GILD gives more data at CROI:
Gilead’s Single-Tablet “Quad” Regimen for HIV Achieves a High Rate of Virologic Suppression in Phase II Study
Posted on : 2010-02-17 | Author : Gilead Sciences, Inc.
FOSTER CITY, Calif. - (Business Wire) Gilead Sciences, Inc. (Nasdaq:GILD) announced Phase II clinical trial results today showing that its investigational fixed-dose single-tablet “Quad” regimen of elvitegravir, GS 9350 (cobicistat) and Truvada® (emtricitabine and tenofovir disoproxil fumarate) for the treatment of HIV infection exhibited antiretroviral activity comparable to that of Atripla® (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg). At 24 weeks, the proportion of patients who achieved HIV RNA (viral load) less than 50 copies/mL was 90 percent in the Quad arm and 83 percent in the Atripla arm (using an analysis where missing equals failure, intent-to-treat population). Discontinuation rates due to adverse events were comparable in both arms of the study. These data will be presented today at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco (Abstract #58LB).
“Simplified treatment regimens of co-formulated, fixed-dose medicines have become the standard of care in HIV therapy because they can help patients adhere to dosing schedules,” said Calvin J. Cohen, MD, M.Sc., principal investigator and Director of Research, Community Research Initiative of New England. “These positive efficacy and safety results indicate that the Quad has the potential to become an important new treatment option in HIV therapy.”
The Quad contains four Gilead compounds in a single, once-daily tablet: elvitegravir, an investigational integrase inhibitor for HIV; cobicistat, a pharmacoenhancing or “boosting” agent that increases blood levels of certain HIV medicines; and Truvada, which is itself a combination of the two HIV medicines emtricitabine and tenofovir disoproxil fumarate.
Gilead is also studying cobicistat as a stand-alone boosting agent for other antiretroviral medications – in particular, once-daily protease inhibitors such as atazanavir. Currently, ritonavir is the only agent used to boost HIV therapy. Data from a Phase II clinical trial evaluating the safety and efficacy of cobicistat-boosted atazanavir plus Truvada compared to ritonavir-boosted atazanavir plus Truvada will also be presented today at CROI.
“We are dedicated to developing new HIV treatment regimens that feature improved efficacy and tolerability profiles, both of which are increasingly important as patients remain on therapy for longer periods of time,” said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. “We are excited about these results and look forward to working with the U.S. Food and Drug Administration to finalize the Phase III clinical program for the Quad and cobicistat.”
Study 236-0104
Study 236-0104 is a double-blind, multicenter, randomized (2:1), active-controlled 48-week clinical trial evaluating the safety and efficacy of the Quad (n=48) versus Atripla (n=23) among HIV-infected treatment-na?ve adults with viral load greater than or equal to 5,000 copies/mL and CD4 cell counts (a measure of immune system strength) greater than 50 cells/mm3 at baseline. Weeks 24 and 48 are the primary and secondary time points, respectively, for efficacy, which is measured by the proportion of patients with HIV RNA less than 50 copies/mL. Secondary objectives include the safety and tolerability of the two treatment regimens through 48 weeks.
At baseline, study participants in the Quad arm had a mean viral load of 4.59 log10 copies/mL and a median CD4 cell count of 354 cells/mm3. Patients in the Atripla arm of the study had a mean viral load of 4.58 log10 copies/mL and a median CD4 cell count of 436 cells/mm3 at baseline.
At 24 weeks, 90 percent of patients in the Quad arm and 83 percent of patients in the Atripla arm achieved the study’s primary objective of HIV RNA levels of less than 50 copies/mL, using an analysis where missing equals failure, intent-to-treat population (difference in stratum-weighted response rate between Quad and Atripla = +5%; 95% CI: -11.0% to 21.1%). While this Phase II study had low power for formal efficacy comparisons, efficacy of the Quad met the statistical criteria of non-inferiority as compared to Atripla as defined by a pre-specified lower bound of the non-inferiority margin of -12 percent. In addition, when using an analysis where missing values are excluded, 96 and 95 percent of patients in the Quad and Atripla arms, respectively, achieved HIV RNA levels of less than 50 copies/mL after 24 weeks.
