www.cdc.gov/ncidod/diseases/hepatitis/b/faqb.htm
11 CDC. Available at: www.cdc.gov/ncidod/diseases/hepatitis/b/faqb.htm
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