看nvr3-778研发思路

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https://noviratherapeutics.com/t ... isting-hbv-therapy/

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Limitations of Existing HBV Therapy
Current treatment for CHB infection is limited to two classes of prescribed therapies: interferon alpha and its pegylated form (PEG-IFN), and nucleos(t)ides analogs (NAs).

Interferon alpha (IFN-α): Interferons are naturally occurring cytokines with immunomodulatory, anti-proliferative and antiviral activities. IFN-α and its pegylated form (PEG-IFN-α) are administered as injectables and are approved for treatment of CHB in most countries. PEG-IFN-α is the most prescribed IFN in CHB because it has longer half-life that requires once-weekly administration compared to daily injections with IFN-α. Durable response rates (functional cure) with PEG-IFNα are higher in patients with HBV genotypes A and C infections (up to 14% for genotype A) and lower with genotypes B and D infections (up to 2% for genotype D). Although IFN-α and PEG-IFNα provide higher sustained virological suppression (functional cure) rates than NAs, they are poorly tolerated by most patients and overall suppression efficacy is low. Recent evidence suggests that HBV infected cells are resistant to Interferon antiviral activity which may explain the poor viral suppression efficacy and low functional cure rates associated PEG-IFN-α in CHB.

Nucleos(t)ide analogs (NAs): NAs are antiviral agents that inhibit the activity of the viral polymerase and thus inhibit the formation of infectious virus progeny. Importantly, NAs do not inhibit the host gene expression machinery that is used in the production of virus proteins; consequently, NAs prescribed for CHB do not block expression of HBV genes from cccDNA or production of non-infectious sub-viral particles. The most potent prescribed NAs for CHB, including Entecavir and Tenofovir, can effectively suppress HBV replication in some patients. However, HBV replication is suppressed to below the limit of HBV DNA detection in only two-thirds of patients after 1 year of treatment. Furthermore, greater than 50% of patients having detectable HBV DNA levels after 1 year still have detectable HBV DNA after 3 years of treatment with Entecavir. Sustained Virological Response (SVR), or functional cure, is rare with use of NA monotherapy, ranging from 0-3% after 1 year of treatment and less than 10 % after longer term treatment. A simple hypothesis to explain the poor functional cure rates after long term NA treatment is that the infectious virus continues to be produced at levels that are sufficient for continuous intra-hepatic viral infection, thus enabling the maintenance of a stable pool of infected hepatocytes even in patients with HBV DNA levels below the limits of detection. This hypothesis is illustrated in Figure 2.

Click to enlarge.

Figure 2. Incomplete suppression of HBV replication can explain poor functional cure rates with current HBV drugs.
Poor functional cure rates after long-term NA treatment can be explained by incomplete suppression of HBV replication, whereby infectious virus is produced at levels sufficient for continual intra-hepatic infection even when HBV DNA levels are below the limit of detection. Figure 2 illustrates this hypothesis and compares HBV DNA and HBsAg levels in plasma (bar graph), and infected hepatocyte number (liver diagram) in CHB patients that are either untreated (left panel), treated with current standard of care (center panel) or treated with a drug combination that provides full suppression of HBV replication (right panel). In patients with CHB, HBV DNA levels are used as a surrogate quantitative measure of circulating virus (HBV replication) and HBsAg levels are used as a surrogate proportionate measure of copies of cccDNA and infected hepatocytes.

Untreated. CHB patients have a stable pool of infected hepatocytes that produce high levels of both infectious virus and sub-viral particles that can be quantified in plasma by measuring HBV DNA and HBsAg levels.
Current standard of care. Current prescribed HBV therapy does not fully suppress HBV replication, even in patients with HBV DNA levels below the limit of detection. The limit of HBV DNA detection is 20 IU/ml or 116 copies per mL; up to 600,000 copies of virus are still circulating in patients that have achieved undetectable HBV DNA status. This level of residual viremia is sufficient to maintain continual new infection of hepatocytes at a rate that is higher than the loss of infected hepatocytes. As such, the cccDNA mini-chromosomes present in this stable pool of infected hepatocytes will continue to produce new virions and sub-viral particles and explains why viral load relapse occurs in CHB patients when NA treatment is stopped.
Standard of care in combination with Core Inhibitor. A drug combination regimen of standard of care and a Core Inhibitor could provide complete suppression of HBV replication. A functional cure of CHB infection will be achieved when virus production is reduced to levels that are lower than those required for intra-hepatic infection and the loss of infected hepatocytes by natural hepatocyte turnover occurs at a rate that exceeds that of new infection of hepatocytes. Core Inhibitors such as NVR 3-778 alone or in combination with existing HBV therapies (NA or IFN) may elicit complete and sustained suppression of viral replication and thereby lead to improved functional cure rates in patients with CHB.
TECHNOLOGY

