免疫调节剂SB 9200临床数据在欧洲协会的2015

StephenW

Spring Bank Pharmaceuticals Presents Preclinical and Clinical Data on Immunomodulatory Agent SB 9200 at the 2015 Annual Meeting of the European Association for the Study of the Liver

    Category: Small Molecules   
    Published on Monday, 27 April 2015 17:22
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Animal Efficacy Studies in Chronically-Infected Woodchucks and Clinical Trial Results in Hepatitis C Patients Provide Support for Targeting RIG-I and NOD2 Sentinel Proteins to Restore Host Antiviral Defense

MILFORD, MA, USA I April 27, 2015 I Spring Bank Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company developing novel therapeutics for the treatment of viral infections, today announced the presentation of scientific data from its Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) programs at The International Liver Congress™ 2015, 50th annual meeting of the European Association for the Study of the Liver (EASL), April 22-26, in Vienna, Austria.

"The data presented at EASL on Saturday, April 25, continue to expand our understanding of the mechanism of action of SB 9200, an oral dinucleotide prodrug derived from our proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology platform," stated Radhakrishnan (Kris) Iyer, Ph.D., Chief Scientific Officer of Spring Bank. "Our studies demonstrate that SB 9200 activates the cell's innate immune response triggering Interferon production which causes the death of the infected cell thereby removing the virus while also providing protection for uninfected cells. Based on the results reported of a preclinical study in chronic hepatitis-carrier woodchucks and a Phase I study in HCV-infected patients, we are excited about the potential of SB 9200 for the treatment of HBV and HCV."

SB 9200 is an oral antiviral agent that uniquely acts by modulating the host immune response to viral infections through activation of host antiviral sensor proteins, RIG-I and NOD2.  RIG-1 and NOD2 are cytosolic viral sensors that are important for the regulation of the innate immune response and activation of intracellular interferon (IFN) signaling pathways in response to viral RNA. Data presented from a Phase I clinical study in HCV-infected patients with SB 9200 demonstrate safety, positive PK/PD characteristics and dose-dependent antiviral activity consistent with host immune modulation within infected cells.  Data presented from a 12-week study in the chronic woodchuck model of HBV infection demonstrate significant reductions in viral loads, surface antigen and cccDNA along with a strong safety profile, suggesting the potential of SB 9200 as a next generation HBV therapy in combination with currently available, direct acting HBV antiviral drugs as well as other agents in development.

"The data presented at EASL continue to build upon a growing body of scientific evidence supporting the development of SB 9200 in the treatment in HBV, HCV and other of viral diseases," said Douglas J. Jensen, President and CEO of Spring Bank. "Collectively, these data are helping to elucidate the underlying mechanisms that are the foundation for our research and development efforts with SB 9200. Based on the body of evidence we have assembled to date, we are  advancing SB 9200 into Phase II clinical trials in patients with HBV this year and evaluating opportunities to partner for Phase II combination studies in HCV."

A summary of the data presented by Spring Bank at the conference is below:

Poster Presentations

Title: Antiviral Efficacy and Induction of Host Immune Responses with SB 9200, an Oral Prodrug of the Dinucleotide SB 9000, in the Woodchuck Model of Chronic Hepatitis B Virus (HBV) Infection
Date and Time: Saturday, April 25, 12:30 pm to 1:00 pm (CEST)
Location: Hall B ePoster Area
Abstract Number: PO636
Session: Viral hepatitis: Hepatitis B & D – c. Clinical (Therapy, new compounds, resistance)

An oral presentation of the poster was made by Dr. Stephan Menne, Research Associate Professor at the Department of Microbiology & Immunology, Georgetown University Medical Center

Summary: The study was a 12-week study in two groups of woodchucks with chronic woodchuck hepatitis virus (WHV) infection (the gold standard for HBV drug development). WHV carrier woodchucks (n=5/group) were treated orally, once daily, with SB 9200 for 12 weeks at doses of 15 or 30 mg/kg. Endpoints included PK, PD, tolerability, and efficacy determined by changes in serum levels of viral DNA, surface antigen (WHsAg), and antibody against WHsAg (anti-WHs). Efficacy in liver was evaluated by changes in levels of viral DNA, RNA, and antigens.

