New Tenofovir Pro-drug GS-7340 Looks Good in Early Study

StephenW

[A Phase 1 trial for HBV has just started. (StephenW)]

[Please note it is being tested for HIV at this stage, but it must have implications for HBV treatment (StephenW)]

New         Tenofovir Pro-drug GS-7340 Looks Good in Early Study
        
        

	SUMMARY:  A new pro-drug formulation of tenofovir              (currently marketed as Viread, also in the Truvada                     and Atripla combination pills) produces a higher drug concentration in lymphoid tissues that harbor HIV, offering the prospect of  lower doses and new fixed-dose formulations, according to  a presentation last week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston. Further studies are needed to determine whether higher tenofovir concentrations will lead to worse  bone or kidney toxicity.

       By           Paul Dalton
         
          Tenofovir,           developed and sold by Gilead Sciences of Foster City, CA, is the most           widely used antiretroviral drug in the U.S. It is currently available           as a pro-drug called tenofovir disporoxil fumerate (TDF). A pro-drug           is a non-active form of a drug that is converted to the active form           inside the body.
        GS-7340           is a new experimental pro-drug formulation of tenofovir, designed to           better target lymphoid tissues and cells, and to remain stable in the           body longer. Pre-clinical research showed that it reaches 400 times           higher levels of active drug in peripheral blood mononuclear cells (PBMCs)           than TDF, and is 200 times more stable in plasma.
        In a late-breaker           oral presentation at CROI, Andrew Zolopa of Stanford University presented           results from a 14-day monotherapy study comparing 2 doses of GS-7340           to the standard dose of TDF, looking at their ability to reduce HIV           viral load.
       A total           of 30 HIV positive treatment-naive participants (27 men) with HIV viral           loads greater than 15,000 copies/mL and CD4 T-cell counts above 200           cells/mm3 were randomly assigned to take 300 mg TDF, or either 50 mg           or 150 mg GS-7340 once daily for 14 days.
        The primary           objective of the study was to measure the drugs' effects on viral load.           The researchers also looked at drug levels and measures of safety and           tolerability.
         
        Results
        

	Time-weighted  average viral load from baseline through day 14 declined by 0.54  log for TDF, compared to 0.95 log for 50 mg GS-7340 and 1.07 log for 150 mg GS-7340.
	At14 days, the mean decrease in HIV viral load was 0.94 log for TDF,  compared to 1.57 log for 50mg GS-7340 and 1.71 log for 150 mg GS-7340.
	There  were no serious adverse effects in any arm of the study.
	Headache   was the most commonly reported side effect.
	There  were no significant laboratory abnormalities in any arm of the study.
	The   2 doses of GS-7340 reached higher drug concentrations in PBMCs compared to plasma.
	In contrast, TDF reached higher levels in plasma.

        Zolopa concluded           that GS-7340 is a candidate for a "next generation pro-drug of           tenofovir, with the potential to improve efficacy and safety over TDF."
      There are,           however, unanswered questions about GS-7340. Tenofovir has been shown           to affect both kidney and bone tissue. This study was too short to assess           GS-7340's effects on kidneys or bones in humans. But animal research           showed that the drug concentration in bone tissue was about 3.5 times           higher with GS-7340 than with TDF; no difference in drug levels was           seen in kidney or liver tissues.
        This short           monotherapy study suggests promise for a new formulation of tenofovir.           GS-7340's ability to selectively target lymphoid or immune system cells           raises the hope that it will prove more potent against HIV. Results           from this trial suggest that this might be the case. GS-7340's superior           stability and penetration into lymphoid tissue also suggest it could           be given at a significantly lower dose than TDF, opening the door for           novel fixed-dose combination pills and greater availability in resource-limited           settings.
        Investigator           affiliations: Rockefeller University, New York, NY; Stanford University,           Palo Alto, CA; Lightsource Med, Los Angeles, CA; Thomas Jefferson University,           Philadelphia, PA; Gilead Sciences, Foster City, CA.
       3/11/11
        Reference
         M           Markowitz, A Zolopa, P Ruane, and others. GS-7340 Demonstrates Greater           Declines in HIV-1 RNA than TDF during 14 Days of Monotherapy in HIV-1-infected           Subjects. 18th Conference on Retroviruses and Opportunistic Infections           (CROI 2011). Boston. February 27-March 2, 2011. Abstract           152LB.
     
         

StephenW

请注意，它正在测试艾滋病毒在这个阶段，但是它必须有对乙肝病毒治疗（StephenW）的影响]

在早期的研究，新临药物泰诺福韦GS - 7340看起来不错
        
        


摘要：一个新的药物的替诺福韦制定（Viread，目前销售也Truvada和Atripla组合丸）生产在淋巴组织的药物浓度较高，港口艾滋病毒，提供了低剂量和新的固定剂量配方的前景，据介绍上周在第18届逆转录病毒和机会性感染（CROI 2011年）在波士顿会议。还需作进一步研究，以确定是否替诺福韦浓度较高会导致糟糕的骨或肾毒性。
            

