Viread(R) for Hepatitis B Maintains Antiviral Suppression with No Development of Resistance Through Four Years of Treatment

BOSTON, Oct 30, 2010 (BUSINESS WIRE) -- Gilead Sciences, Inc. (Nasdaq: GILD) today announced new data from the open-label phase of two pivotal Phase III clinical trials (Studies 102 and 103) evaluating the four-year efficacy of Viread^(R) (tenofovir disoproxil fumarate) for the treatment of chronic hepatitis B virus (HBV) infection. Significantly, no resistance to Viread emerged over 192 weeks of treatment, and 10.8 percent of patients receiving Viread in Study 103 (HBeAg-positive) for four years experienced surface, or "s", antigen (HBsAg) loss, which is a marker of the resolution of chronic HBV infection. Additional data from these studies and from Study 106 show the durable antiviral efficacy of Viread among several key patient subpopulations, including patients with high baseline viral levels, individuals of Asian descent and treatment-experienced patients. These findings are being presented at the 61^st annual meeting of the American Association for the Study of Liver Diseases (The Liver Meeting 2010) in Boston.

"The complete absence of Viread-related resistance detected among study participants shows that this therapy has a high and durable barrier to viral resistance, which is essential for the long-term success of HBV therapy," said Patrick Marcellin, MD, of Hôpital Beaujon in Clichy, France, INSERM CRB3 and University of Paris Denis Diderot, and the principal investigator of Study 102. "These four-year results underscore the long-term benefits of Viread for diverse patient populations, including those who are difficult to treat."

The 192-week data from Studies 102 and 103 evaluate the intent-to-treat population (with the exception of those who left the study for administrative reasons). In Studies 102 and 103, the majority of patients who received Viread for up to 192 weeks experienced sustained suppression of HBV DNA levels in the blood below 400 copies/mL and normalization of alanine aminotransferase (ALT, an enzyme that serves as a measure of liver damage). Notably, no HBV pol/RT amino acid substitutions associated with tenofovir resistance were detected through 192 weeks of Viread.

Among HBeAg-positive patients, 29 percent (based on observed data at week 192) experienced "e" antigen seroconversion, which 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 to this antigen (making the patient "HBe-antibody positive"). Additionally, among HBeAg-positive patients receiving Viread through 192 weeks, the cumulative probability (estimated by Kaplan-Meier) of "s" antigen loss, suggesting that HBV infections may have cleared completely, was 10.8 percent.

"Over the years, physicians have come to understand the critical role of 's' antigen loss in the cessation of disease activity," said Jenny Heathcote, MD, of the University of Toronto, Canada, and the principal investigator for Study 103. "The 10.8 percent 's' loss observed in this trial is a significant finding that makes Viread a highly attractive treatment option for HBV."

Viread for HBV was approved by the U.S. Food and Drug Administration (FDA) in 2008 and has since become the most-prescribed HBV medicine in the United States. It is the only recommended first-line therapy for hepatitis B to demonstrate continuous efficacy and safety through four years in pivotal studies. In October 2010, the FDA expanded Viread's indication to include the treatment of chronic hepatitis B among patients with decompensated liver disease, the end stage of hepatitis B in which liver function is marginal and clinical complications frequently occur. Decompensated liver disease is an indication for consideration of liver transplantation.

Viread Data at The Liver Meeting

Studies 102 and 103 are both multi-center, randomized, double-blind Phase III clinical trials comparing Viread to Hepsera^(R) (adefovir dipivoxil) among HBeAg-negative presumed pre-core mutant (Study 102; n=375) and HBeAg-positive (Study 103; n=266) chronic hepatitis B patients with compensated liver disease. Patients had HBV DNA (viral load) above 100,000 copies/mL and elevated levels of ALT upon study initiation. The majority of patients were treatment-naïve, although some patients had prior lamivudine treatment experience. Patients originally randomized to Hepsera in both studies rolled over to open-label Viread treatment (n=196) at week 48, while patients originally randomized to Viread continued open-label Viread (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 by substituting Truvada^(R) (emtricitabine and tenofovir disoproxil fumarate) for Viread. The number of patients entering year four was 218 (Study 102) and 130 (Study 103) for those originally randomized to receive Viread and 109 (Study 102) and 71 (Study 103) for those originally randomized to receive Hepsera.