Patients taking the Quad experienced a median increase in CD4 cell count of 123 cells/mm3, compared to a median increase of 124 cells/mm3 among Atripla patients at 24 weeks.
Discontinuation rates and adverse events were similar in both arms of the study. Three patients discontinued treatment in each arm of the study; one of them, an Atripla patient, discontinued treatment due to an adverse event (suicidal ideation), whereas no patients discontinued the Quad due to an adverse event. The Quad arm had fewer drug-related adverse events, particularly fewer central nervous system (CNS) adverse events. The most commonly observed treatment-emergent adverse events occurring in greater than 5 percent of patients in either treatment arm were abnormal dreams/nightmares, dizziness, fatigue, somnolence, diarrhea and headache. There were no Grade 3 or 4 adverse events among Quad patients. Two Grade 3 or 4 adverse events were reported among Atripla patients (B-cell lymphoma with lymphadenopathy and neutropenia).
There was a similar incidence of laboratory abnormalities (Grades 2-4) across both arms of the study. Laboratory abnormalities occurring in greater than 5 percent of patients in either treatment arm included increases in amylase, decreased neutrophils, increases in total cholesterol and proteinuria. Median increases in cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were small and similar in both arms of the study.
Study 216-0105
Study 216-0105 is a double-blind, multicenter, randomized (2:1), active-controlled 48-week clinical trial evaluating the safety and efficacy of cobicistat-boosted atazanavir (n=50) compared to ritonavir-boosted atazanavir (n=29), each in combination with Truvada, in HIV-infected treatment-na?ve adults with viral load greater than or equal to 5,000 copies/mL and CD4 cell counts greater than 50 cells/mm3 at baseline. This study has the same primary and secondary objectives as the Quad Phase II study.
At baseline, study participants in the cobicistat arm had a mean viral load of 4.56 log10 copies/mL and a median CD4 cell count of 341 cells/mm3. Patients in the ritonavir arm of the study had a mean viral load of 4.69 log10 copies/mL and a median CD4 cell count of 367 cells/mm3 at baseline.
At 24 weeks, 84 percent of patients in the cobicistat group and 86 percent of those in the ritonavir group met the primary objective of achieving HIV RNA levels of less than 50 copies/mL, using an analysis where missing equals failure, intent-to-treat population (difference in stratum-weighted response rate between cobicistat and ritonavir = -1.9%; 95% CI: -18.4% to 14.7%). In addition, when using an analysis where missing values are excluded, 91 and 96 percent of patients in the cobicistat and ritonavir arms, respectively, achieved HIV RNA levels of less than 50 copies/mL after 24 weeks.
Patients taking a cobicistat-boosted regimen experienced a median increase in CD4 cell count of 206 cells/mm3, compared to a median increase of 190 cells/mm3 among patients taking a ritonavir-boosted regimen at 24 weeks.
Discontinuation rates were similar between study arms. Two cobicistat patients discontinued treatment due to adverse events (vomiting and rash) as did one ritonavir patient (scleral icterus). The most commonly observed treatment-emergent adverse events occurring in greater than 5 percent of patients in either treatment arm were nausea, diarrhea and fatigue. There were two Grade 3 or 4 adverse events among cobicistat-treated patients (anemia and rash) and none among patients in the ritonavir arm.
There was a similar incidence of laboratory abnormalities (Grades 2-4) across both arms of the study. Laboratory abnormalities (Grades 2-4) occurring in greater than 5 percent of patients in either treatment arm included elevations in bilirubin (greater than 2.5 x ULN), increases in amylase and increases in total cholesterol. Median increases in cholesterol, LDL, HDL and triglycerides were small and similar in both arms of the study.
In the two Phase II studies, no patients receiving cobicistat experienced Grade 3 or 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations, which are measures of liver function. Small increases in serum creatinine (a value used to estimate kidney function) with resulting decreases in estimated creatinine clearance (by Cockroft-Gault) were observed in the Phase II studies. Results from a separate renal study in healthy volunteers indicate that cobicistat does not affect actual glomerular filtration rates (GFR) as assessed by iohexol clearance (a true measure of kidney function). The increase in serum creatinine with cobicistat occurs within days of drug initiation and is reversible with values returning to baseline within days after cessation of cobicistat.
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