       到保罗道尔顿
         
          泰诺福韦，加利福尼亚州福斯特城，由吉利德科学开发和销售，是在美国最广泛使用的的抗逆转录病毒药物，它是目前所谓的替诺福韦disporoxil fumerate（TDF）亲药物。有利于药物是一个非活性形式，一个是身体内转化为活性形式的药物。
        GS - 7340是一个新的实验性药物的制定泰诺福韦，设计更好的目标淋巴组织和细胞，并保持稳定在体内较长。临床前研究表明，达到外周血单个核细胞（PBMCs）中比华盈活性药物的水平高出400倍，是血浆中的稳定的200倍以上。
        在后期断路器在CROI的口头介绍，斯坦福大学的安德鲁Zolopa提出了14天的单一疗法比较2剂GS - 7340标准剂量华盈，寻找自己的能力，以减少HIV病毒载量的研究结果。
       共有30艾滋病毒呈阳性的治疗，天真的参与者（27人）与HIV病毒载量超过15000拷贝/ ml和CD4 T细胞计数大于200 cells/mm3被随机分配采取TDF，300毫克或50毫克或150毫克GS - 7340，每天一次，14天。
        该研究的主要目标是对病毒载量来衡量药物的效果。研究人员还研究在安全性和耐受性的药物浓度和措施。
         
        结果
        
通过14天的时间加权平均从基线病毒载量下降了0.54 TDF日志相比，0.95为50毫克，GS - 7340和1.07日志的日志150毫克GS - 7340。
At14天，HIV病毒载量平均下降0.94 TDF日志，相比1.57日志为150毫克GS - 7340 GS - 7340为50毫克和1.71日志。
目前还没有任何研究的手臂严重的不良影响。
头痛是最常见的副作用。
有没有显著的实验室研究的手臂在任何异常。
GS - 7340的2剂量达到较高的药物浓度在外周血相比，血浆。
相比之下，华盈血浆中达到更高的水平。
        Zolopa的结论是，GS - 7340是一个“下一代亲药物泰诺福韦的潜力，以提高对TDF的疗效和安全性，为候选人。”
      然而，有关于GS - 7340的悬而未决的问题。替诺福韦已被证明影响肾脏和骨组织。这项研究是太短，GS - 7340的评估肾脏或在人类骨骼的影响。但动物研究表明，在骨组织中的药物浓度高于GS - 7340与华盈约3.5倍;在肾脏或肝脏组织药物浓度没有差别。
        这个简短的单药治疗研究表明，替诺福韦的一个新的提法的承诺。 GS - 7340选择性地针对淋巴或免疫系统细胞的能力提出了希望，这将证明对艾滋病毒更有力。从这个试验的结果表明，这种可能的情况下。 GS - 7340的超强的稳定性和渗透到淋巴组织，也表明它可以在比华盈显著低剂量，在资源有限的情况下打开门新颖的固定剂量复方药和更高的可用性。
        调查背景：洛克菲勒大学，纽约，帕洛阿尔托，加利福尼亚斯坦福大学，洛杉矶，加州光源MED;托马斯杰斐逊大学，费城，PA，Gilead Sciences公司，福斯特城，加利福尼亚。
       11年3月11日
        参考
         中号马科维茨，一个Zolopa，P Ruane和其他。 GS - 7340演示在单药治疗14天，HIV - 1感染者HIV - 1 RNA的跌幅比华盈大。逆转录病毒和机会性感染（CROI 2011年）第18次会议。波士顿。 2月27日，2011年3月2日。摘要152LB。

StephenW

A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naive Adults with Chronic Hepatitis B (CHB) Infection
一个1b期随机，开放标签，主动控制的研究，以评估与慢性乙型肝炎（CHB）感染的安全性，病毒动力学和抗HBV治疗过的成年人GS- 7340的活动

Countries of recruitment:	Australia
Postcode:	6009, 3181
	Outside Australia
	United Kingdom - London
	United Kingdom - Birmingham
	United Kingdom - Nottingham
	Canada - British Columbia
	Canada - Ontario
	Canada - Quebec
	Canada - Alberta
	New Zealand - Auckland
Brief summary:	This is a randomized, open-label, active-controlled study whose primary objective is to evaluate the safety and efficacy of several doses of GS-7340. This study will evaluate the safety, viral kinetics, and antiviral activity of each of four doses of GS-7340 over 28 days of therapy.  In addition, the study will evaluate the antiviral activity of an optimal dose of GS-7340 versus TDF 300-mg over 28 days of therapy. Approximately 50 eligible subjects with chronic HBV infection who are naïve to anti-HBV treatment will be randomized 1:1:1:1:1 to receive treatment with GS-7340 8-, 25-, 40-, or 120-mg or TDF 300-mg orally once daily. Subjects may be HBeAg+ or HBeAg-. Enrollment will be stratified by HBeAg status with approximately a 1:1 distribution resulting in approximately 25 HBeAg+ and 25 HBeAg- subjects. All subjects must be followed for safety for 30 days after the 28-day treatment. Optional blood samples may be obtained for exploratory biomarker and pharmacogenomic discovery research at any time during the study or at a separate post study visit, if necessary. Subjects who agree to have blood drawn for pharmacogenomic research will sign a separate informed consent form.