EASL 2017：Besifovir和替诺福韦Exalidex看起来对乙型肝炎有希望

StephenW

                                                                                EASL 2017: Besifovir and Tenofovir Exalidex Look Promising for Hepatitis B                                                               

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                 Details                                                                                Category: Experimental HBV Drugs                                                                Published on Wednesday, 03 May 2017 00:00                                                        Written by Liz Highleyman               
                                                                                               

HBV © Russell Kightley

                                       
               
               
                A pair of investigational nucleotide analog antivirals were shown to be active against hepatitis B virus (HBV) with minimal potential for kidney and bone toxicity, researchers reported at the EASL International Liver Congress last month in Amsterdam. Besifovir is in Phase 3 clinical trials, while tenofovir exalidex is in early development.

        Nucleoside/nucleotide antivirals for hepatitis B can suppress viral replication during treatment, but they usually do not lead to a cure. Ongoing therapy is generally required, so long-term safety and tolerability is a priority.
        One of the most widely used drugs for hepatitis B and HIV, the nucleotide analog tenofovir disoproxil fumarate or TDF (Viread), is generally considered safe, but it can cause bone loss and kidney problems in some people.
        A newer pro-drug formulation, tenofovir alafenamide or TAF (Vemlidy), produces high levels of the active drug in hepatocytes and CD4 T-cells with smaller doses, which gives a lower concentration in the blood and less exposure for organs. Other research presented at the conference showed that TAF works as well as TDF with less kidney toxicity and bone loss, and people who switched from TDF to TAF showed improvements in kidney and bone biomarkers.
        Other companies are working on related hepatitis B drug candidates that minimize kidney and bone toxicity. Having more options allows clinicians to tailor therapy to individual patients, and having competing drugs on the market can bring down the cost of treatment.
        Sang Hoon Ahn from Yonsei University in Seoul, South Korea, presented findings from a Phase 3 trial of besifovir, a guanosine nucleotide analog pro-drug formerly known as LB80380 (LG Life Science) and ANA380 (Anadys Pharmaceuticals).
        Besifovir has been in development for more than a decade. Prior studies showed that it has potent activity against HBV, including drug-resistant variants. It accumulates less in the kidneys than TDF or adefovir (HepSera), so it is expected to cause less renal toxicity. In a Phase 2b study besifovir suppressed HBV as well as entecavir (Baraclude).
        The only notable side effect of besifovir was reduced levels of carnitine, a compound that plays a role in cellular energy production. In further trials participants received preventive carnitine supplementation.
        The Phase 3 trial was a head-to-head comparison of 150 mg besifovir versus 300 mg TDF taken for 48 weeks, followed by open-label besifovir through week 192. All participants also received 660 mg L-carnitine.
        The study included 187 chronic hepatitis B patients, about 60% of whom were hepatitis B "e" antigen (HBeAg)-positive. About two-thirds were men and the mean age was approximately 45 years. Almost all had HBV genotype A and about 20% had compensated cirrhosis; people with decompensated liver disease were excluded. No exclusion criteria related to kidney function were reported.
        Results

