吉利德将在2019年国际肝病大会上展示多种肝病研究和开发项

StephenW

Gilead to Present New Data From Multiple Liver Disease Research and Development Programs at The International Liver Congress™ 2019FOSTER CITY, Calif.--(BUSINESS WIRE)--Mar 27, 2019--Gilead Sciences, Inc. (Nasdaq: GILD) today announced that data from the company’s research and development programs in nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC) and viral hepatitis will be presented at The International Liver Congress™ 2019 in Vienna, Austria from April 10-14, 2019. These data reflect Gilead’s ongoing focus and commitment to advancing research and patient care across the field of liver disease.
“For 20 years, Gilead has been focused scientifically on the treatment of liver diseases and brought innovative medicines and access programs to people around the world,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead Sciences. “At this year’s International Liver Congress, we are proud to share new data from studies that aim to improve our understanding of challenging liver diseases such as PSC, enable broader NASH diagnosis rates and strive to bring forward new therapies for patients with unmet medical needs in NASH and viral hepatitis.”
Advanced Fibrosis due to NASH
Patients with advanced fibrosis due to NASH, defined as bridging fibrosis (F3) or cirrhosis (F4), are at a significantly higher risk of liver-related mortality. Gilead will share data on multiple investigational compounds, noninvasive testing for NASH diagnosis and patient-reported outcomes.
Data being presented at the meeting highlight the potential utility of investigational compounds in development to address this significant medical need.

• A combination of the ACC inhibitor GS-0976 and the non-steroidal FXR agonist GS-9674 improves hepatic steatosis and liver stiffness in patients with nonalcoholic steatohepatitis (NASH): a proof-of-concept study (poster #0352)
• The addition of fenofibrate to a liver-targeted acetyl CoA carboxylase inhibitor reverses plasma TG increases and positively impacts efficacy (poster #0284)
  

The diagnosis of advanced fibrosis due to NASH currently requires a liver biopsy, which is an invasive procedure that can lead to serious complications. Data evaluating the use of noninvasive tests for the identification of patients with advanced fibrosis will be presented at the meeting.

• Clinical utility and application of noninvasive tests of fibrosis in selection of patients with advanced fibrosis due to NASH in the Phase 2 ATLAS trial (poster #0315)
• Impact of age on routinely available noninvasive tests for the discrimination of advanced fibrosis due to NASH in the Phase 3 STELLAR trials of the ASK1 inhibitor selonsertib (poster #0273)
  

Data regarding patient-reported outcomes from Gilead’s ongoing development program will also be presented.

• What are the predictors of impairment of patient-reported outcomes in non-alcoholic steatohepatitis (poster #0151)
• Patients with non-alcoholic steatohepatitis (NASH) experience severe impairment of health-related quality of life (HRQL) (poster #0348)
• The presence of type 2 diabetes is independently associated with impairment of patient-reported outcomes in patients with non-alcoholic steatohepatitis (poster #0438)
  

Cilofexor (GS-9674), firsocostat (GS-0976) and selonsertib are investigational compounds and are not approved by the U.S. Food and Drug Administration (FDA) or any other regulatory authority. Their safety and efficacy have not been established.
Primary Sclerosing Cholangitis (PSC)
PSC is a rare and chronic condition that causes inflammation and scarring of the bile ducts, which may lead to liver failure. The natural history and progression of the disease in patients are not well understood. Data being presented help inform future clinical development in PSC for which a large unmet need for effective therapy exists.

• Validation of histologic and noninvasive measures of fibrosis as surrogate endpoints of disease progression in patients with primary sclerosing cholangitis (PSC) (oral presentation #0012)
• Prospective evaluation of serum alkaline phosphatase variability and prognostic utility in primary sclerosing cholangitis using controlled clinical trial data (oral presentation #0016)
• Methylation signatures in blood show accelerated epigenetic aging in patients with primary sclerosing cholangitis compared to healthy controls (poster #0024)
  

Viral Hepatitis Treatment and Cure
Gilead is committed to improving care for people living with chronic hepatitis B virus (HBV) infection and delivering the potential for cure to all chronic hepatitis C virus (HCV) patients. New HBV and HCV data being presented include safety and efficacy findings with switching to Vemlidy ® (tenofovir alafenamide 25mg, TAF) treatment in virologically suppressed HBV patients treated with tenofovir disoproxil fumarate (TDF), and safety and efficacy results with Epclusa ® (sofosbuvir 400 mg/velpatasvir 100 mg) in difficult-to-cure HCV patients. Further evidence of the use of Epclusa and Harvoni ® (ledipasvir 90mg/sofosbuvir 400mg) in a range of patient types and populations in the real-world setting will also be presented.

