February 9, 2009
Montreal, Canada -- Gilead Sciences, Inc. (Nasdaq: GILD) today announced preclinical data and results from two Phase I studies for GS 9350, an investigational compound being developed as a pharmacoenhancing agent ("booster") to increase blood levels and allow once-daily dosing for certain medicines, including Gilead's investigational HIV integrase inhibitor, elvitegravir. These data suggest that GS 9350 has significant and selective pharmacoenhancing ability, no antiviral activity against HIV and differentiated biological properties in vitro compared to ritonavir, currently the only drug used to boost certain HIV treatments, including protease inhibitors. Study results also show that GS 9350 effectively boosts elvitegravir, when both drugs are dosed as part of a single tablet complete fixed-dose regimen with Truvada® (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg). These data were presented today during an oral session at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal (Abstract# N-121).
"These data represent the first major step forward in Gilead's clinical development of a new 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. "Results also indicate that GS 9350 holds promise as a stand-alone alternative to ritonavir for patients receiving boosted HIV protease inhibitor-based treatment regimens."
A boosting agent is used to increase the blood levels of certain antiretroviral drugs prescribed to treat HIV infection. Gilead is developing GS 9350 to enable once-daily dosing for elvitegravir, which is currently being evaluated in combination with ritonavir-boosted HIV protease inhibitors, in comparison to twice-daily raltegravir, in a Phase III clinical trial among treatment-experienced HIV patients. The company plans to initiate a Phase II study of the complete single tablet fixed-dose regimen containing elvitegravir, GS 9350 and Truvada in treatment-naive patients in the second quarter of this year. Currently, the only available single tablet regimen for the treatment of HIV is Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), which is jointly marketed in the United States by Gilead and Bristol Myers-Squibb Company.
Gilead is also examining GS 9350's potential to boost HIV protease inhibitors, which are used in many HIV treatment regimens. Gilead has initiated a pharmacokinetic study of GS 9350 that will assess its ability to boost atazanavir, one of the most widely prescribed HIV protease inhibitors.
In vitro data presented at CROI showed that GS 9350 has no anti-HIV activity at concentrations up to 90µM. These data also suggest that GS 9350 is a more specific inhibitor of human cytochrome P450 3A (a key enzyme that metabolizes drugs in the body) than ritonavir. Further, GS 9350 exhibited reduced effects on adipocytes (cells that play a role in the synthesis and storage of fat) when compared with ritonavir, including no inhibition of lipid accumulation in adipocytes at 30µM and less than 10 percent inhibition of insulin-stimulated glucose uptake at 10µM. Interference with adipocyte function is believed to be involved in some metabolic disorders associated with antiretroviral therapy, such as elevated levels of triglycerides (fat) in the blood and insulin resistance (hyperglycemia).
This Phase I double-blind, double-dummy study evaluated the safety, tolerability, pharmacokinetics and boosting capacity of GS 9350 compared to ritonavir 100 mg in healthy volunteers over a 14-day period. Single and multiple doses of three dose levels of GS 9350 (50, 100 and 200 mg once daily) were assessed in separate cohorts each comprising 18 evaluable patients. Within each cohort, subjects were randomized to receive GS 9350 (n=12), ritonavir 100 mg (n=3) or placebo (n=3). Trial participants also received oral midazolam, at the beginning of the study and when receiving study drug, as a standardized test compound to assess boosting properties.
GS 9350 doses of 100 mg and 200 mg inhibited midazolam clearance by 92 percent and 95 percent, respectively, compared with 95 percent for the 100 mg dose of ritonavir, thereby providing clinical proof-of-concept of GS 9350 as a pharmacokinetic booster in humans.
Both single and multiple doses of GS 9350 were well tolerated. One drug-related Grade 3 adverse event (discoordination) occurred in one trial participant during multiple dose administration of GS 9350 100 mg. No trial participants developed drug-related Grade 3 or 4 laboratory abnormalities or Grade 4 adverse events.
This open-label, partially-randomized, adaptive Phase I study evaluated the relative bioavailability, pharmacokinetics and safety of a fixed-dose single tablet regimen containing elvitegravir 150 mg, GS 9350 and Truvada in healthy volunteers (n=44). Two versions of this fixed-dose combination regimen were assessed -- one containing GS 9350 100 mg and one containing GS 9350 150 mg. The pharmacokinetic profile of elvitegravir when dosed as part of the single-tablet regimen was compared to the profile of elvitegravir boosted with ritonavir 100 mg and the components of Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg).
In this study, both the 100 mg and 150 mg doses of GS 9350 effectively boosted elvitegravir when administered as part of the fixed-dose regimen. The 150 mg GS 9350 dose resulted in elvitegravir pharmacokinetics that were at the targeted levels based on ritonavir boosting, including maintenance of appropriately high trough concentrations. Additionally, the study verified achievement of needed exposures of the agents in Truvada following administration of the fixed-dose regimen containing elvitegravir, GS 9350 and Truvada compared to when emtricitabine plus tenofovir disoproxil fumarate were administered individually.
All observed treatments were well tolerated. A single trial participant discontinued study with a drug-related Grade 3 laboratory abnormality (elevated liver aspartate aminotransferase) that was considered an adverse event. There were no other drug-related Grade 3 or 4 laboratory abnormalities or adverse events observed.
GS 9350 is a potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Gilead's goal is to develop and bring to market a pharmacokinetic enhancer that does not have HIV activity, can be dosed once daily as a solid dosage form and is stable at room temperature, such that it can be co-formulated with elvitegravir and Truvada into a single tablet. 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.
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.
Truvada, a combination of Emtriva® and Viread®, 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.
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.
Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and 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 coinfected with HIV-1 and HBV and discontinue Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
It is important for patients to be aware that anti-HIV medicines including Truvada do not cure HIV infection or AIDS and do not reduce the risk of transmitting HIV to others.
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 of 30-49 ml/min. Truvada should not be administered to patients with CrCl <30 mL/min or patients requiring hemodialysis.
Coadministration of Truvada with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No drug interaction studies have been conducted using Truvada. The U.S. package insert advises that 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 coadministered with Truvada, it is recommended that atazanavir be given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered 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.
The most common (incidence >10%, any severity) and/or treatment-emergent (Grade 2.4, occurring in >5% of patients) adverse reactions occurring in Study 934 through 144 weeks include diarrhea, nausea, fatigue, sinusitis, upper respiratory tract infections, nasopharyngitis, headache, dizziness, depression, insomnia, abnormal dreams and rash. 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.
For complete prescribing information for Truvada, visit www.truvada.com. For full prescribing information outside of the United States, physicians should consult their local product labeling.