Treatment with SB 9200 at two select dose levels resulted in up to 4.2 and 2.2 log10 reductions in serum WHV DNA or WHsAg loads, respectively, from pretreatment levels. Treatment was also associated with reduced hepatic levels of WHV DNA replicative intermediate (RI) (up to 41%), WHV covalently-closed circular (ccc) DNA (up to 32%), and WHV RNA (up to 50%), lower hepatic expression of WHV core and surface antigens, and reduced liver disease progression. Following cessation of SB 9200 treatment, recrudescence of WHV replication was observed in all woodchucks treated with 15 mg/kg, whereas woodchucks administered 30 mg/kg had delays in the relapse of serum WHV DNA and WHsAg. The development of an anti-WHs antibody response was not observed in any of the woodchucks. Furthermore, the antiviral effects were associated with the dose-dependent induction of type I IFNs (IFN-α and IFN-β), ISGs (OAS-1, CXCL10, and ISG15), and cytokine (IL-6) in blood and liver. Prolonged SB 9200 administration at both dose levels was well tolerated with CBC, hematology and serum biochemistry parameters all appearing normal through the treatment period.

During this study, once-daily oral administration of SB 9200 in woodchucks with chronic WHV infection resulted in marked reductions in serum and hepatic levels of viral DNA, RNA, and antigens that were associated with (or were a result of) the induction of host immune responses. These results suggest that SB 9200 can induce an antiviral immune response during chronic active hepadnaviral infection that has the potential for a functional cure in the treatment of chronic hepatitis B, most likely in combination with approved anti-HBV drugs.

Title: SB 9200, A Novel Immunomodulator for Patients with Viral Hepatitis: Phase 1 MAD Study in
Patients with Hepatitis C Virus (HCV) Infection
Date and Time: Saturday, April 25, 2015, 3:30 pm to 4:00 pm (CEST)
Location: Hall B ePoster Area
Session: Late Breaker

Summary: This was a first in man randomized, placebo-controlled, multiple ascending dose study of SB 9200 in treatment-naïve, HCV-infected adults. Subjects were randomized 6:2 to SB 9200 or placebo for 7 days. Doses evaluated were 200 mg (N=8), 400 mg (N=8), 900 mg (N=8 HCV-1, N=6 HCV-3). The results showed that increases in SB 9200 AUC0-t and Cmax were dose-proportional. The terminal plasma half-life (t1/2) on Days 1 and 7 ranged from 0.684 to 1.07 hours for SB 9200, and was slightly longer for the metabolites: Sp-SB 9000 t1/2 was 4.65-8.90 hours, Rp-SB 9000 t1/2 was 4.31-5.94 hours. SB 9200 Cmax ranged from 0.531 to 6.66 ng/mL at 0.817 and 3.00 hours. Sp-SB 9000 Cmax ranged from 7.13 to 22.0 ng/mL at 1.00 and 12.0 hours. Rp-SB 9000 Cmax ranged from 4.32 to 14.7 ng/mL at 1.00 and 12.0 hours. Peak individual viral load drop improved from 1.5 to 1.9 log10 when the dose increased from 200 to 400 mg. Further dose increases did not result in response increases. Inter-individual variability in antiviral response was observed.

A significant relationship between SB 9200 Cmax and maximum suppression of HCV RNA on Day 7 was observed (p=0.015) after exclusion of two subjects with extreme Cmax values for SB 9200. Seventy-three adverse events (AEs) were reported by 25 subjects (83.3%), mostly mild in severity. No dose limiting toxicities or systemic interferon-like side effects were observed and no serious adverse events were reported. There was no relationship between incidences, severity or relationship of AEs and dose of SB 9200 received or placebo. Results of this study suggest an anti-viral effect similar to interferon but without systemic side effects. Based on the reported HCV data, Spring Bank believes SB9200 merits further evaluation in combination trials with direct-acting antivirals (DAAs).