• A Phase 3 study comparing switching from tenofovir disoproxil fumarate to tenofovir alafenamide with continued TDF treatment in virologically-suppressed patients with chronic hepatitis B (CHB): week 48 efficacy and safety results (poster #0183)
• Bone and renal safety are improved in chronic HBV patients switched to tenofovir alafenamide (TAF) after either 2 or 3 years of prior tenofovir disoproxil fumarate (TDF) treatment (poster #0158)
• High efficacy and improvement in CPT class with sofosbuvir/velpatasvir plus ribavirin for 12 weeks in patients with CPT C decompensated cirrhosis (poster #0138)
• Ledipasvir/sofosbuvir for 8, 12, or 24 weeks is safe and effective in patients undergoing dialysis (poster #0144)
• Global real-world evidence of sofosbuvir/velpatasvir as a simple, effective regimen for the treatment of chronic hepatitis C patients: Integrated Analysis of 12 clinical practice cohorts (oral presentation #0003)
  

Finally, as part of Gilead’s HBV cure program, the latest findings on the potential role of investigational GS-9688, will be presented.

• In vitro modulation by TLR8 agonist GS-9688 of multiple regulatory cell types in patients with chronic hepatitis B (poster #0132)
  

EPCLUSA and HARVONI are each indicated in the U.S. for the treatment of chronic HCV infection in patients with no cirrhosis or with compensated cirrhosis: EPCLUSA for adults with genotypes 1-6; and HARVONI for adults with genotypes 1, 4, 5 and 6. EPCLUSA in combination with ribavirin is indicated in the U.S. for the treatment of chronic HCV infection in patients with decompensated cirrhosis. VEMLIDY is indicated for the treatment of chronic HBV infection in adults with compensated liver disease. The US product labels for EPCLUSA, HARVONI, and VEMLIDY each contain a BOXED WARNING: for EPCLUSA and HARVONI, the risk of HBV reactivation in HCV/HBV co-infected patients; and for VEMLIDY, the risk of post-treatment severe acute exacerbation of HBV. See below for U.S. Important Safety Information.
The safety and efficacy of HARVONI in HCV patients undergoing dialysis has not been established.
GS-9688 is an investigational compound and is not approved by the FDA or any other regulatory authority. Its safety and efficacy has not been established.
For more information, including a complete list of abstract titles at the meeting, please visit: [ https://ilc-congress.eu/programme-highlights/ ].

StephenW

吉利德将在2019年国际肝病大会上展示多种肝病研究和开发项目的新数据
加利福尼亚州福斯特城 - （美国商业资讯） -  2019年3月27日 - 吉利德科学公司（纳斯达克股票代码：GILD）今天宣布该公司在非酒精性脂肪性肝炎（NASH），原发性硬化性胆管炎研发项目中的数据（PSC）和病毒性肝炎将于2019年4月10日至14日在奥地利维也纳举行的2019年国际肝病大会上展示。这些数据反映了吉利德一直致力于推动肝病领域的研究和患者护理。

“20年来，吉利德一直专注于肝脏疾病的治疗，并为世界各地的人们提供创新药物和获取方案，”John McHutchison医学博士，首席科学官，吉利德科学研究与开发主管。 “在今年的国际肝病大会上，我们很自豪地分享研究中的新数据，这些研究旨在提高我们对PSC等具有挑战性肝病的认识，实现更广泛的NASH诊断率，并努力为未满足医疗需求的患者提供新的治疗方法。 NASH和病毒性肝炎。“

由NASH引起的晚期纤维化

NASH引起的晚期纤维化患者，定义为桥接纤维化（F3）或肝硬化（F4），肝脏相关死亡风险显着增高。吉利德将分享多种研究化合物的数据，NASH诊断的无创检测和患者报告的结果。

