April 17, 2009
Foster City, Calif. -- Gilead Sciences, Inc. (Nasdaq:GILD) today announced that it has begun enrolling patients in a Phase II clinical trial of its investigational integrase-based, single-tablet, once-daily regimen of elvitegravir, GS 9350 and Truvada® (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) for the treatment of HIV-1 infection. GS 9350 is an investigational compound being developed as a pharmacoenhancing or "boosting" agent to increase blood levels and allow once-daily dosing for certain medicines, including Gilead's investigational HIV integrase inhibitor, elvitegravir. The Phase II study is designed to evaluate the safety and efficacy of the regimen compared to once-daily Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg). The study will enroll 75 HIV-1 infected, antiretroviral treatment-naive adults across approximately 50 investigative sites in the United States.
"The initiation of this Phase II study is an important milestone in the development of our integrase-based, single-tablet, once-daily regimen for HIV," said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. "The single-dose regimen of Atripla has become the standard of care for many patients, particularly those new to therapy. If proven safe and effective, this new single-tablet regimen has the potential to provide an important alternative for them."
Since its approval in 2006, Atripla has remained the only once-daily, single-tablet regimen available for the treatment of HIV. Atripla is jointly marketed in the United States and Europe by Gilead and Bristol-Myers Squibb Company. Gilead is also examining GS 9350 as a stand-alone boosting agent for other antiretrovirals, in particular, protease inhibitors. Later this quarter, Gilead plans to initiate a Phase II clinical trial evaluating the safety and efficacy of GS 9350-boosted atazanavir compared to ritonavir-boosted atazanavir each in combination with Truvada. Ritonavir is currently the only boosting agent available for HIV therapy.
The Phase II study is a randomized, double-blind, 48-week clinical trial that will evaluate the safety and efficacy of a single-tablet containing elvitegravir, GS 9350 and Truvada versus Atripla, each administered in HIV-infected treatment-naive adults with HIV RNA levels (viral load) greater than or equal to 5,000 copies/mL and CD4 cell counts greater than 50 cells/mm3. Entry criteria require that patients do not have nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor or primary protease inhibitor resistance mutations, as defined by International AIDS Society-USA guidelines, and no prior use of antiretroviral treatments.
Seventy-five trial participants will be randomized (2:1) to receive a once-daily tablet containing elvitegravir 150 mg/GS 9350 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (n=50) or Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (n=25).
The primary endpoint will be the proportion of patients with viral loads less than 50 copies/mL at 24 weeks of treatment. Secondary endpoints will include the proportion of patients with viral loads less than 50 copies/mL at 48 weeks of treatment, and the safety and tolerability of the two treatment regimens through 48 weeks of treatment.
After week 48, subjects will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all subjects will be given the option to participate in an open-label rollover extension and receive the single-tablet regimen containing elvitegravir, GS 9350 and Truvada.
Additional information about the study can be found at www.clinicaltrials.gov.
Elvitegravir is an HIV integrase inhibitor. Unlike other classes of antiretroviral agents, integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir, also known as GS 9137 or JTK 303, was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead's agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights. Elvitegravir is an investigational therapy and has not yet been determined safe or efficacious in humans.
GS 9350 is Gilead's proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Gilead is also examining GS 9350's potential role in boosting commercially available HIV protease inhibitors, which are used in many HIV treatment regimens. GS 9350 is an investigational therapy and has not yet been determined safe or efficacious in humans.
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 including Viread (tenofovir disoproxil fumarate) a component of Truvada. Truvada and Atripla are not approved for the treatment of chronic hepatitis B virus (HBV) infection and their safety and efficacy have not been established in patients co-infected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients co-infected with HIV-1 and HBV who have discontinued Emtriva (emtricitabine) or Viread, which are components of Truvada and Atripla. 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-1 and HBV and discontinue Truvada or Atripla. If appropriate, initiation of anti-hepatitis B treatment may be warranted.
It is important for patients to be aware that anti-HIV medicines including Truvada and Atripla do not cure HIV infection or AIDS and do not reduce the risk of transmitting HIV to others.
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.
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.
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, a component of Truvada. 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. 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.
No drug interaction studies have been conducted using Truvada. 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. 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 given 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. 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 long-term health effect of these conditions are unknown. Immune Reconstitution Syndrome has been reported in patients treated with combination therapy, including Viread and Emtriva.