Overall Efficacy and Safety at Week 192 (Abstracts 476 and 477)

In an on-treatment analysis, 99 percent of patients in Study 102 and 96 percent of patients in Study 103 who were originally randomized to receive Viread through 192 weeks achieved viral suppression below 400 copies/mL. Among those who were originally randomized to receive Hepsera, 100 percent of patients in Study 102 and 99 percent of patients in Study 103 achieved viral suppression below 400 copies/mL. In an analysis in which the addition of emtricitabine equals failure, 84 percent and 68 percent of patients (Studies 102 and 103, respectively) originally randomized to receive Viread and 87 percent and 72 percent of patients (Studies 102 and 103, respectively) originally randomized to receive Hepsera experienced sustained viral suppression. The majority of patients with elevated ALT at baseline achieved normalized ALT on treatment (ranging from 77 percent to 86 percent across both arms in both studies). Viread was well-tolerated in both studies. During the open-label period (week 48 through week 192), seven patients discontinued treatment due to an adverse event. Creatinine levels, an indicator of kidney function, remained stable through 192 weeks.

Patients with High Viral Load (Abstract 137)

In a subgroup analysis pooling data from Studies 102 and 103, 71 percent of patients who entered the trials with high viral levels (HBV DNA of at least 9 log₁₀ copies/mL) (n=129), achieved sustained viral suppression after 192 weeks of Viread treatment. Of 29 patients who opted to add emtricitabine treatment after 72 weeks due to confirmed viremia, 20 had viral suppression at week 192. At week 192, ALT levels were normalized in 77 percent of patients with high viral load at baseline. Among HBeAg-positive patients (n=118) in this group, 35 percent achieved HBeAg loss and 23 percent experienced HBeAg seroconversion. Overall, 15 percent of patients with high viral load experienced HBsAg loss.

Patients of Asian Descent (Abstract 481)

In another subgroup analysis pooling four-year data from Studies 102 and 103, 77 percent of Asian patients achieved sustained viral suppression (163 patients entered the open-label study phase). Of seven Asian patients who added emtricitabine treatment during the study, four of six remaining on study had viral suppression at week 192. ALT levels normalized in 86 percent of Asians after 192 weeks on treatment. Of 65 HBeAg-positive Asian patients with week 192 serology results, 35 percent achieved HBeAg loss and 26 percent experienced HBeAg seroconversion. Viread was well tolerated among this group of patients. During the open-label phase of Viread treatment, serious adverse events occurred in 6 percent of Asian patients, while grade 3-4 laboratory abnormalities occurred in 15 percent. During the study, one Asian patient had a confirmed serum phosphorus level less than 2 mg/dL, which normalized by week 192, and another had a confirmed increase of at least 0.5 mg/dL in serum creatinine.

Treatment-Experienced Patients (Abstract 136)

In Study 106, Viread showed sustained efficacy in patients with prior Hepseratreatment experience through 168 weeks. Patients with an incomplete virologic response after receiving Hepsera for at least six months were randomly assigned to Viread (n=53) or Truvada (n=52). More than half of all patients also had prior treatment experience with lamivudine. Sixteen patients in the Viread arm and nine patients in the Truvada arm remained viremic (HBV DNA greater than 400 copies/mL) after week 24 and initiated open-label Truvada.

The percent of patients achieving viral suppression (HBV DNA below 400 copies/mL) through 168 weeks was the same in both arms of the study at 82 percent. Additionally, 100 percent of patients with baseline resistance mutations to lamivudine (13/13 patients) and 90 percent of patients with baseline resistance mutations to adefovir (9/10 patients) achieved viral suppression. ALT normalization occurred in 68 percent of Viread and 67 percent of Truvada patients. Both Viread and Truvada were well tolerated, and no unexpected or clinically important adverse events related to renal function were reported among these treatment-experienced patients. Notably, no patient experienced a confirmed increase of at least 0.5 mg/dL in serum creatinine, calculated creatinine clearance less than 50 mL/min or serum phosphorus less than 2.0 mg/dL.

Important Information About Viread for Chronic Hepatitis B

Viread (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults. This indication is based primarily on data from the treatment of nucleoside-treatment-naïve patients, and a smaller number of patients who had previously received lamivudine or adefovir. Patients were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease. Viread was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease. The number of patients in clinical trials who had lamivudine- or adefovir-associated substitutions at baseline was too small to reach conclusions of efficacy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleos(t)ide analogs, including Viread, 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, including those who have previously experienced renal events while receiving Hepsera. Administering Viread with concurrent or recent use of nephrotoxic drugs should be avoided.

Viread should not be used with other tenofovir-containing products (e.g. Atripla, Truvada). Viread should not be administered in combination with Hepsera.

Due to the risk of development of HIV-1 resistance, Viread should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with Viread.

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. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.

Coadministration of Viread with didanosine increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (eg, pancreatitis, neuropathy). Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with Viread. Data are not available to recommend a dose adjustment of didanosine for patients weighing

In controlled clinical trials in patients with chronic hepatitis B with compensated liver disease, the most common adverse reaction (all grades) was nausea, observed in 9 percent of patients taking Viread at week 48. Other adverse reactions observed at week 48 in greater than 5 percent of patients treated with Viread include abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.

