Gilead Announces Two-Year Data from Pivotal Phase III Studies Evaluating Viread® for Chronic Hepatitis B
- No Resistance Observed Through Two Years of Treatment -
- Significant Viral Suppression Seen in Patients Switching to Viread -
November 1, 2008 --SAN FRANCISCO--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq:GILD) today announced the presentation of two-year (96-week) data from two Phase III pivotal clinical trials, Studies 102 and 103, evaluating the safety and efficacy of once-daily Viread® (tenofovir disoproxil fumarate) among adult patients with chronic hepatitis B virus (HBV) infection. These data will be presented during oral sessions at the annual meeting of the American Association for the Study of Liver Diseases (The Liver Meeting 2008) being held this week in San Francisco (October 31-November 4).
Studies 102 and 103 will evaluate treatment with Viread for up to eight years among patients with HBeAg-negative and HBeAg-positive chronic hepatitis B, respectively, with compensated liver disease. Patients in both studies were originally randomized to receive Viread or Hepsera® (adefovir dipivoxil). After the completion of 48 weeks of randomized blinded therapy, all eligible patients were rolled over to open-label Viread monotherapy.
These new data show that patients who received Viread for up to 96 weeks experienced sustained suppression of HBV levels in the blood (91 percent and 78 percent for Studies 102 and 103, respectively). The studies also show that all Hepsera-treated patients whose HBV levels were suppressed at week 48 maintained viral suppression after rolling over to Viread, while Hepsera-treated patients with HBV DNA levels above 400 copies/mL at week 48 experienced significant viral suppression after rolling over to Viread. Additionally, by week 96 of Study 103, 6 percent of all patients continuing treatment in both groups experienced "s" antigen (HBsAg) loss, which contributes to resolution of chronic hepatitis B infection (HBsAg seroconversion rates were 4 percent among patients originally randomized to receive Viread and 5 percent for patients who rolled over from Hepsera).
Notably, no mutations associated with resistance to Viread were reported among patients receiving Viread monotherapy for up to 96 weeks or in Hepsera-treated patients who rolled over to Viread.
"In this study, Viread produced a significant and sustained effect over two years of treatment with no evidence of resistance, which is a substantial clinical finding," said Patrick Marcellin, MD of Hôpital Beaujon in Clichy, France, the principal investigator of Study 102. "Additionally, patients in this study taking Hepsera were rolled over to Viread without new safety signals and without compromising the efficacy of anti-HBV treatment."
The U.S. Food and Drug Administration (FDA) approved Viread for chronic HBV in adults in August 2008 based on earlier (48-week) results from these studies. Viread and Hepsera are both manufactured by Gilead.
"One of the most important considerations in treating chronic hepatitis B is resistance. It is reassuring to see that no patients from either arm of the study demonstrated resistance to Viread at 96 weeks of treatment," said Jenny Heathcote, MD of the University of Toronto, Canada, the principal investigator for Study 103. "It is also notable that 6 percent of HBeAg-positive patients experienced "s" antigen loss."
Chronic HBV affects an estimated 400 million people worldwide, including two million people in the United States. Many are unaware that they are infected because the disease may not produce obvious symptoms.
One in four people with chronic hepatitis B die from complications such as cirrhosis and liver cancer. In the United States, Asian Americans are disproportionately affected: Foreign-born Asians are 100 times more likely to have the disease compared to non-Asians in the U.S. population. In September 2008, partly in response to advances in HBV therapy, the U.S. Centers for Disease Control and Prevention (CDC) published new HBV screening guidelines recommending that all individuals from Asian countries be tested for the disease.
In addition to its indication for HBV, Viread is also indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults, and is currently the most-prescribed molecule in antiretroviral therapy in the United States.
About Studies 102 and 103
Studies 102 and 103 were multi-center, randomized, double-blind Phase III clinical trials comparing Viread to Hepsera among patients with compensated liver disease and HBeAg-negative presumed pre-core mutant (n=375) and HBeAg-positive (n=266) chronic hepatitis B, respectively. The majority of patients were treatment-naïve, although some patients (n=75) were lamivudine-experienced.
Patients originally randomized to Hepsera in both studies rolled over to Viread (n=196) at week 48, while patients originally randomized to Viread continued Viread treatment in the second 48 weeks (n=389). After 72 weeks, patients with confirmed viremia (HBV DNA levels at or above 400 copies/mL on two consecutive visits) had the option of adding emtricitabine treatment in the form of Truvada®, an investigational product for the treatment of chronic hepatitis B.