•                 In an intent-to-treat analysis at 48 weeks, 81% of participants taking besifovir and 85% of those taking TDF achieved viral suppression with HBV DNA <400 copies/mL or <69 IU/mL.
•                  64% and 69%, respectively, met a stricter cut-off of <116 copies/mL or <20 IU/mL.
•                 As expected, response was better among HBeAg-negative patients, with 97% on besifovir and 100% on TDF having HBV DNA <400 copies/ml.
•                 Among HBeAg-positive participants, the corresponding response rates were 70% and 75%, respectively.
•                 5 people (5%) in each treatment arm experienced virological breakthrough, but none had drug resistance mutations.
•                 Levels of HBV cccDNA in liver cells did not differ between groups.
•                 1 person in the TDF arm achieved hepatitis B surface antigen (HBsAg) loss.
•                 About three-quarters of participants in both treatment arms experienced ALT normalization; HBeAg-positive people were significantly more likely to see their ALT return to normal on TDF, while among HBeAg-positive patients this was more likely on besifovir.
•                 Histological response measures favored besifovir: among 29 patients who underwent liver biopsy, those taking besifovir were twice as likely to see a reduction of 2 or more points in necroinflammatory activity (78% vs 36%, respectively).
•                 The proportion of people with the most severe fibrosis (stage 6 on the 6-point Ishak scale) fell from 17% to 11% in the besifovir group, while rising from 9% to 18% in the TDF group.
•                 Besifovir was generally safe and well-tolerated.
•                 1 person taking besifovir had a serious adverse drug reaction of muscle spasms, considered possibly related to treatment.
•                 1 person on besifovir stopped treatment due to liver cancer and 1 person on TDF did so due to a rise in creatine phosphokinase.
•                 Kidney and bone safety measures were better with besifovir.
•                 Serum creatinine rose significantly less with besifovir than with TDF.
•                 Estimated glomerular filtration rate (eGFR) declined more on TDF, but the difference did not reach statistical significance.
•                 Bone mineral density (BMD) T-scores decreased less in the besifovir group (-0.02 vs -0.10) -- a small but significant difference.
•                 The proportion of people with osteopenia or osteoporosis did not change after 48 weeks on besifovir, but rose in the TDF arm.
  

        "In treatment-naive chronic hepatitis B patients, 48-week treatment of besifovir was non-inferior to tenofovir in virologic response (HBV DNA <400 copies/ml)," the researchers concluded. "It had a good profile in BMD, nephrotoxicity, and histological response."
        Tenofovir Exalidex        Tawesak Tanwandee from Siriraj Hospital in Bangkok presented results from a study of another tenofovir pro-drug further back in the development pipeline. Tenofovir exalidex or TXL (formerly known as CMX157) is being developed by ContraVir Pharmaceuticals in Edison, New Jersey.
        TXL takes advantage of lipid uptake mechanisms to increase bioavailability and enhance tissue penetration. It produces lower levels of active drug in the bloodstream than TDF and is expected to cause less kidney and bone toxicity. This formulation was designed to produce a higher drug concentration in liver cells, where it is needed to fight HBV.
        In an early study of healthy volunteers, TXL was tested at doses ranging from 5 mg to 100 mg for 2 week. Pharmacokinetics were favorable -- supporting once-daily dosing -- and there were no notable safety signals and no serious adverse events or drug discontinuations for this reason.
        TXL was then evaluated for 28 days in 52 people with hepatitis B, while 10 control patients took 300 mg TDF. All were Asian, the average age was in the early thirties, and a majority were HBeAg-positive.
        Participants in the highest (100 mg) dose group had a larger viral load reduction at the end of treatment than those taking TDF, but all the lower doses did not work as well as TDF. TXL appeared safe and well-tolerated, with no serious adverse events or drug discontinuations due to adverse events.
        Based on these early findings, the researchers concluded, "TXL was safe and effective…Lower systemic circulating [tenofovir] levels may mitigate bone and kidney toxicities previously reported for [TDF]." 

        Tanwandee said that the first-generation prototype formulation of TXL is now being optimized in the hopes of using a reduced dose and improving its potential for combining in coformulations.
        5/3/17
        Sources
        SH Ahn, W Kim, YK Jung, et al. Safety and efficacy of besifovir in treatment-naive chronic hepatitis B virus infection: a randomized, double-blind, double dummy, phase 3 study
. EASL International Liver Congress. Amsterdam, April 19-23, 2017. Abstract GS-017.
        T Tanwandee, S Chatsiricharoenkul, S Thongsawat, et al. Pharmacokinetics, safety and antiviral activity of CMX157, a novel prodrug of tenofovir, administered as ascending multiple doses to healthy volunteers and Hepatitis B virus-infected subjects. EASL International Liver Congress. Amsterdam, April 19-23, 2017. Abstract PS-040.
        ContraVir Pharmaceuticals. ContraVir’s Tenofovir Exalidex (TXL) Antiviral Activity in Hepatitis B (HBV) Patients at the International Liver Congress (ILC). Press release. April 20, 2017.
       