In HBV-infected patients with decompensated liver disease, the most common adverse reactions (all grades) reported in greater-than or equal to 10 percent of patients treated with Viread were abdominal pain (22 percent), nausea (20 percent), insomnia (18 percent), pruritus (16 percent), vomiting (13 percent), dizziness (13 percent), and pyrexia (11 percent).

The recommended dose for the treatment of chronic hepatitis B is 300 mg once daily taken orally without regard to food. The dosing interval of Viread should be adjusted and renal function closely monitored in patients with moderate and severe renal impairment.

The parent compound of Viread was discovered through a collaborative research effort between Dr. Antonin Holy, Institute for Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for Medical Research, Katholic University in Leuven, Belgium. The inventors of Viread have agreed to waive their right to a royalty on sales of Viread and Truvada in Gilead Access Program countries to ensure the product can be offered at a no-profit price in parts of the world where the HIV/AIDS epidemic has hit the hardest.

Important Information about Hepsera (adefovir dipivoxil)

Hepsera (adefovir dipivoxil) 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-positive and HBeAg-negative 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 less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg-positive chronic hepatitis B virus infection with compensated liver function.

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, particularly for those with pre-existing or other risks for renal impairment and patients taking concomitant nephrotoxic agents. Patients with renal insufficiency at baseline or during treatment may require dose adjustment. Caution should be exercised when prescribing Hepsera to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored.

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, which 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 nucleos(t)ide analogs alone or in combination with other antiretrovirals.

Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcomes. To reduce the risk of resistance in patients with lamivudine resistant HBV, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy. To reduce the risk of resistance in all patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment.

The most common adverse reaction (less than 10 percent) in compensated disease patients is asthenia and in pre- and post-transplantation lamivudine-resistant liver disease patients is increased creatinine.

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.

Important Information About Truvada

Truvada is a fixed-dose combination tablet containing 200 mg of emtricitabine (Emtriva^(R)) and 300 mg of tenofovir disoproxil fumarate (Viread). In the United States, Truvada is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleos(t)ide analogs, including Viread, a component of Truvada.

Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued Truvada. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Truvada should not be coadministered with Atripla, Emtriva, Viread or lamivudine-containing products, including Combivir^(R) (lamivudine/zidovudine), Epivir^(R) or Epivir-HBV^(R) (lamivudine), Epzicom^(R) (abacavir sulfate/lamivudine) or Trizivir^(R) (abacavir sulfate/lamivudine/zidovudine). In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.

Emtricitabine and tenofovir are principally eliminated by the kidneys. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of Viread. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy with Truvada and as clinically appropriate during therapy.

Routine monitoring of calculated creatinine clearance and serum phosphorous should be performed in patients at risk for renal impairment including patients who have previously experienced renal events while receiving Hepsera^(R) (adefovir dipivoxil).

Dosing interval adjustment and close monitoring of renal function are recommended in all patients with creatinine clearance 30-49 ml/min. Truvada should be avoided with concurrent or recent use of a nephrotoxic agent. Truvada should not be administered with Hepsera.

Coadministration of Truvada and didanosine should be undertaken with caution. Patients should be monitored closely for didanosine-associated adverse events and didanosine should be discontinued if these occur. Dose reduction of didanosine should be considered, if warranted. Patients on atazanavir and lopinavir/ritonavir plus Truvada should be monitored for Truvada-associated adverse events and Truvada should be discontinued if these occur. When co-administered with Truvada, it is recommended that atazanavir be boosted with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with Truvada.

Decreases in bone mineral density (BMD) at the lumbar spine and hip have been seen with the use of Viread. The effect on long-term bone health and future fracture risk is unknown. BMD monitoring should be considered in patients with a history of pathologic fractures or who are at risk for osteopenia. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.

Changes in body fat have been observed in patients taking anti-HIV medicines. Immune Reconstitution Syndrome has been reported in patients treated with combination therapy, including Viread and Emtriva, and may necessitate further evaluation and treatment.

The most common adverse reactions (incidence greater-than or equal to 10 percent) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams and rash.

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.

Forward-Looking Statement

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 other existing or future HBV medications. In addition, as Viread is used over longer periods of time by many patients with underlying health problems, taking numerous other medicines, safety, resistance, drug interaction or other issues may arise, which could reduce the market acceptance of Viread. 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 2009 Annual report on Form 10-K and in Quarterly Reports on Form 10-Q for the first and second quarters of 2010, 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 Truvada is available at www.Truvada.com.U.S. full prescribing information for Hepsera is available at www.Hepsera.com.

Viread, Truvada and Hepsera are registered trademarks of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

SOURCE: Gilead Sciences, Inc.

Gilead Sciences, Inc.Patrick O'Brien, 650-522-1936InvestorsorCara Miller, 650-522-1616Media