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GILEAD ANNOUNCES 72-WEEK DATA FROM TWO PIVOTAL PHASE III STUDIES EVALUATING VIREAD (tenofovir)
FOR THE TREATMENT OF CHRONIC HEPATITIS B
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-- Oral Presentations at EASL Following Recent CHMP Positive Opinion Support Viread as Potential New Treatment for Life-Threatening Liver Disease --
For Immediate Release
Press release from Gilead
Milan, Italy, April 24, 2008 - Gilead Sciences, Inc. (Nasdaq: GILD) today announced the presentation of detailed 72-week data from two pivotal Phase III 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 Friday, April 25, at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) currently taking place in Milan, Italy (April 23-27).
Studies 102 and 103 were designed to evaluate treatment with Viread over 240 weeks among patients with HBeAg-negative (presumed pre-core mutant) and HBeAg-positive chronic hepatitis B, respectively. Patients in both studies were originally randomized to receive Viread or GileadŐs Hepsera (adefovir dipivoxil). The studiesŐ primary efficacy endpoints were reached at 48 weeks, at which time Viread demonstrated superior efficacy over Hepsera. After the completion of 48 weeks of randomized blinded therapy, all eligible patients were offered open-label Viread monotherapy.
The 72-week data demonstrate that the majority of patients in each study who were originally randomized to receive Viread had a virologic response below 400 copies/mL through week 72 (91 percent and 79 percent, respectively). The studies also show that all 88 Hepsera-treated patients who achieved HBV DNA levels below 400 copies/mL at week 48 maintained viral suppression after switching to Viread.
Additionally, Hepsera-treated patients with HBV DNA levels above 400 copies/mL at week 48 experienced rapid viral suppression after switching to Viread in each study (94 percent and 78 percent, respectively). Viread was generally well tolerated through week 72.
"These 72-week data indicate that Viread has the potential to produce a significant and sustained effect on HBV DNA suppression," said Patrick Marcellin, MD, PhD, H™pital Beaujon University of Paris and the principal investigator for Study 102. "When considered alongside its well-established safety profile, including more than one million patient years of experience in HIV, I believe Viread will be an important new treatment option for patients living with chronic hepatitis B."
Study 102
Study 102 is a multi-center, randomized, double-blind Phase III clinical trial evaluating the efficacy, safety and tolerability of Viread among patients with HBeAg-negative presumed pre-core mutant chronic hepatitis B. Study participants were either new to HBV therapy (treatment-naive), or had previous experience with lamivudine (treatment-experienced). Three hundred seventy-five patients were originally randomized in a 2:1 ratio to receive either Viread (300 mg once daily; n=250) or Hepsera (10 mg once daily; n=125) for 48 weeks. Baseline characteristics were similar between patients in both study arms.
After the completion of 48 weeks of randomized blinded therapy, all eligible patients were offered open-label Viread monotherapy. At week 72, 91 percent of patients who were originally randomized to receive Viread had a virologic response below 400 copies/mL. For Hepsera-treated patients who switched to Viread after week 48, 88 percent achieved HBV DNA levels below 400 copies/mL by week 72. Notably, through week 72, viral suppression was maintained among all patients who switched to Viread and who were previously virologically controlled with Hepsera (n=76). Additionally, rapid viral suppression to less than 400 copies/mL was achieved by week 72 in 94 percent of viremic Hepsera treated patients who switched to Viread.
At week 72, normal alanine aminotransferases (ALT, a measure of liver damage) was observed in 79 percent of patients who were originally randomized to receive Viread and in 77 percent of Hepsera-treated patients who switched to Viread after Week 48.
Viread was generally well tolerated through week 72. In Study 102, treatment related serious adverse events occurred in less than 1 percent of patients who were originally randomized to receive Viread and less than 1 percent of patients originally randomized to receive Hepsera. The incidence of Grade 3-4 laboratory abnormalities was comparable in each arm (14 percent versus 13 percent for Grade 3 abnormalities and 5 percent versus 2 percent for Grade 4 abnormalities). No patient had a confirmed creatinine clearance of less than 50 mL/minute.
Resistance surveillance through week 72 did not detect any tenofovir-associated mutations. Two patients exhibited loss of viral response as defined by study investigators with documented non-adherence and were evaluated via genotypic analysis. Neither developed mutations associated with Viread resistance.