会议上提供的数据强调了研究化合物在开发中的潜在效用，以满足这一重要的医疗需求。

    ACC抑制剂GS-0976和非甾体FXR激动剂GS-9674的组合可改善非酒精性脂肪性肝炎（NASH）患者的肝脂肪变性和肝硬度：概念验证研究（海报＃0352）
    将非诺贝特添加到肝脏靶向的乙酰辅酶A羧化酶抑制剂中可逆转血浆TG的增加并对疗效产生积极影响（海报＃0284）

由NASH引起的晚期纤维化的诊断目前需要肝脏活组织检查，这是一种可导致严重并发症的侵入性手术。将在会议上介绍评估使用非侵入性检测鉴定晚期纤维化患者的数据。

    在2期ATLAS试验中，纤维化无创检查在选择NASH晚期纤维化患者中的临床应用和应用（海报＃0315）
    在ASK1抑制剂selonsertib的第3阶段STELLAR试验中，年龄对常规可用的非侵入性试验对NASH引起的晚期纤维化的影响（海报＃0273）

还将介绍吉列德正在进行的发展计划中有关患者报告结果的数据。

    非酒精性脂肪性肝炎患者报告结果受损的预测因素是什么（海报＃0151）
    非酒精性脂肪性肝炎（NASH）患者的健康相关生活质量（HRQL）严重受损（海报＃0348）
    2型糖尿病的存在与患有非酒精性脂肪性肝炎患者的患者报告结果的损害独立相关（海报＃0438）

Cilofexor（GS-9674），firsocostat（GS-0976）和selonsertib是研究化合物，未经美国食品药品管理局（FDA）或任何其他监管机构批准。他们的安全性和有效性尚未确定。

原发性硬化性胆管炎（PSC）

PSC是一种罕见的慢性疾病，可引起胆管炎症和瘢痕形成，可导致肝功能衰竭。患者的疾病的自然病史和进展尚不清楚。所呈现的数据有助于为PSC中未来的临床开发提供信息，因为PSC存在大量未满足的有效治疗需求。

    验证纤维化的组织学和非侵入性测量作为原发性硬化性胆管炎（PSC）患者疾病进展的替代终点（口头报告＃0012）
    使用对照临床试验数据前瞻性评估原发性硬化性胆管炎的血清碱性磷酸酶变异性和预后效用（口头报告＃0016）
    与健康对照相比，血液中的甲基化特征显示原发性硬化性胆管炎患者的表观遗传老化加速（海报＃0024）
病毒性肝炎治疗和治疗

吉利德致力于改善对患有慢性乙型肝炎病毒（HBV）感染者的护理，并为所有慢性丙型肝炎病毒（HCV）患者提供治愈的潜力。提交的新HBV和HCV数据包括安全性和疗效结果，在替诺福韦地索普西富马酸盐（TDF）治疗的病毒学抑制的HBV患者中转用Vemlidy®（替诺福韦艾拉酚胺25mg，TAF）治疗，Epclusa®的安全性和疗效结果（sofosbuvir 400） mg / velpatasvir 100 mg）在难以治愈的HCV患者中。还将介绍在现实环境中使用Epclusa和Harvoni®（ledipasvir 90mg / sofosbuvir 400mg）在一系列患者类型和人群中的进一步证据。

    一项3期研究比较替诺福韦地索普西富马酸盐与替诺福韦艾拉酚胺的转换，继续TDF治疗病毒抑制的慢性乙型肝炎（CHB）患者：第48周疗效和安全性结果（海报＃0183）
    在先前替诺福韦地索普西富马酸盐（TDF）治疗2年或3年后，改用替诺福韦艾拉酚胺（TAF）的慢性HBV患者的骨和肾安全性得到改善（海报＃0158）
    CPT C失代偿期肝硬化患者使用sofosbuvir / velpatasvir加利巴韦林治疗CPT的疗效高达12周（海报＃0138）
    Ledipasvir / sofosbuvir治疗8周，12周或24周对接受透析的患者安全有效（海报＃0144）
    sofosbuvir / velpatasvir作为治疗慢性丙型肝炎患者的简单有效方案的全球现实证据：12项临床实践队列的综合分析（口头报告＃0003）

