Basel, 28 October 2003

Pegasys found superior to current hepatitis B treatments
New study shows Pegasys more effective than lamivudine in most difficult-to-treat form of Hepatitis B disease

In patients infected with the most difficult-to-treat hepatitis B virus (HBeAg negative or ‘variant’ HBV), Pegasys is more effective than lamivudine and the addition of lamivudine to Pegasys does not provide additional efficacy, according to results presented at a conference* today.

This Phase III study, conducted in 13 countries, is the largest multinational study of pegylated interferon in patients with ’variant’ hepatitis B virus and it is the first large-scale head-to-head study to compare Roche’s pegylated interferon against lamivudine. Lamivudine is the most commonly used therapy for infections with the hepatitis B virus.

“With Pegasys, we have for the first time a hepatitis B therapy which can produce a high sustained treatment response, and this is extremely encouraging to physicians looking for treatment solutions,” said Professor Patrick Marcellin, Hepatologist from the Hôpital Beaujon, Clichy, France and the lead investigator for the study. “What is also important is that with Pegasys we have a defined treatment period, which is what most patients want .”

“These are highly encouraging results for physicians and patients in the fight against this serious liver infection,” said William M. Burns, Head of the Pharmaceutical Division at Roche. “Based on these extremely positive results ,we plan to file Pegasys in hepatitis B with health authorities next year.”

About the study
The 537 patients enrolled in the study, all of whom had HBeAg negative HBV and raised blood levels of ALT, a specific liver enzyme serving as a marker for liver inflammation, were treated for 48 weeks with either Pegasys 180 ?g once weekly plus placebo, lamivudine 100 mg once daily or a combination of the two. They were then observed for a further 24 weeks with no treatment. The treatment was considered effective if ALT levels fell to normal and viral DNA levels, a measure for the concentration of virus in the bloodstream, were reduced below 20,000 copies/ml at the end of the follow-up period.

Viral load and ALT levels significantly impacted
At the end of the follow-up period, the study found for the two primary endpoints that:
• 42.9% of patients treated with Pegasys monotherapy reduced their hepatitis B viral DNA to less than 20,000 copies per/ml compared to only 29.3% of those treated with lamivudine. This result is statistically highly significant. The combination of Pegasys and lamivudine yielded a reduction in hepatitis B viral DNA in 44.1% of patients, demonstrating that the addition of lamivudine to Pegasys does not improve the treatment outcome.
• In addition Pegasys had a better impact on ALT than lamivudine: 59.3 per cent of patients treated with Pegasys had their elevated ALT levels return to normal; compared to only 44.2% of lamivudine-treated patients. The combination of Pegasys and lamivudine (59.8%) was not statistically different to Pegasys alone.

Patients typically relaps after treatment is stopped
HBeAg negative HBV, also known as ‘variant’ or ’pre-core mutant‘ hepatitis B, is caused by a genetic mutation to the virus. Patients infected with the HBeAg negative HBV are more likely to have severe destructive inflammatory changes to their liver and fibrosis when they first see their physician than those infected with the HBeAg positive disease. Patients typically relapse after treatment is stopped. HBeAg negative HBV accounts for approximately 40 per cent of cases in the US and over 80 per cent of cases in Southern Europe.

“We have shown previously that Pegasys is an effective treatment for the more common HBeAg-positive strain of HBV,1” said Professor Graham Cooksley, Senior Principal Research Fellow, Clinical Research Centre, Royal Brisbane Hospital, Australia. “These results mean we can now also use Pegasys with confidence to treat patients with the more challenging HBeAg negative strain of the disease.”

About Hepatitis B
Hepatitis B is a blood-born virus that attacks the liver and is the most common serious liver infection in the world. The hepatitis B virus is highly contagious and is relatively easy to transmit from one infected individual to another. It is 100 times more infectious than the HIV virus.

Despite a highly effective vaccine, more than two billion people have been infected by HBV and 350 million people have chronic infection, which can be easily transmitted by blood-to-blood contact, during birth, sex, and by sharing needles. HBV and HCV rank among the top four causes of cancer deaths in most countries in Asia and the Western Pacific rim2. For those chronically infected with HBV, treatment is the only option.

About Pegasys
Pegasys, a new generation hepatitis therapy that is different by design, provides significant benefit over conventional interferon therapy in patients infected with HBV and HCV. The benefits of Pegasys are derived from its new generation large 40 kilodalton branched-chain polyethylene glycol (PEG) construction, which allows for constant viral suppression over the course of a full week. Pegasys also distributes more readily to the liver (the primary site of infection) than conventional interferon. In HCV Pegasys provides superior efficacy compared to conventional interferon combination therapy in HCV patients of all genotypes. Pegasys is the only pegylated interferon available as a ready-to-administer solution. Each weekly subcutaneous injection contains 180 mcg of pegylated interferon alfa-2a which is the approved dose for all patients, regardless of body weight.

Roche in hepatitis
Roche is committed to the viral hepatitis disease area, having introduced Roferon-A for hepatitis B and C, followed by Pegasys in hepatitis C and now Pegasys also demonstrates superior efficacy over current treatments: conventional interferon and lamivudine in hepatitis B. Roche has also launched its own brand of ribavirin, Copegus, to be used in conjunction with Roferon A or Pegasys for HCV. Roche also manufactures HBV and HCV diagnostic and monitoring systems: The COBAS AMPLICOR Test, and the AMPLICOR MONITOR Test, two testing systems used to detect the presence of, and quantity of, HBV DNA or HCV RNA in a person’s blood. Roche's commitment to hepatitis has been further reinforced by the in-licensing of Levovirin, an alternative antiviral. Levovirin will be studied with the objective of demonstrating superior tolerability over the current standard, ribavirin.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading innovation-driven healthcare groups. Its core businesses are pharmaceuticals and diagnostics. Roche is number one in the global diagnostics market, the leading supplier of pharmaceuticals for cancer and a leader in virology and transplantation. As a supplier of products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche employs roughly 65,000 people in 150 countries. The Group has alliances and R&D agreements with numerous partners, including majority ownership interests in Genentech and Chugai.

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* 54th American Association for the Study of Liver Diseases (AASLD) Annual Meeting

NOTES TO THE EDITOR:
• New guidelines on HBV were recently developed by the European Association for the Study of Liver (EASL)3. Conventional interferon monotherapy was recommended as the first therapeutic approach when treating these patients. The EASL Jury noted however, that the optimal treatment of hepatitis B will require regular revision in light of new data.

1) Cooksley, W. Graham E et al. Peginterferon alfa-2a (40KD): An advance in the treatment of HBeAg-Positive Chronic Hepatitis B. J. Viral Hepatitis. 2003;10:298-305
2) Chu, CM. Natural History of Chronic Hepatitis B Virus Infection in Adults with Emphasis on the Occurrence of Cirrhosis and Hepatocellular carcinoma. J Gastroenterol. Hepatol. 2000;15 (suppl.):E25-30.
3) EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002: Geneva, Switzerland. Consensus statement (short version). J Hepatol, 2003.38:533-40.