Chronic Hepatitis B
HBV Lifecycle
Limitations of Existing HBV Therapy
The Novira Therapeutics

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现有乙肝治疗的局限性
慢性乙型肝炎感染目前的治疗是有限的两类处方治疗：干扰素α和聚乙二醇化形式（PEG-IFN），和核苷类似物（T）IDE（NAS）
α-干扰素（IFN-α）：干扰素是自然发生的细胞因子，具有免疫调节，抗增殖和抗病毒活性。IFN-α及其聚乙二醇化形式（PEG-干扰素-α）是用于注射剂和批准在大多数国家，慢性乙型肝炎治疗。聚乙二醇干扰素-α是最常用的干扰素在慢性乙型肝炎具有更长的半衰期，要求每周一次给药相比，干扰素每日注射α。持久应答率（功能性治愈）与聚乙二醇干扰素α较高患者感染HBV基因型A和C（14%对基因型）和较低的基因型B和D感染（多达2%个D型）。虽然干扰素和长效干扰素αα提供更高的持续病毒学抑制（功能性治愈率比NAS），他们是不好的大多数患者的耐受性和整体的抑制效能低。最近的证据表明，HBV感染的细胞是抗干扰素抗病毒活性，这可以解释可怜的病毒抑制效果和低功能治愈率相关的干扰素
核苷类似物（T）IDE（NAS）：NAS是抗病毒药物抑制病毒聚合酶的活性，从而抑制传染性病毒后代的形成。重要的是，NAS不抑制宿主基因表达的机械，用于病毒蛋白质的合成；因此，NAS用于CHB不阻断HBV基因表达的非感染性亚病毒颗粒cccDNA或生产。最有效的规定NAS CHB，包括恩替卡韦和替诺福韦，能有效地抑制HBV复制的一些患者。然而，只有三分之二的患者在1年的治疗后，乙肝病毒复制被抑制到低于乙肝病毒核酸检测的限制。此外，3年后，恩替卡韦治疗大于患者检测HBV DNA水平在1年后仍有HBV DNA检测的50%。持续病毒学应答（SVR），或功能性治愈，是那单一使用稀有，从0.3%治疗1年后，低于10%的长期治疗后。一个简单的假说来解释长期钠治疗后的可怜的功能治愈率，感染病毒仍然是足够的连续性肝内病毒感染的水平，从而使一个稳定的感染的肝细胞，即使在检测限值低于检测限的感染的肝细胞的维护。这一假设在图2中所示

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图2。不完全抑制HBV复制功能可以解释of穷人经常错过与HBV药物治疗。
可怜的脾脏功能治疗后长期NA治疗can be explained by不完全抑制HBV复制的病毒，传染性is produced at whereby Levels sufficient for连续性肝内感染HBV DNA水平，即使是below the limit of检测。图2对HBV DNA例举这假说和HBsAg水平与血浆（图表），and感染肝细胞数（liver图）在慢性乙型肝炎患者that are either untreated（左面板），处理以及电流标准of Care（中心Panel）或处理与药物组合，提供完整的HBV复制的抑制（right of Panel）。慢性乙型肝炎患者HBV DNA水平，are used as a Surrogate Measure of circulating病毒定量（HBV复制）和HBsAg水平are used as a替代proportionate Measure of拷贝of cccdna and感染肝细胞。
untreated。CHB患者有稳定的感染肝细胞产生高池of that levels of both传染性病毒和亚病毒颗粒that can be量化血浆HBV DNA和乙肝表面抗原水平的测量。
目前的护理标准。目前的规定禁止乙肝HBV therapy does not fully复制，HBV DNA水平甚至患者below the limit of检测。the limit of HBV DNA检测是20 IU /毫升每毫升116份金；up to 600000份病毒are still of that have achieved装上引信的循环在患者HBV DNA的地位。This level of残余病毒血症足够to maintain持续不断的新感染的肝细胞在脾脏of that is higher than the loss of感染肝细胞。是这样的，cccdna迷你染色体present in this稳定池of感染肝细胞产生新的病毒将继续与亚病毒颗粒和病毒负荷形容词说明哪些为什么CHB患者发生在当Na treatment is stopped。
标准of Care in combination with core抑制剂。有药物组合制度标准of Care and核心能提供完整的抑制剂抑制HBV复制的。功能康复of CHB病毒感染will be achieved reduced to是当生产水平下than those that are required for肝内肝细胞感染and the loss of infected by自然发生在脾，肝细胞的营业额超过that of New感染的肝细胞。核心抑制剂如专用3 778单独或组合以及现有的疗法，在HBV（Na或IFN）可能持续抑制病毒和引出完整的复制和从而of lead to改进治疗CHB患者脾功能。
科技
慢性乙型肝炎
乙型肝炎病毒的生命周期
现有的乙肝治疗的局限性
the novira疗法

