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GILEAD ANNOUNCES 48-WEEK DATA FROM TWO PIVOTAL PHASE III STUDIES EVALUATING VIREAD FOR THE TREATMENT OF CHRONIC HEPATITIS B
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-- Detailed Results from Studies 102 and 103 Presented at The Liver Meeting 2007 --
Boston, MA, November 2, 2007 - Gilead Sciences, Inc. (Nasdaq: GILD) today announced the presentation of detailed 48-week data from two phase III pivotal clinical trials, Studies 102 and 103, which evaluate the safety and efficacy of once-daily Viread (tenofovir disoproxil fumarate) among adult patients with chronic hepatitis B virus (HBV) infection. The data are being presented this week in late-breaker sessions at the annual meeting of the American Association for the Study of Liver Diseases (The Liver Meeting 2007), currently taking place in Boston, Massachusetts (November 2-6).
Studies 102 and 103 compare Viread to Gilead's Hepsera (adefovir dipivoxil) among patients with HBeAg-negative (presumed pre-core mutant) chronic hepatitis B and patients with HBeAg-positive hepatitis B, respectively. Results from both studies show that patients with chronic hepatitis B who received Viread for 48 weeks experienced superior efficacy results compared to those who received Hepsera, as shown by the significantly higher percentage of Viread patients in each trial achieving the primary efficacy endpoint. Forty-eight week data show that Viread was well-tolerated by patients in both studies. Gilead announced the topline results from both studies in June 2007.
"The efficacy and tolerability results observed among patients in the Viread arm of the study are impressive," said Patrick Marcellin, MD, Hopital Beaujon, Clichy, France, the principal investigator for Study 102. "Hepsera is commonly considered today's standard of care in chronic hepatitis B therapy and these data demonstrate that with Viread, it may be possible to achieve an even greater antiviral response and further improve outcomes for patients."
"Effective antiviral treatment can suppress viral replication and slow or even halt the progression of liver damage for patients with chronic hepatitis B," said Jenny Heathcote, MD, University of Toronto, Toronto, Canada, the principal investigator for Study 103. "Viread has a well-established safety profile with over a million years of patient experience in HIV and this study indicates that it also may be an effective treatment option for chronic hepatitis B."
Worldwide, an estimated 400 million people are infected with chronic hepatitis B, and it is among the top ten causes of mortality. The data from Studies 102 and 103 form the basis of Gilead's recent filings of marketing applications for Viread for the treatment of chronic HBV in the United States and European Union, which were announced on October 11, 2007. 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.
"Gilead is committed to playing a leadership role in advancing the treatment of chronic viral hepatitis and we are excited to make another important contribution to the field with the development of Viread," said Franck Rousseau, MD, Vice President, Clinical Research, Gilead Sciences. "We believe significant unmet
medical need remains for this serious disease and are working with regulatory authorities in the United States and European Union to make Viread available for the treatment of HBV at the earliest opportunity."
Study 102
Study 102 (late-breaker presentation #LB2) is a multi-center, randomized, double-blind Phase III clinical trial evaluating the efficacy, safety and tolerability of Viread compared to Hepsera among patients with HBeAg-negative presumed pre-core mutant chronic hepatitis B. Study participants were either new to HBV
therapy (treatment-naïve), or had previous experience with lamivudine (treatment-experienced). Three hundred and seventy-five patients were 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.
The primary efficacy endpoint was the proportion of patients at Week 48 with a complete response as defined by serum HBV DNA levels below 400 copies/mL and histologic improvement characterized by at least a two point reduction in the Knodell necroinflammatory score (a measure of necro-inflammation - an inflammatory process in the liver including or leading to death of liver cells) with no concurrent worsening of fibrosis (scarring of liver tissue). Baseline characteristics were similar among patients in both study arms. At baseline, mean HBV RNA levels were 6.86 log10 c/mL in the Viread group and 6.98 log10 c/mL in the Hepsera group.
At week 48, 71 percent of patients in the Viread arm had a complete response compared to 49 percent in the Hepsera arm (p<0.001, intent-to-treat analysis where missing equals failure). Ninety-three percent of Viread patients compared to 63 percent of Hepsera patients achieved a reduction in HBV DNA levels to
below 400 copies/mL (p<0.001). Normal alanine aminotransferases (ALT, a measure of liver damage) was observed in 77 percent of patients in both arms of the study at week 48.
