吉利德是艾滋病（HIV/AIDS）领域的绝对领导者，该公司四合一新药Stribild分别于2012年和2013年在美欧上市，很大程度上简化了HIV治疗程序，该药本年度第二季度销售额达2.7亿美元，销售稳步增长，前途非常看好。近日，吉利德新研发的四合一HIV新药(E/C/F/TAF)临床疗效媲美Stribild，安全性更高，适用人群更广，该药将成为吉利德HIV专营权中的又一员猛将，也是全球HIV群体的新福音。
吉利德（Gilead）近日宣布，艾滋病（HIV/AIDS）实验性4合1新药(E/C/F/TAF)（elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg ）在2项III期研究（Study 104，Study 111）中达到了主要终点。吉利德已计划在今年晚些时候向FDA和欧盟提交上市申请。
这2项研究在HIV-1初治成人患者中开展，将四合一新药（E/C/F/TAF）与吉利德已上市的四合一HIV药物Stribild（elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg）进行了对比，数据表明，四合一新药(E/C/F/TAF)疗效媲美Stribild，达到了研究的主要终点。
Stribild分别于2012年8月和2013年5月获美国和欧盟批准，该药在2014年第二季度的销售额为2.7亿美元。吉利德表示，随着HIV患者寿命的延长，目前对疗效好、安全性更高的HIV新药仍存在着巨大的医疗需求。
基于这些III期研究的积极数据，E/C/F/TAF单片方案有望为广泛的HIV初治群体，提供一种优化的治疗方案。目前，在HIV临床治疗中，组合疗法已全面流行。葛兰素史克（GSK）旗下ViiV的三合一HIV新药Triumeq于今年8月获FDA批准，该药是由ViiV最新的抗病毒药物Tivicay（dolutegravir）和另2种常规药物abacavir和lamivudine（拉米夫定）组成的固定剂量组合（FDC）复方单片。
目前，数个正在进行的III期研究，正评估四合一HIV新药（E/C/F/TAF）用于多个HIV患者群体，包括从含Truvada单药或多药方案转向E/C/F/TAF方案的患者群体、对抗病毒药物有耐药史的患者群体、伴有轻度至中度肾功能损害的患者群体、初治HIV青少年群体。此外，吉利德正在开展另一项IIIb期研究（WAVES），在HIV女性患者中，评估由多药方案转向E/C/F/TAF方案。
过去艾滋病毒药物属于多药丸式，即患者需同时服用多种药丸，但是随着临床试验的深入研究，出现了多种单一药丸治疗方案，Stribild是吉利德四合一HIV新药，该药的上市，在很大程度上简化了HIV治疗程序。但Stribild药物标签上有一些加框警示信息，表明该药将会引起血液乳酸增高并产生严重的肝脏问题，这两种不良反应都会十分致命。
同时，FDA要求吉利德开展后续研究，证明Stribild在妇女和儿童群体中的安全性，以及该药与其他药物联用时的药效反应等。据美国疾病控制与预防中心最新数据显示，美国境内约有120万人被诊断患有艾滋病毒。
Stribild（elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg)
英文原文：Gilead’s Investigational Tenofovir Alafenamide (TAF)-based Single Tablet HIV Regimen Meets 48-Week Primary Objective in Two Phase 3 Studies
FOSTER CITY, Calif.--(BUSINESS WIRE)--
Gilead Sciences, Inc. (GILD) today announced that two Phase 3 clinical trials (Studies 104 and 111) evaluating an investigational once-daily single tablet regimen containing tenofovir alafenamide (TAF) for the treatment of HIV-1 infection in treatment-naïve adults met their primary objectives. The studies demonstrated that the single tablet regimen comprising elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and TAF 10 mg (E/C/F/TAF), was non-inferior to Gilead’s Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) based on the proportion of patients with HIV RNA levels (viral load) of less than 50 copies/mL at 48 weeks of therapy. In addition, E/C/F/TAF demonstrated more favorable renal and bone safety compared to Stribild.
“As individuals with HIV are living longer, there is a need for treatments that are not only highly effective, but also offer an improved safety profile,” said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. “based on these Phase 3 results, we believe that the E/C/F/TAF single tablet regimen has the potential to optimize HIV therapy for a wide range of treatment-naïve patients.”
In Study 104, 93.1 percent (n=405/435) of patients taking E/C/F/TAF compared to 92.4 percent (n=399/432), of patients taking Stribild, with 95 percent CI from -2.6% to 4.5%, achieved HIV RNA of less than 50 copies/mL at week 48. In Study 111, 91.6 percent (n=395/431) of E/C/F/TAF patients compared to 88.5 percent (n=385/435) of Stribild patients, with 95 percent CI from -1.0% to 7.1%, achieved HIV RNA of less than 50 copies/mL at week 48. Both regimens were generally well tolerated. Discontinuation rates due to adverse events, safety and resistance profiles were comparable between E/C/F/TAF and Stribild in both studies.