Study 103
Study 103 is a multi-center, randomized, double-blind Phase III clinical trial evaluating the efficacy, safety and tolerability of Viread among treatment-na•ve patients with HBeAg-positive chronic hepatitis B.
Two hundred sixty-six patients were originally randomized in a 2:1 ratio to receive either Viread (300 mg once daily; n=176) or Hepsera (10 mg once daily; n=90). Baseline characteristics were similar between patients in both study arms. As with Study 102, after the completion of 48 weeks of randomized blinded therapy, all eligible patients were offered open-label Viread monotherapy.
At week 72, 79 percent of patients who were originally randomized to receive Viread had a virologic response below 400 copies/mL. Among Hepsera-treated patients who switched to Viread after Week 48, 76 percent achieved HBV DNA below 400 copies/mL by week 72. Through week 72, viral suppression was maintained among all patients who switched to Viread and who were previously virologically controlled with Hepsera (n=12). Additionally, rapid viral suppression to less than 400 copies/mL was achieved by week 72 in 78 percent of viremic Hepsera-treated patients who switched to Viread after week 48.
At week 72, normal ALT levels were observed in 77 percent of patients who were originally randomized to receive Viread and 61 percent of Hepsera-treated patients who switched to Viread.
Among patients for whom seroconversion data was available through week 64, 26 percent of patients who were originally randomized to receive Viread "e" antigen seroconverted, compared to 21 percent of Hepsera-treated patients who switched to Viread. Seroconversion is defined as both the disappearance of the hepatitis B "e" antigen (HBe-antigen negative), a marker of HBV replication, and the appearance of antibodies specific for this antigen (HBe-antibody positive). In addition, 5 percent of patients who were originally randomized to receive Viread compared to zero percent of Hepsera-treated patients who switched to Viread after week 48 experienced "s" antigen (HBsAg) loss (p=0.004), which can indicate that a patient has cleared chronic hepatitis B infection.
As with Study 102, Viread was generally well tolerated. At week 72, treatment related serious adverse events occurred in 4 percent of patients who were originally randomized to receive Viread and 7 percent of Hepsera-treated patients. The incidence of Grade 4 laboratory abnormalities was comparable in each arm (12 percent versus 11 percent). Grade 3 laboratory abnormalities, excluding ALT elevations, were 18 and 10 percent, respectively. Grade 3 ALT elevations were 15 and 10 percent, respectively, in the Viread and Hepsera arms. No patient had a confirmed creatinine clearance of less than 50 mL/minute.
The most common adverse reactions among patients receiving Viread for chronic hepatitis B in Studies 102 and 103 were headache, diarrhea, vomiting, abdominal pain, nausea, abdominal distension, flatulence, ALT increase and fatigue. In terms of resistance surveillance, between weeks 48 and 72 no patients experienced a loss of virologic response.
Additional Oral Presentations at EASL
Three additional oral presentations, one of which features the first data to be presented from Study 106, will be highlighted at EASL. Study 106 is an ongoing, randomized, double-blind Phase II study of individuals with chronic hepatitis B infection randomized in a 1:1 ratio to receive monotherapy with Viread (n=53) or combination therapy with Truvada (emtricitabine and tenofovir disoproxil fumarate), a fixed-dose combination of Viread and Emtriva (emtricitabine) (n=52).
At study entry, participants were experiencing suboptimal virological response (HBV DNA levels greater than or equal to 1,000 copies/mL) with Hepsera therapy (for greater than 24 weeks but less than 96 weeks). The majority of study participants (58 percent) had previously been treated with lamivudine and 22 percent (n=23) had developed resistance mutations to lamivudine or Hepsera.
Through week 48, there were no statistically significant differences between the Viread and Truvada arms, with 81 percent of patients in both groups achieving HBV DNA suppression below 400 c/mL. Virologic response was independent of pre-existing lamivudine or adefovir-associated mutations. The study is ongoing and will continue to assess the best long-term treatment strategy for these difficult-to-treat patients.
Also being presented Friday are two sub-set analyses examining the efficacy of Viread in cirrhotic patients, as well as in lamivudine-experienced and treatment naive patients.
Viread for HBV
Viread is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and is the most-prescribed molecule in HIV combination therapy in the United States and in several European Union nations.
