AASLD 2017：免疫调节剂Inarigivir看起来有希望乙型肝炎

StephenW

AASLD 2017: Immune Modulator Inarigivir Looks Promising for Hepatitis B

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    Category: Experimental HBV Drugs   
    Published on Wednesday, 13 December 2017 00:00
    Written by Liz Highleyman

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Inarigivir, or SB 9200, an immune-modulating drug that has a dual mechanism of action against hepatitis B virus (HBV), reduced levels of HBV DNA, RNA, and antigens, and potency was enhanced when followed by tenofovir, according to early results from the ACHIEVE trial presented at the recent 2017 AASLD Liver Meeting in Washington, DC.

Nucleoside/nucleotide antivirals like tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy), and entecavir (Baraclude) can suppress HBV replication over the long term during therapy. But they usually do not lead to a cure -- as indicated by loss of hepatitis B surface antigen (HBsAg) and development of anti-HBs antibodies -- and researchers are working on several therapies they hope will offer better options.

Inarigivir soproxil, being developed by Spring Bank Pharmaceuticals,is an oral immune modulator that activates RIG-I (retinoic acid inducible gene I), a pattern recognition receptor that plays a role in detecting viruses like HBV and initiating immune responses against them. Inarigivir fights HBV both by interfering with viral replication and by stimulating production of interferons, which trigger antiviral immune responses. In earlier trials it also showed modest activity against hepatitis C virus (HCV).

Man-Fung Yuen of the University of Hong Kong reported results from the first cohort in Part A of the Phase 2 ACHIEVE trial, which is evaluating various doses of inarigivir followed by tenofovir DF.

Participants are randomly assigned to receive inarigivir monotherapy at doses of 25, 50, 100, or 200 mg once daily, or else a placebo, for the first 12 weeks. Everyone then switches to 300 mg tenofovir DF monotherapy for the second 12 weeks. Yuen reported findings from the initial cohort, which received the 25 mg dose.

This cohort included 20 patients who were either hepatitis B treatment-naive or had been off therapy for more than 6 months; 60% were men, most were Asian, and the mean age was 41 years. 9 inarigivir recipients were hepatitis B "e" antigen (HBeAg)-positive and 7 were HBeAg-negative They had modestly elevated alanine transaminase (ALT) levels and mild fibrosis. People with advanced fibrosis or cirrhosis, liver cancer, poor kidney function, or coinfection with HCV, hepatitis delta, or HIV were excluded.

Overall, participants taking inarigivir saw only a small decrease in HBV DNA during monotherapy while the placebo group had a small rise, so at week 12 viral load had fallen significantly more in the inarigivir group (mean -0.58 vs +0.33 log). As expected, both groups saw steep viral load drops after switching to tenofovir DF.

However, HBV DNA fell more during inarigivir monotherapy in HBeAg-negative compared with HBeAg-positive patients. In the HBeAg-negative group viral load decreased by a mean -0.86 logat 12 weeks and -3.96 logat 24 weeks. In the HBeAg-positive group the corresponding reductions were -0.37 logand -4.48 log.

Levels of HBV RNA, indicating active viral replication, also fell during treatment, but this was mostly limited to HBeAg-negative people. Among the 7 HBeAg-negative participants, 3 had undetectable HBV RNA at week 12 and 5 did so at week 24.

Three HBeAg-negative patients saw a sustained reduction in HBsAg levels of more than -0.5 log on inarigivir alone at week 12. Six people (3 HBeAg-negative and 3 HBeAg-positive) experienced this much HBsAg decline at week 24 after switching to tenofovir DF. Several HBeAg-positive patients also saw a decline in HBeAg levels, averaging -0.54 log at week 24.

Inarigivir was generally safe and well tolerated, with no serious adverse events or severe laboratory abnormalities reported. The most common adverse events were fatigue, headache, and gastrointestinal symptoms. Three people had their dose reduced due to ALT "flares," or sudden steep increases.

The better performance of inarigivir in the HBeAg-negative group suggests that this low dose works better in people with lower baseline viral load, the researchers suggested.