Study 102 Results (Oral Presentation #146)
HBeAg-negative patients
Using a long-term evaluation, intent-to-treat analysis algorithm through 96 weeks, which excluded some patients who discontinued the study for administrative reasons and had HBV DNA below 400 copies/mL at last study visit (n=7), 91 percent of those originally randomized to Viread achieved HBV DNA levels below 400 copies/mL compared to 89 percent of those originally randomized to Hepsera who rolled over to Viread at week 48 (p=0.672).
Among patients who received Viread for the entire 96 weeks, 99 percent achieved HBV DNA levels below 400 copies/mL. In addition, all patients who rolled over from Hepsera to Viread at week 48, regardless of whether they were well controlled on Hepsera or viremic, achieved viral load suppression below 400 copies/mL with Viread by week 96.
Two patients in Study 102 added emtricitabine treatment in the form of Truvada between week 72 and week 96 due to confirmed viremia. One of these patients achieved viral suppression by week 96 and is counted among the 91 percent of patients who experienced sustained suppression with Viread throughout the 96-week period.
Levels of alanine aminotransferase (ALT, an enzyme that serves as a measure of liver damage), which had been high at baseline, remained at near-normal levels between 48 and 96 weeks of treatment in both Viread and Hepsera-to-Viread groups (mean of 35 and 34 U/L, respectively, at week 96; p=0.827).
Viread was generally well tolerated by study subjects. The incidence of drug-related serious adverse events was low, with one event reported in the Viread group and none reported in the Hepsera-to-Viread group. There was one death in the study, in the Viread group, due to metastatic liver carcinoma, a known complication of chronic hepatitis B infection. The incidence of grade 3-4 laboratory abnormalities was 10 percent for both Viread and Hepsera-to-Viread groups. No patients experienced a confirmed 0.5 mg/dL increase in serum creatinine or creatinine clearance of less than 50 ml/min. No resistance to Viread was detected among patients who received Viread monotherapy over two years.
Study 103 Results (Oral Presentation #158)
HBeAg-positive patients
Using a long-term evaluation, intent-to-treat analysis algorithm through 96 weeks, which excluded some patients who discontinued the study for administrative reasons and had HBV DNA below 400 copies/mL at last study visit (n=8), 78 percent of those originally randomized to Viread achieved HBV DNA levels below 400 copies/mL compared to 78 percent of those originally randomized to Hepsera who rolled over to Viread at week 48 (p=0.801).
Among patients who received Viread for the entire 96 weeks, 89 percent achieved HBV DNA levels below 400 copies/mL compared to 85 percent of patients who remained on Viread at week 96 after switching from Hepsera at week 48 (p=0.374). As in Study 102, all patients who were well controlled at week 48 on Hepsera (n=12) maintained viral suppression after switching to Viread. Viremic Hepsera patients responded rapidly after rolling over to Viread, with 82 percent achieving HBV suppression below 400 copies/mL by week 96.
Twenty-eight patients in Study 103 added emtricitabine treatment in the form of Truvada between 72 and 96 weeks due to confirmed viremia. Five of these patients achieved viral suppression by week 96, two of whom were counted among the 78 percent of patients who experienced sustained suppression with Viread over 96 weeks and three of whom were counted among the 78 percent who achieved suppression after rolling over from Hepsera.
As with Study 102, ALT levels, which had been elevated at baseline in both patient groups, remained stable at near-normal levels by week 96 in both Viread and Hepsera-to-Viread groups (mean of 35 and 39 U/L, respectively; p=0.765).
Among patients who continued treatment to week 96, a similar proportion of patients in the Viread and Hepsera-to-Viread groups experienced HBeAg seroconversion (26 percent versus 24 percent, respectively; p=NS). Seroconversion is defined as both the disappearance of the hepatitis B "e" antigen, a marker of HBV replication (rendering the patient "HBe-antigen negative"), and the appearance of antibodies specific for this antigen (making the patient "HBe-antibody positive"). In addition, 6 percent of patients in both treatment groups experienced "s" antigen (HBsAg) loss, which contributes to resolution of chronic hepatitis B infection (HBsAg seroconversion rates were 4 percent among patients originally randomized to receive Viread and 5 percent for patients who rolled over from Hepsera).