最后，作为吉利德HBV治愈计划的一部分，将介绍有关研究GS-9688潜在作用的最新发现。

    TLR8激动剂GS-9688对慢性乙型肝炎患者多种调节细胞类型的体外调节（海报＃0132）

EPCLUSA和HARVONI均在美国用于治疗无肝硬化或代偿性肝硬化患者的慢性HCV感染：基因型为1-6的成人的EPCLUSA;对于患有失代偿性肝硬化的患者，EPCLUSA与利巴韦林组合用于治疗患有失代偿性肝硬化的患者的慢性HCV感染，其中EPCLUSA与利巴韦林组合使用。并且对于具有基因型1,4,5和6的成人具有HARVONI。 VEMLIDY适用于治疗伴有代偿性肝病的成人慢性HBV感染。 EPCLUSA，HARVONI和VEMLIDY的美国产品标签均含有BOXED警告：对于EPCLUSA和HARVONI，HCV / HBV合并感染患者HBV再激活的风险;对于VEMLIDY，治疗后HBV严重急性发作的风险。请参阅下面的美国重要安全信息。

尚未确定HARVONI在接受透析的HCV患者中的安全性和有效性。

GS-9688是一种研究化合物，未经FDA或任何其他监管机构批准。其安全性和有效性尚未确定。

有关更多信息，包括会议的完整摘要标题列表，请访问：[https://ilc-congress.eu/programme-highlights/]。

齐欢畅

左罗

－－－－－最后，作为吉利德HBV治愈计划的一部分，将介绍有关研究GS-9688潜在作用的最新发现。
   
      至今，本人仍然期盼并坚持看好GS-9688的精彩亮相，遗憾的只是目前相关资料信息不够多，拭目以待祈如愿以偿！

StephenW

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FRI-132
In vitro modulation by TLR8 agonist GS-9688 of multiple
regulatory cell types in patients with chronic hepatitis B
Oliver E Amin1, Emily Colbeck1, Stephane Daffis2,
Divya Pattabiraman2, Colette Sitali3, William Rosenberg4,
Simon Fletcher2, Mala Maini1, Laura J Pallett1. 1UCL, Infection and
Immunity, London, United Kingdom; 2Gilead Sciences, Foster City,
United States; 3UCL, Infection, Immunity and Transplantation, London,
United Kingdom; 4UCL, Infection, Immunity and Transplantation,
London, United Kingdom
Email: [email protected]
Background and aims: HBV-specific T cell responses are characterised
by functional exhaustion and premature deletion.
Immunosuppressive cell types targeting this antiviral T cell response
include granulocytic myeloid-derived suppressor cells (gMDSC),
CD4 + regulatory T cells (Tregs), and regulatory TRAIL + NK cells.
Signalling through different toll-like receptors (TLR) induces selective
cytokine profiles capable of differentially modulating immune cell
subsets. Herewe have tested the impact of a selective small molecule
agonist of TLR8 (GS-9688), currently in Phase 2 trials for the
treatment of chronic HBV infection (CHB), on these three different
regulatory populations and on HBV-specific CD8 + T cells in vitro.
Method: PBMC obtained from a cohort of CHB patients were treated
with 1-500 nM GS-9688 for 2-7 days. Cytokine responses were
measured by luminex assay. Sixteen-colour flowcytometry was used
to analyse changes in the frequency and phenotype of gMDSC
(CD11bhighCD33+HLADR-CD14-CD15+, n = 14 CHB patients), Tregs
(CD4+CD25hiCD127loFoxp3+, n = 8 CHB patients), NK cells (CD3-
CD56+, n = 20 CHB patients) and HBV-specific CD8+ T cells (binding a
panel of HLA-A2/peptide dextramers, n = 12 CHB patients).
Results: In line with previous studies, GS-9688 induced cytokines in
PBMC cultures (e.g. TNF-α, IFN-γ, IL-12p70 and IL-18) with the
potential to modify regulatory cell subsets. Consistent with this
cytokine profile, GS-9688 treatment induced gMDSC to switch to a
more mature and less suppressive phenotype, resulting in a > 50%
reduction in the frequency of this regulatory cell type (p < 0.001).
Similarly, GS-9688 treatment induced a dose-dependent reduction in
the frequency of conventional Tregs (p < 0.05). In contrast, GS-9688
triggered dose-dependent activation of CD56bright and CD56dim NK
cells, and a rapid upregulation of their expression of the death ligand
TRAIL (p < 0.05). Despite this, HBV-specific CD8+ T cell frequencies
remained stable, suggesting they were protected from NK cell TRAILmediated
deletion in the presence of GS-9688.
Conclusion: Overall, these in vitro data suggest that GS-9688 has the
potential to reduce the suppressive activity of regulatory populations
in the liver that collectively limit the antiviral response of HBVspecific
T cells. Further studies will explore how HBV-specific T cells
are protected from deletion by the GS-9688-driven expansion of
TRAIL+ NK cells and whether these changes are recapitulated using
intrahepatic lymphocytes.