Laboratory abnormalities were generally similar for both regimens, with the exception of renal and bone safety indicators, which favored the TAF-based regimen. There was a statistically significant difference in the median change in estimated glomerular filtration rate (eGFR) from baseline to week 48, favoring the TAF-based regimen (-6.8 mL/min for E/C/F/TAF vs. -10.4 mL/min for Stribild in Study 104 (p<0.001); -5.7 mL/min for E/C/F/TAF vs. -11.9 mL/min for Stribild in Study 111 (p<0.001)). Additionally, patients taking the TAF-based regimen experienced a significantly smaller median percentage decrease from baseline in lumbar spine bone mineral density compared to Stribild patients (-1.19 vs. -2.67 in Study 104 (p<0.001); -1.11 vs. -2.81 in Study 111 (p<0.001)) and in hip bone mineral density (-0.77 vs. -3.24 in Study 104 (p<0.001); -0.74 vs. -2.78 in Study 111 (p<0.001)).
In Study 104, median changes from baseline in total fasting cholesterol, HDL (high-density lipoprotein or “good” cholesterol) and LDL (low-density lipoprotein or “bad” cholesterol) were, respectively, 30, 7 and 15 mg/dL for E/C/F/TAF and 12, 3 and 2 mg/dL for Stribild (total cholesterol, p<0.001; HDL, p<0.001; LDL, p<0.001). In Study 111, median changes from baseline in total cholesterol, HDL and LDL were respectively, 27, 7 and 11 mg/dL for E/C/F/TAF and 14, 4 and 2 mg/dL for Stribild (total cholesterol, p<0.001; HDL, p<0.001; LDL, p<0.001).
Gilead plans to submit data from Studies 104 and 111 for presentation to a scientific conference in early 2015.
Several additional ongoing Phase 3 studies are evaluating E/C/F/TAF among multiple HIV patient populations, including patients who switch to E/C/F/TAF from either a single tablet or multi-pill Truvada-containing regimens, patients with a history of antiviral drug resistance, patients with mild to moderate renal impairment and treatment-naïve HIV-positive adolescents. An additional Phase 3b study, WAVES, is evaluating E/C/F/TAF among HIV-positive women who switched from a multi-pill regimen.
based on the results of Studies 104 and 111 and data from these additional ongoing studies, Gilead plans to submit regulatory applications for E/C/F/TAF in the United States and European unio in the fourth quarter of 2014.
about the E/C/F/TAF Studies
Study 104 and Study 111 are randomized, double-blind, 96-week clinical trials among 1,744 treatment-naïve HIV-1 infected adults with viral load greater than or equal to 1,000 copies/mL. In Study 104, 867 patients were randomized (1:1) and received E/C/F/TAF (n=435) or Stribild (n=432). In Study 111, 866 patients were randomized (1:1) and received E/C/F/TAF (n=431) or Stribild (n=435).
The primary efficacy endpoint of the studies is the proportion of patients with viral load < 50 copies/mL at 48 weeks of treatment as determined by the FDA-defined snapshot analysis. Key secondary endpoints include change from baseline in bone mineral density at the hip and spine at weeks 48, and change from baseline in serum creatinine at weeks 48. Other secondary endpoints include the proportion of patients with viral load < 20 copies/mL at 48 and 96 weeks of therapy as defined by the FDA snapshot analysis, the proportion of patients with viral load < 50 copies/mL at week 96 as defined by the FDA snapshot and change from baseline in CD4+ cell count at weeks 48 and 96.
The studies are ongoing in a blinded fashion. After week 96, patients will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all will be given the option to participate in an open-label rollover extension and receive E/C/F/TAF. Additional information about the study can be found at www.clinicaltrials.gov.
Elvitegravir, cobicistat and E/C/F/TAF are investigational products in the United States and have not yet been determined safe or efficacious in humans.
about Tenofovir Alafenamide
Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor (NtRTI). It is an investigational novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate), which is also an NtRTI. Phase 1b dose-ranging studies identified a dose of TAF that is ten times lower than Viread. The smaller milligram size of TAF may enable the development of new fixed-dose combinations and single tablet regimens for HIV therapy that are not feasible with Viread.
about Elvitegravir
Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds, which interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir 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, wher JT retains rights. Elvitegravir is approved under the tradename Vitekta® in Europe, Australia and Canada, and is currently under review by the U.S. Food and Drug Administration.
about Cobicistat
Cobicistat is a cytochrome P450 3A (CYP3A) inhibitor. It boosts blood levels of the HIV protease inhibitors atazanavir and darunavir by suppressing CYP3A, an enzyme that metabolizes these drugs in the body. Cobicistat acts only as a pharmacokinetic enhancer and has no antiviral activity. Cobicistat is approved under the tradename Tybost® in Europe, Australia and Canada, and is currently under review by the U.S. Food and Drug Administration.
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 and South America, Europe and Asia Pacific.
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