As in Study 102, the incidence of drug-related serious adverse events was similar between the Viread group (one patient) and the Hepsera-to-Viread group (two patients). The incidence of grade 3-4 laboratory abnormalities was also similar: 7 percent for the Viread-only patients and 10 percent for the Hepsera-to-Viread patients. No patients experienced creatinine clearance of less than 50 ml/min. Two patients in the Hepsera-to-Viread group had a confirmed 0.5 mg/dL increase in serum creatinine, compared to none in the Viread group. As with Study 102, no resistance was detected among patients who received Viread monotherapy over two years.
Continued treatment with Viread for 96 weeks did not reveal any new adverse reactions and no change in the tolerability profile observed during the first 48 weeks of treatment. Treatment-related adverse events observed in greater than 5 percent of patients during the first 48 weeks of studies 102 and 103 included: nausea, abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.
Important Information about Viread
Viread (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults. This indication is based on data from one year of treatment in primarily nucleoside-treatment-naïve adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease. The numbers of patients in clinical trials who were nucleoside-experienced or who had lamivudine-associated mutations at baseline was too small to reach conclusions of efficacy. Viread has not been evaluated in patients with decompensated liver disease.
Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The following points should be considered when initiating therapy with Viread for the treatment of HIV-1: Viread should not be used in combination with Truvada (emtricitabine/tenofovir disoproxil fumarate) or Atripla® (efavirenz/emtricitabine/tenofovir disoproxil fumarate).
The recommended dose for the treatment of chronic hepatitis B and HIV is 300 mg once daily taken orally without regard to food. The dosing interval of Viread should be adjusted in patients with renal impairment.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.
Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Viread. 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, including Viread. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
New onset or worsening of renal impairment including cases of acute renal failure and Fanconi syndrome has been reported with the use of Viread. It is recommended to assess creatinine clearance (CrCl) before initiating treatment with Viread and monitor CrCl and serum phosphorus in patients at risk. Administering Viread with concurrent or recent use of nephrotoxic drugs should be avoided. Viread should not be administered in combination with Hepsera.
HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with Viread. Viread should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection.
Decreases in bone mineral density (BMD) have been observed in HIV-infected patients. It is recommended that BMD monitoring be considered for patients with a history of pathologic fracture or who are at risk for osteopenia. The bone effects of Viread have not been studied in patients with chronic HBV infection.
Redistribution/accumulation of body fat has been observed in HIV-infected patients receiving antiretroviral combination therapy.
Immune reconstitution syndrome has been observed in HIV-infected patients receiving antiretroviral combination therapy, including Viread, which may necessitate further evaluation and treatment.
In controlled clinical trials in patients with chronic hepatitis B, the most common adverse reaction (all grades) is nausea. In HIV-infected patients, the most common adverse reactions (incidence ≥10 percent, grades 2-4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea.
Important Information about Hepsera (adefovir dipivoxil)
Hepsera is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
For patients 12 to <18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function.
The recommended dose for the treatment of chronic hepatitis B is 10 mg once daily taken orally without regard to food. The dosing interval of Hepsera should be adjusted in patients with renal impairment.
Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B therapy, including Hepsera. 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.
In patients at risk of or having underlying renal dysfunction, chronic administration of Hepsera may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment. It is important to monitor renal function for all patients during treatment with Hepsera.
HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection treated with anti-hepatitis B therapies, such as therapy with Hepsera, that may have activity against HIV. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with Hepsera.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.
For patients with lamivudine-resistant HBV adefovir dipivoxil should be used in combination with lamivudine. For all patients, consider modifying treatment in case serum HBV DNA remains above 1000 copies/mL with continued treatment.
Co-administration with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir and/or the co-administered drug. Monitor for Hepsera associated adverse events. The most common adverse reaction (>10 percent) in compensated disease patients is asthenia and in pre- and post-transplantation lamivudine resistant liver disease patients is increased creatinine.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Australia.
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risks that physicians may not prescribe Viread over existing HBV medications and that the safety and efficacy data obtained through 96 weeks of Studies 102 and 103 may not be observed in other studies or in clinical practice. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Annual Report on Form 10-K for the year ended December 31, 2007 and its Quarterly Report on Form 10-Q for the first, second and third quarters of 2008, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
U.S. full prescribing information for Viread is available at www.Viread.com
U.S. full prescribing information for Hepsera is available at www.Hepsera.com
U.S. full prescribing information for Truvada is available at www.Truvada.com
Viread, Hepsera and Truvada are registered trademarks of Gilead Sciences, Inc.
For more information on Gilead, please call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit www.gilead.com.