On March 19, 2008, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion on GileadŐs application to extend the indication for Viread to include chronic hepatitis B in adults. The European Commission generally issues an updated Marketing Authorisation within a few months of a CHMP recommendation. The product was recently approved for the treatment of chronic hepatitis B in Turkey and New Zealand, and marketing applications are currently pending in the United States, Canada and Australia.
About Chronic Hepatitis
Chronic hepatitis B is caused by the hepatitis B virus (HBV), which is up to 100 times more easily transmitted than HIV, the AIDS virus. Chronic hepatitis B is frequently referred to as a "silent killer" because it can gradually destroy the liver over the course of years, often without producing symptoms. Worldwide, an estimated 400 million people are infected with the disease.
About Viread (tenofovir disoproxil fumarate) for HIV
In the United States, Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. Viread is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Viread have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued Viread. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV and HBV and discontinue Viread. If appropriate, initiation of anti-hepatitis B treatment may be warranted.
It is important for patients to be aware that anti-HIV medicines including Viread do not cure HIV infection or AIDS, and do not reduce the risk of transmitting HIV to others.
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 Viread 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. Dosing interval adjustment and close monitoring of renal function are recommended in all patients with creatinine clearance less than 50mL/min.
Viread should be avoided with concurrent or recent use of a nephrotoxic agent.
The U.S. package insert advises that co-administration of Viread 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. Patients on atazanavir and lopinavir/ritonavir plus Viread should be monitored for Viread-associated adverse events and Viread should be discontinued if these occur. When co-administered with Viread, it is recommended that atazanavir be given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with Viread.
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. Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of Viread.
Changes in body fat have been observed in patients taking anti-HIV medicines. The mechanism and longterm health effect of these changes are unknown.
Immune Reconstitution Syndrome has been reported in patients treated with combination therapy, including Viread.
The most common adverse events among patients receiving Viread with other antiretroviral agents in a pivotal clinical study (Study 903) were mild to moderate gastrointestinal events and dizziness. Moderate to severe adverse events occurring in more than 5 percent of patients receiving Viread included rash (rash, pruritis, maculopapular rash, urticaria, vesiculobullous rash and pustular rash), headache, pain, diarrhea, depression, back pain, fever, nausea, abdominal pain, asthenia (weakness) and anxiety. In another pivotal study (Study 907), less than 1 percent of patients discontinued participation because of gastrointestinal events.
For full prescribing information outside of the United States, physicians should consult their local product labeling.
About Hepsera (adefovir dipivoxil)
In the United States, 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. Hepsera is not recommended for use in children less than 12 years of age.
Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B therapy, including Hepsera. Hepatic function should be closely monitored in both clinical and laboratory follow-up for at least several months in patients who discontinue hepatitis B therapy. If appropriate, resumption of therapy may be warranted. In patients at risk of 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. Dose adjustment is recommended in patients with serum creatinine <50 mL/min.
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.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone and in combination with other antiretrovirals.
Adverse reactions identified from placebo-controlled and open label studies include the following: asthenia, headache, abdominal pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and hypophosphatemia. Additional adverse reactions observed from an open-label study in pre- and posttransplant patients include abnormal renal function, renal failure, vomiting, rash and pruritus.
For full prescribing information outside of the United States, physicians should consult their local product labeling.
Viread and Hepsera are the result of 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.
About Truvada (emtricitabine/tenofovir disoproxil fumarate)
Truvada is a fixed-dose combination tablet containing 200 mg of emtricitabine (Emtriva) 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 nucleoside analogues alone or in combination with other antiretrovirals. Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Truvada has not been established in patients co-infected with HBV.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued Emtriva or Viread, the components of Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected with HBV and discontinue Truvada. If appropriate, initiation of anti-hepatitis B treatment may be warranted.
It is important for patients to be aware that Truvada does not cure HIV infection or AIDS and do not reduce the risk of transmitting HIV to others.
It is not recommended that Truvada be used as a component of a triple nucleoside regimen. Truvada should not be coadministered with Atripla, Emtriva, Viread or lamivudine-containing products, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir
sulfate/lamivudine) or Trizivir (abacavir sulfate/lamivudine/zidovudine). In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.
For full prescribing information outside of the United States, physicians should consult their local product labeling.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops an commercializes innovative therapeutics in areas of unmet medical need. The companyŐs 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.
# # #
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, Emtriva 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.
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