StephenW

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FRI-132
体外调节TLR8激动剂GS-9688多重
慢性乙型肝炎患者的调节细胞类型
Oliver E Amin1，Emily Colbeck1，Stephane Daffis2，
Divya Pattabiraman2，Colette Sitali3，William Rosenberg4，
Simon Fletcher2，Mala Maini1，Laura J Pallett1。 1UCL，感染和
免疫，伦敦，英国;福斯特城2吉利德科学
美国; 3UCL，感染，免疫和移植，伦敦，
英国; 4UCL，感染，免疫和移植，
伦敦，英国
电子邮件：[email protected]
背景和目的：表征HBV特异性T细胞反应
通过功能衰竭和过早删除。
针对这种抗病毒T细胞反应的免疫抑制细胞类型
包括粒细胞源性抑制细胞（gMDSC），
CD4 +调节性T细胞（Tregs）和调节性TRAIL + NK细胞。
通过不同的Toll样受体（TLR）发出信号诱导选择性
能够差异调节免疫细胞的细胞因子谱
子集。在这里我们测试了选择性小分子的影响
TLR8的激动剂（GS-9688），目前正在进行2期临床试验
治疗慢性HBV感染（CHB），就这三种不同
调节群体和体外HBV特异性CD8 + T细胞。
方法：治疗从一组CHB患者获得的PBMC
用1-500nM GS-9688处理2-7天。细胞因子反应是
通过luminex测定法测量。使用16色流式细胞术
分析gMDSC的频率和表型的变化
（CD11bhighCD33 + HLADR-CD14-CD15 +，n = 14 CHB患者），Tregs
（CD4 + CD25hiCD127loFoxp3 +，n = 8例CHB患者），NK细胞（CD3-
CD56 +，n = 20个CHB患者）和HBV特异性CD8 + T细胞（结合a
一组HLA-A2 /肽dextramers，n = 12个CHB患者）。
结果：与先前的研究一致，GS-9688诱导细胞因子
PBMC培养物（如TNF-α，IFN-γ，IL-12p70和IL-18）具有
修改监管细胞亚群的潜力。与此一致
细胞因子谱，GS-9688处理诱导gMDSC转为a
更成熟和更少抑制表型，导致> 50％
减少这种调节细胞类型的频率（p <0.001）。
类似地，GS-9688治疗诱导剂量依赖性减少
常规Tregs的频率（p <0.05）。相比之下，GS-9688
引发CD56bright和CD56dim NK的剂量依赖性激活
细胞，以及它们死亡配体表达的快速上调
TRAIL（p <0.05）。尽管如此，HBV特异性CD8 + T细胞频率
保持稳定，表明它们受到保护免受NK细胞TRAIL介导
在GS-9688存在下删除。
结论：总的来说，这些体外数据表明GS-9688具有
有可能降低监管人群的抑制活动
在肝脏，共同限制HBV特异性的抗病毒反应
T细胞。进一步的研究将探讨HBV特异性T细胞的情况
受到GS-9688驱动的扩展保护不被删除
TRAIL + NK细胞以及是否使用这些变化进行概括
肝内淋巴细胞。

StephenW

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不要太有希望, GS-9688(TLR8)或GS-9620(TLR7).

左罗

谢谢了！今后还会继续关注 ”吉利德HBV治愈计划“ 的整体部分，并希望了解更多相关信息。

泡泡苹苹

newchinabok

左罗 发表于 2019-3-29 14:29
谢谢了！今后还会继续关注 ”吉利德HBV治愈计划“ 的整体部分，并希望了解更多相关信息。 ...

吉利德最新研发的口服PD-L1今年将进入临床试验，这是用来治愈乙肝和治疗肿瘤非常重要的一环。