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Novira Therapeutics的思路，核苷药不完全抑制HBV复制，cccdna得到补充。开发核衣壳抑制剂，和核苷药联合治疗最大抑制病毒，由单一核苷抗病毒向多靶点抗病毒发展，abus同样思路。

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nvr3-778能抗病毒有试验数据为证，靶点为核衣壳，应该是真实的

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nvr3-778思路

Untreated. CHB patients have a stable pool of infected hepatocytes that produce high levels of both infectious virus and sub-viral particles that can be quantified in plasma by measuring HBV DNA and HBsAg levels.
Current standard of care. Current prescribed HBV therapy does not fully suppress HBV replication, even in patients with HBV DNA levels below the limit of detection. The limit of HBV DNA detection is 20 IU/ml or 116 copies per mL; up to 600,000 copies of virus are still circulating in patients that have achieved undetectable HBV DNA status. This level of residual viremia is sufficient to maintain continual new infection of hepatocytes at a rate that is higher than the loss of infected hepatocytes. As such, the cccDNA mini-chromosomes present in this stable pool of infected hepatocytes will continue to produce new virions and sub-viral particles and explains why viral load relapse occurs in CHB patients when NA treatment is stopped.
Standard of care in combination with Core Inhibitor. A drug combination regimen of standard of care and a Core Inhibitor could provide complete suppression of HBV replication. A functional cure of CHB infection will be achieved when virus production is reduced to levels that are lower than those required for intra-hepatic infection and the loss of infected hepatocytes by natural hepatocyte turnover occurs at a rate that exceeds that of new infection of hepatocytes. Core Inhibitors such as NVR 3-778 alone or in combination with existing HBV therapies (NA or IFN) may elicit complete and sustained suppression of viral replication and thereby lead to improved functional cure rates in patients with CHB.

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未经处理的。慢性乙型肝炎患者有一个稳定的被感染的肝细胞，产生高水平的病毒库和病毒颗粒可量化的测量血浆中HBV DNA和HBsAg水平。
现行标准。目前规定的乙肝治疗并没有完全抑制乙肝病毒的复制，即使在患者的乙肝病毒核酸水平低于检测限。乙型肝炎病毒DNA检测的极限是20国际单位/毫升或116拷贝每毫升；到600000份病毒仍然在取得检测不到HBV DNA的患者的循环状态。这一水平的残余病毒血症是足以维持肝细胞持续性的新感染率高于感染肝细胞损失。因此，cccDNA微型染色体在这个稳定的受感染的肝细胞会不断产生新的病毒和亚病毒颗粒并对CHB患者停止治疗时，Na发生病毒载量的复发原因。
结合核心抑制剂的护理标准。一种药物组合方案的标准和一个核心抑制剂，可以提供完全抑制乙肝病毒复制。慢性乙型肝炎病毒感染的功能性治愈会实现当病毒产量降低的水平是低于肝内感染的肝细胞的营业额要求自然感染的肝细胞的损失发生在一个超：肝细胞新感染率。核心抑制剂如NVR 3-778单独或结合现有乙肝治疗（Na或IFN）可能引起完全和持续地抑制病毒复制，从而导致功能性治愈率提高慢性乙型肝炎患者

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一切由试验回答。任何人回答都要  呵呵一下

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