In a related poster on the mechanism of action of inarigivir, investigators concluded that the 25 mg dose resulted in significant antiviral effects on HBV replication, with the drug appearing to inhibit HBV directly at the level of RNA packaging (encapsidation) and copying (reverse transcription). They added that the 25 mg dose did not activate innate or adaptive immune responses in the prior HCV studies, but doses of 200 mg or higher did so.

In a November press release, Spring Hill announced initial results from the 50 mg hepatitis B cohort. This analysis included 10HBeAg-positive, 4 HBeAg-negative, and 4 placebo patients. Inarigivir at this dose was also well tolerated with no serious adverse events.

HBV DNA fell by mean of -1.05 log in the HBeAg-negative patients and -0.61 log in the HBeAg-positive group. HBV RNA also fell more in the HBeAg-negative group, all of whom became undetectable at the end of inarigivir monotherapy. These declines were about double those seen in the 25 mg cohort. One HBeAg-positive patient had a greater than 0.5 log reduction in HBsAg, but the 4 HBeAg-negative participants saw no major reduction in HBsAg.

The 100 mg cohort is now enrolling and results from the higher dose cohorts are forthcoming. Researchers plan to study initial combination therapy using both inarigivir and tenofovir alafenamide, Gilead Science's new, better tolerated version of the drug.

"The antiviral dose response in both HBV DNA and HBV RNA at a dose not yet associated with full immune activation is encouraging and supports further development as we move towards combination therapies with inarigivir serving as a potential backbone treatment, with the ultimate goal of achieving elevated functional cure rates for HBV patients," said Spring Hill chief medical officer Nezam Afdhal.

12/13/17

Sources

MF Yuen, C Coffin, M Elkhashab B et al. SB 9200 an oral selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients: Results from Cohort 1 of the ACHIEVE trial. AASLD: The Liver Meeting. Washington, DC, October 20-24, 2017. Abstract 39.

S Locarnini, D Wong, K Jackson et al. Novel anti-viral activity of SB 9200, a RIGI agonist; results from Cohort 1 of the ACHIEVE trial. AASLD: The Liver Meeting. Washington, DC, October 20-24, 2017. Abstract 25-LB

StephenW

AASLD 2017：免疫调节剂Inarigivir看起来有希望乙型肝炎

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细节
    类别：实验性HBV药物
    2017年12月13日星期三00:00发布
    由Liz Highleyman撰写

ALT

Inarigivir或SB 9200是一种对乙型肝炎病毒（HBV）具有双重作用机制的免疫调节药物，降低了HBV DNA，RNA和抗原的水平，根据早期的结果，替诺福韦的效力增强来自华盛顿特区最近举行的2017年AASLD肝脏会议上提交的ACHIEVE试验。

核苷/核苷酸类抗病毒药物如替诺福韦二吡呋酯富马酸酯（Viread），替诺福韦艾拉酚胺（Vemlidy）和恩替卡韦（Baraclude）可长期抑制HBV复制。但是他们通常不能治愈 - 乙肝表面抗原（HBsAg）的丧失和抗-HBs抗体的产生 - 研究人员正在研究几种治疗方法，希望能提供更好的治疗选择。

由Spring Bank Pharmaceuticals开发的Inarigivir soproxil是一种口服免疫调节剂，能够激活RIG-I（视黄酸诱导型基因I），这是一种模式识别受体，可用于检测HBV等病毒并启动针对它们的免疫应答。 Inarigivir通过干扰病毒复制和刺激干扰素的产生来抵抗HBV，从而引发抗病毒免疫反应。在早期的试验中，它也显示出对丙型肝炎病毒（HCV）的适度活性。

香港大学的Man-Fung Yuen报告了第二阶段ACHIEVE试验A部分的第一个队列的结果，该阶段正在评估不同剂量的inarigivir，然后是替诺福韦DF。

参与者被随机分配接受inarigivir单药治疗，剂量为25,50,100或200 mg，每天一次，或安慰剂，前12周。然后每个人在第二个12周内转用300mg替诺福韦DF单药治疗。 Yuen报告了来自最初队列的研究结果，其中接受了25mg剂量。

该队列包括20名乙型肝炎治疗无效或已经停药超过6个月的患者; 60％为男性，大部分为亚洲人，平均年龄为41岁。接受抗病毒治疗的患者有乙型肝炎e抗原（HBeAg）阳性，7人HBeAg阴性。丙氨酸转氨酶（ALT）水平轻度升高，轻度纤维化。患有晚期肝纤维化或肝硬化，肝癌，肾功能不良，或合并感染HCV，肝炎三角洲或HIV的患者被排除在外。