StephenW

EASL 2017：Besifovir和替诺福韦Exalidex看起来对乙型肝炎有希望

细节
类别：实验性HBV药物
于2017年5月3日星期三00:00发布
由Liz Highleyman撰写


HBV©Russell Kightley

在上个月在阿姆斯特丹举行的EASL国际肝脏大会上，一对研究性核苷酸科学抗病毒药物被证明对乙肝病毒（HBV）具有极低的肾脏和肝损伤潜力。 Besifovir在3期临床试验中，而替诺福韦exalidex正处于早期发展阶段。

乙型肝炎的核苷/核苷酸抗病毒药物可以抑制治疗期间的病毒治疗，但通常不会导致治愈。通常需要持续治疗，因此长期的安全和耐受性是优先考虑的。

乙型肝炎和艾滋病毒使用最广泛的药物之一，核苷酸类似物替诺福韦地索普洛尔富马酸盐或TDF（Viread）通常被认为是安全的，但有些人可能会导致骨质流失和肾脏问题。

较高的前药制剂，替诺福韦甲酰胺或TAF（Vemlidy）在肝细胞和CD4 T细胞中产生高水平的活性药物，剂量减少，这使得血液中的浓度降低，器官的暴露较少。在TAF工作的同时，TDF和阻力和骨丢失较少的TDF也是如此，从TDF转换到TAF的人在肾脏和骨骼生物标志物中都有注意。

其他公司正在研究吸收肾脏和肝脏的相关乙型肝炎药物候选物。有更多的选择允许临床医生为个别患者量身订做治疗，并且有竞争药物可以降低治疗费用。

来自韩国首尔延世大学的Sang Hoon Ahn从以前称为LB80380（LG Life Science）和ANA380（Anadys Pharmaceuticals）的鸟苷核苷酸类似物前体药物贝司肽的第3期试验中提出。

Besifovir已经发展了十多年。先前的研究表明，它具有抗HBV活性，包括抗药性变异。它在肾脏中比TDF或阿德福韦酯（HepSera）积累的较少，因此预计会导致肾脏较少的Ina Phase 2b研究包头抑制HBV以及恩替卡韦（Baraclude）。

贝伐呋韦唯一显着的副作用是降低肉碱的含量，肉碱是在细胞能量生产中发挥作用的化合物。

第3期试验是一项头对头的比较，其中150mg西替韦韦与300mg TDF服用48周，其次是开放标签的besifovir至192周。所有参与者还接受了660mg左旋肉碱。

该研究包括187例慢性乙型肝炎患者，其中约60％为乙肝“e”抗原（HBeAg）阳性。男子约三分之二，平均年龄为45岁。几乎所有人都有HBV基因型A，约20％患有肝硬化补偿;失代偿期肝病患者被排除。没有报告与肾功能相关的排除标准。

结果

在48周的意向治疗分析中，81％的受试者接受了besifovir，85％的受试者接受HBV DNA <400拷贝/ mL或<69IU / mL的病毒抑制。
64％和69％分别达到<116拷贝/ mL或<20IU / mL更严格的截止值。
如预期的那样，HBeAg阴性患者的反应更好，贝替福韦为97％，HBV DNA为400拷贝/ ml的TDF为100％。
在HBeAg阳性参与者中，相应的应答率分别为70％和75％
每个治疗组中有5人（5％）患有病毒学突破，但具有耐药性突变。
肝细胞中HBV cccDNA的水平没有差异。
TDF手臂1人实现乙型肝炎表面抗原（HBsAg）损失。
四分之三的治疗武器参与者经历了ALT正常化; HBeAg阳性患者在TDF中更有可能看到其ALT恢复正常，而在HBeAg阳性的病例中，更有可能发生在乙肝病毒。
组织学应答措施有利于贝伐呋韦：在接受肝活检的29例患者中，服用西他韦的患者在坏死性炎症活动中观察到减少2分以上的可能性是两倍（分别为78％和36％）。
最严重纤维化的患者比例（Ishak 6级6级）从贝伐替韦组的17％下降到11％，TDF组从9％上升到18％。
Besifovir是完全安全和良好的耐受。
1人服用贝非那韦具有严重的药物不良反应的肌肉痉挛，被认为是相关的相关治疗。
贝伐替韦1人停止治疗肝癌，1例TDF因肌酸磷酸激酶升高
贝地昔韦对肾脏和骨骼的安全措施更好。
贝伐单抗的血清肌酐升高明显低于TDF。
    TDF估计的肾小球滤过率（eGFR）下降更多，但差异无统计学意义。
    贝伐他韦组骨密度（BMD）T值降低较少（-0.02 vs -0.10），差异无统计学意义。
    在贝伐替韦48周后，骨质减少或骨质疏松症患者的比例没有改变，但在TDF组中升高。