Patients in the Viread arm experienced a comparable treatment response regardless of treatment history. Among treatment-experienced patients, 93 percent of Viread patients achieved a reduction in HBV DNA levels to below 400 copies/mL. Viread and Hepsera were generally well tolerated. The incidence of Grade 2-4 adverse events observed in both arms was similar. Adverse events leading to study discontinuation included bladder neoplasm, cervix carcinoma, feeling hot, anorexia and fatigue in the Viread arm and myopathy and liposarcoma in the Hepsera arm. The incidence of ALT flares was low and similar in both arms (1.2 vs. 0.8 percent for Viread and Hepsera, respectively). No Viread patient experienced a confirmed 0.5 mg increase in serum creatinine or creatinine clearance of less than 50 ml/min.
All Viread patients with HBV DNA of more than 400 copies/mL at week 48 or with confirmed viral breakthrough before week 48 were evaluated with genotypic analysis of the virus, and none had developed mutations associated with resistance to Viread.
Study 103
Study 103 (late-breaker presentation #LB6) is a multi-center, randomized, double-blind Phase III clinical trial that evaluates the efficacy, safety and tolerability of Viread compared to Hepsera among treatmentnaive patients with HBeAg-positive chronic hepatitis B. Two hundred and sixty-six patients were randomized in a 2:1 ratio to receive either Viread (300 mg once daily; n=176) or Hepsera (10 mg once daily; n=90).
Similar to Study 102, the primary efficacy endpoint was the proportion of patients at week 48 with a complete response as defined by serum HBV DNA levels below 400 copies/mL and histologic improvement characterized by at least a two point reduction in the Knodell necroinflammatory score with no concurrent worsening of fibrosis. Baseline characteristics were similar among patients in both study arms. At baseline, mean HBV RNA levels were 8.64 log10 c/mL in the Viread group and 8.88 log10 c/mL in the Hepsera group.
At 48 weeks, 67 percent of patients in the Viread arm had a complete response compared to 12 percent in the Hepsera arm (p<0.001). In addition, 76 percent of Viread patients compared to 13 percent of Hepsera patients achieved a reduction in HBV DNA levels to below 400 copies/mL (p<0.001). Normal ALT was
observed in 69 percent of Viread patients compared to 54 percent of patients treated with Hepsera (p=0.018).
Among patients for whom seroconversion data are available at 48 weeks, 21 percent of Viread patients (n=158) "e" antigen seroconverted by week 48, compared to 18 percent of Hepsera patients (n=82; p>0.05). 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, three percent of Viread patients (n=153) compared to zero percent of Hepsera patients (n=80; p=0.018) experienced "s" antigen (HBsAg) loss, which can indicate that a patient has
cleared chronic hepatitis B infection.
As with Study 102, Viread and Hepsera were generally well tolerated. The incidence of Grade 2-4 adverse events observed in both arms were similar. Early transient Grade 3 or 4 ALT flares were more frequent in the Viread group, with 11 percent of Viread patients compared to 4 percent of Hepsera patients experiencing flares greater than five times the upper limit of normal and two times baseline values. ALT flares were associated with a strong decline in HBV DNA typically observed in the first eight weeks of therapy.
Renal profile and drug resistance findings in Study 103 were the same as those observed in Study 102, with no Viread patient experiencing a confirmed 0.5 mg increase in serum creatinine or creatinine clearance of less than 50 mL/min and no patient developing mutations associated with Viread resistance.
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 co-infected 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 <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 coadministered 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.
The parent compound of Viread was discovered through a collaborative research effort between Dr. Antonin Hol, 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 Hepsera (adefovir dipivoxil)
In the United States, Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
The U.S. package insert advises that the adverse reactions considered at least possibly related to treatment reported in 3 percent or greater of patients in the first 48 weeks in Hepsera pivotal clinical studies were asthenia, headache, abdominal pain, nausea, flatulence, diarrhea and dyspepsia. With extended treatment, mild to moderate increases in serum creatinine were observed uncommonly in patients with chronic hepatitis B and compensated liver disease treated with Hepsera for a median of 49 weeks up to a maximum of 240 weeks. Changes in serum creatinine were observed very commonly in patients pre- and posttransplantation with lamivudine-resistant liver disease and multiple risk factors for changes in renal function who were treated with Hepsera for up to 129 weeks, with a median time on treatment of 19 and 56 weeks, respectively. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after
discontinuation of treatment with antiviral therapies for hepatitis B, including Hepsera. Special warnings and precautions for use are included in the U.S. package insert regarding monitoring of renal function, posttreatment
exacerbations of hepatitis, and the occurrence of lactic acidosis and severe hepatomegaly with steatosis. For physicians in the United States, dosing instructions for patients with underlying renal impairment and for patients co-infected with HIV are also provided in the U.S. package insert, which is
available for download online at www.hepsera.com. 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 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.
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