Here’s GILD’s full PR for archival purposes. GS9350 is the PK-boosting agent in the 4-drug combo called Quadro, one of the leading candidates to eventually become a standard regimen in the early lines of HCV treatment (#msg-35447718).
›Gilead Announces Data Demonstrating Pharmacokinetic Boosting Activity of GS 9350
Phase I Data Support Development of a Fixed-Dose Combination Regimen Containing GS 9350, Elvitegravir and Truvada® for the Treatment of HIV/AIDS
Monday February 9, 2009, 12:00 pm EST
MONTREAL--(BUSINESS WIRE)--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-naïve 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.
Preclinical Results
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).
About the GS 9350 Phase I Studies
Study GS-216-0101
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.
Study GS-236-0101
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.
About GS 9350
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.
About Elvitegravir
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.‹
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