Adverse events observed with Viread and Emtriva used in combination in Study 934 were generally consistent with those seen in other studies in treatment-experienced or treatment-naive patients receiving Viread and/or Emtriva. Treatment-emergent adverse events occurring in at least 3 percent of patients receiving Viread and Emtriva in Study 934 included dizziness (8%), diarrhea (7%), nausea (8%), fatigue (7%), sinusitis (4%), upper respiratory tract infections (3%), nasopharyngitis (3%), somnolence (3%), headache (5%), dizziness (8%), depression (4%), insomnia (4%), abnormal dreams (4%) and rash (5%).
Skin discoloration has been reported with higher frequency among Emtriva-treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
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 the Gilead Access Program countries to ensure the product can be offered at a no-profit price in parts of the world where the epidemic has hit the hardest.
For complete prescribing information for Truvada, visit www.truvada.com.
In the United States, Atripla is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
Atripla contains the components Truvada (emtricitabine and tenofovir disoproxil fumarate) and Sustiva (efavirenz), co-formulated as a single tablet. As such, the important safety information appearing in the above Truvada section also applies to Atripla, in addition to the following important product information.
As a fixed-dose regimen of Viread (tenofovir disoproxil fumarate), Emtriva (emtricitabine) and Sustiva (efavirenz), Atripla should not be coadministered with Viread, Emtriva, Truvada (emtricitabine and tenofovir disoproxil fumarate) or Sustiva. Due to similarities between Emtriva and lamivudine, Atripla should not be coadministered with drugs containing lamivudine, including Combivir® (lamivudine/zidovudine), Epivir® or Epivir-HBV® (lamivudine), Epzicom™ (abacavir sulfate/lamivudine) or Trizivir® (abacavir sulfate/lamivudine/zidovudine).
Atripla should not be taken with Hismanal® (astemizole), Vascor® (bepridil), Propulsid® (cisapride), Versed® (midazolam), Orap® (pimozide), Halcion® (triazolam), ergot medicines (for example, Wigraine® and Cafergot®), or Vfend® (voriconazole) due to a contraindication with efavirenz. Use of Atripla with St. John's wort (Hypericum perforatum) or St. John's wort-containing products is not recommended. This list of medicines is not complete. Patients should discuss all prescription and non-prescription medicines, vitamin and herbal supplements, or other health preparations they are taking or plan to take with their healthcare provider.
Atripla should not be given to patients with creatinine clearance less than 50 ml/min.
Serious psychiatric adverse experiences, including severe depression (2.4 percent), suicidal ideation (0.7 percent), nonfatal suicide attempts (0.5 percent), aggressive behavior (0.4 percent), paranoid reactions (0.4 percent) and manic reactions (0.2 percent) have been reported in patients treated with efavirenz, a component of Atripla. In addition to efavirenz, factors identified in a clinical study that were associated with an increase in psychiatric symptoms included a history of injection drug use, psychiatric history and use of psychiatric medication. There have been occasional reports of death by suicide, delusions, and psychosis-like behavior, but it could not be determined if efavirenz was the cause. Patients with serious psychiatric adverse experiences should be evaluated immediately to determine whether the risks of continued therapy outweigh the benefits. Patients should tell their doctor if they have a history of mental illness or are using drugs or alcohol.
Fifty-three percent of patients in clinical studies have reported central nervous system symptoms including dizziness (28.1 percent), insomnia (16.3 percent), impaired concentration (8.3 percent), somnolence (7.0 percent), abnormal dreams (6.2 percent) and hallucinations (1.2 percent) when taking efavirenz compared to 25 percent of patients receiving control regimens. These symptoms usually begin during the first or second day of therapy and generally resolve after the first two to four weeks of therapy. After four weeks of therapy, the prevalence of central nervous system symptoms of at least moderate severity ranged from 5 to 9 percent in patients treated with regimens containing efavirenz. Nervous system symptoms are not predictive of the less frequent psychiatric symptoms.
Women should not become pregnant or breastfeed while taking Atripla. Serious birth defects have been seen in children of women treated with efavirenz during pregnancy. Women must use a reliable form of barrier contraception, such as a condom, even if they also use other methods of birth control.
Rash is a common side effect that usually goes away without any change in treatment. Rash may be a serious problem in some children.
Patients with liver disease may require the healthcare provider to check liver function or check drug levels in the blood.
Atripla should be used with caution in patients with a history of seizures. Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known medical history of seizures. Invirase® (saquinavir) should not be used as the only protease inhibitor in combination with Atripla.
The most significant adverse events observed in patients treated with Sustiva are nervous system symptoms, psychiatric symptoms and rash. The most common adverse events (at least 5 percent) observed in clinical studies with Sustiva include fatigue, pain, dizziness, headache, insomnia, impaired concentration, nausea, vomiting, diarrhea, depression, rash, and pruritus.
For complete prescribing information for Atripla, visit www.atripla.com.