总体而言，服用inarigivir的受试者在单药治疗期间仅观察到HBV DNA的轻微下降，而安慰剂组有小幅上升，因此在第12周，inarigivir组的病毒载量显着下降（平均值-0.58 vs +0.33 log）。正如所料，两组病人在转用替诺福韦DF后都出现了急剧的病毒载量下降。

然而，与HBeAg阳性患者相比，单用HBeAg阴性的单药治疗期间HBV DNA下降更多。在HBeAg阴性组中，病毒载量下降了12周的平均值-0.86logat和24周的-3.96logat。在HBeAg阳性组中，相应的降低分别为-0.37对数和-4.48对数。

指示活跃的病毒复制的HBV RNA水平也在治疗期间下降，但是这主要限于HBeAg阴性人群。在7名HBeAg阴性参与者中，3名在第12周检测不到HBV RNA，5名在第24周检测到。

三名HBeAg阴性患者HBsAg水平持续下降超过-0.5对数inarigivir在第12周。6人（3 HBeAg阴性和3 HBeAg阳性）经历了这么多的乙肝表面抗原下降转换为替诺福韦后24周DF。一些HBeAg阳性患者的HBeAg水平也有所下降，第24周平均为-0.54 log。

Inarigivir通常安全且耐受性良好，没有严重的不良事件或严重的实验室异常报告。最常见的不良事件是疲劳，头痛和胃肠道症状。由于ALT“耀斑”或者急剧增加，三个人的剂量减少了。

研究人员指出，HBeAg阴性组患者的更好的宫内避孕药表现表明，这种低剂量在基线病毒载量较低的人群中效果更好。

在一个关于inarigivir的作用机制的相关海报中，研究人员得出结论，25mg剂量导致对HBV复制的显着的抗病毒作用，该药似乎直接在RNA包装（包壳）和拷贝（逆转录）。他们补充说，25毫克的剂量在先前的HCV研究中没有激活固有的或适应性的免疫反应，但是200毫克或更高的剂量是这样做的。

在11月份的新闻稿中，Spring Hill宣布了50毫克乙型肝炎队列的初步结果。该分析包括10HBeAg阳性，4个HBeAg阴性和4个安慰剂患者。此剂量的Inarigivir耐受性良好，无严重不良事件。
HBeAg阴性患者HBV DNA平均下降-1.05 log，HBeAg阳性组平均下降-0.61 log。 HBeAg阴性组的HBV RNA也下降更多，所有患者在单用Inarigivir治疗结束后都无法检出。这些下降大约是25毫克队列中的两倍。一名HBeAg阳性患者的HBsAg下降幅度大于0.5个百分点，但4名HBeAg阴性患者的HBsAg未见明显下降。

现在正在招募100毫克的队列，而高剂量队列的结果即将到来。研究人员计划研究最初的联合治疗，使用吉那德科学公司的新型耐受性较好的新药，即inarigivir和替诺福韦艾拉酚胺。

“在与完全免疫激活相关的剂量中，HBV DNA和HBV RNA中的抗病毒剂量反应是令人鼓舞的并且支持进一步的发展，因为我们正朝着与inarigivir的组合疗法作为潜在的骨干治疗，最终目标是实现升高Spring Hill首席医疗官Nezam Afdhal说，

17年12月13日

来源

MF Yuen，C Coffin，M Elkhashab B et al。 SB 9200口服选择性免疫调节剂在未治疗的非肝硬化HBV患者中是安全和有效的：来自ACHIEVE试验的队列1的结果。 AASLD：肝脏会议。华盛顿特区，2017年10月20 - 24日。摘要39。

S Locarnini，D Wong，K Jackson et al。 RIGI激动剂SB 9200的新型抗病毒活性;来自ACHIEVE试验的队列1的结果。 AASLD：肝脏会议。华盛顿特区，2017年10月20 - 24日。摘要25-LB

windu

2018年见分晓

zgct

意思是讲了什么好消息？

neilhbver

免疫调节为何要单药治疗呢？岂不是扬短避长？