研究人员总结说：“在治疗无效的慢性乙型肝炎患者中，贝伐替韦48周治疗不逊于替诺福韦病毒学应答（HBV DNA <400拷贝/ ml）。 “它具有良好的骨密度，肾毒性和组织学反应。”
替诺福韦Exalidex

曼谷Siriraj医院的Tawesak Tanwandee介绍了另一项替诺福韦前体药物研究进展的结果。替诺福韦exalidex或TXL（以前称为CMX157）正由新泽西州爱迪生的ContraVir Pharmaceuticals开发。

TXL利用脂质摄取机制提高生物利用度并增强组织穿透。它在血液中产生比TDF更低水平的活性药物，并且预期会导致较少的肾和骨毒性。该制剂设计用于在肝细胞中产生较高的药物浓度，其中需要对抗HBV。

在健康志愿者的早期研究中，以5mg至100mg的剂量测试TXL 2周。药代动力学有利 - 支持每日一次给药 - 由于这个原因，没有显着的安全信号，没有严重的不良事件或药物停药。

然后在52例乙型肝炎患者中评估TXL 28天，10例对照患者服用300 mg TDF。全部为亚洲人，平均年龄为三十年代初，绝大多数为HBeAg阳性。

最高（100mg）剂量组的参与者在治疗结束时的病毒载量减少比使用TDF的患者减少，但是所有较低剂量的TDF都不能正常工作。 TXL出现安全，耐受性良好，不良反应发生严重不良事件或药物停药。

基于这些早期发现，研究人员得出结论：“TXL是安全有效的...降低系统性循环[替诺福韦]水平可以缓解以前报告的[TDF]的骨和肾毒性。

Tanwandee表示，TXL的第一代原型配方现在正在优化，希望使用减少剂量并提高其在配方中的组合潜力。

17年5月3日

来源

SHAhn，W Kim，YK Jung，et al。贝伐呋韦治疗原发性慢性乙型肝炎病毒感染的安全性和有效性：一项随机，双盲，双假，3期研究。 EASL国际肝脏大会。阿姆斯特丹，1977年4月19日至23日。摘要GS-017。

T Tanwandee，S Chatsiricharoenkul，S Thongsawat，et al。 CMX157的药代动力学，安全性和抗病毒活性，替诺福韦的新型前药，以健康志愿者和乙型肝炎病毒感染的受试者的多次剂量递增。 EASL国际肝脏大会。阿姆斯特丹，1977年4月19日至23日。摘要PS-040。

ContraVir制药公司ContraVir在国际肝脏大会（ILC）乙型肝炎（HBV）患者中的替诺福韦Exalidex（TXL）抗病毒活性。新闻稿。 2017年4月20日

yelanglms

何意？

LITTLELITTLELIT

                The proportion of people with the most severe fibrosis (stage 6 on the 6-point Ishak scale) fell from 17% to 11% in the besifovir group, while rising from 9% to 18% in the TDF group.
besifovir 降低了肝纤维化，TDF没能控制肝纤维化？
若是这样，此药真是好药。
除此外，看不出此药对TDF的明显优势，抗病毒能力甚至不如TDF
副作用小一些。

yelanglms

回复 LITTLELITTLELIT 的帖子

TDF可以逆转肝硬化（部分），唯一不好就是肾毒性。

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马克