About SB 9200

SB 9200, derived from Spring Bank's proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology platform, is a novel anti-viral agent that uniquely acts by modulating the host immune response to viral infections through activation of the intracellular sentinel proteins RIG-I and NOD2. SB 9200 is being developed for the treatment of chronic Hepatitis B and C and other viral infections.

About Spring Bank Pharmaceuticals

Spring Bank Pharmaceuticals is a clinical stage biopharmaceutical company. Based on its proprietary SMNH chemistry platform, Spring Bank is developing a pipeline of products representing a new class of pharmaceuticals with a wide range of applications. These rationally designed molecules combine the selectivity of naturally occurring nucleotides with the drug-like properties of classical pharmaceuticals.  The SMNHs have the properties of oral delivery, good pharmacokinetic profile, low side effects and ease of manufacture. The Company's most advanced clinical candidate, SB 9200, is a potential breakthrough drug for the treatment for HBV, HCV and other viral diseases. SB 9200 has a novel mechanism of action that involves modulation of the host immune response in the presence of viral infection.

Note Regarding NIH-Funded Research

Certain studies mentioned in this press release were partly supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI094469 and NIAID contract laboratories. The content of this press release is solely the responsibility of Spring Bank Pharmaceuticals and does not necessarily represent the official views of the National Institutes of Health.

SOURCE: Spring Bank Pharmaceuticals

StephenW

春季银行药品临床前介绍和免疫调节剂SB 9200临床数据在欧洲协会的2015年年度会议对肝脏的研究

    类别：小分子
    周一公布，2015年4月27日17:22
    点击数：75


动物药效学在慢性感染的土拨鼠和丙型肝炎患者的临床试验结果提供支持针对RIG-I和NOD2哨兵蛋白质以恢复主机抗病毒防御

米尔福德，MA，USA我2015年4月27日我行春制药公司，临床阶段的生物技术企业，开发创新疗法对病毒感染的治疗，今天宣布其乙型肝炎病毒（HBV）的科学数据的表示和丙型肝炎病毒（HCV）在国际肝病会议™2015年的方案，欧洲协会为肝脏研究（EASL），4月22日至26日，在奥地利维也纳的第50届年会。

“在EASL上周六，4月25日提供的数据，继续扩大我们的SB 9200的作用机理的理解，一种口服核苷酸药物前体来源于我们专有的小分子核酸杂交（SMNH）技术平台，”拉达克里希南表示（克里斯）艾耶，博士，春季银行的首席科学官。 “我们的研究表明，SB 9200激活细胞的先天免疫应答触发干扰素生产导致受感染的细胞，从而除去病毒，同时还提供保护为未感染的细胞。基于报道的临床前研究中的慢性肝炎载波的结果的死亡旱獭和I期研究中HCV感染患者，我们感到非常兴奋SB 9200对HBV和HCV治疗的潜力。“

SB 9200是一种口服抗病毒剂，它唯一的作用通过调制到病毒感染是通过激活宿主抗病毒传感器蛋白，RIG-I和NOD2的宿主免疫应答。 RIG-1和NOD2是响应于病毒RNA的信号通路胞质病毒传感器是先天免疫反应的细胞内干扰素（IFN）的调节和活化重要。从I期临床研究，9200 SB呈现在HCV感染患者的数据证明其安全性，正面PK / PD特点和剂量依赖性的抗病毒活性与受感染细胞内的宿主免疫调节一致。从12周的研究在HBV感染的慢性土拨鼠模型中表示的数据表明显著减少病毒载量，表面抗原和cccDNA的沿着具有较强的安全性，这表明SB 9200的电位作为下一代的HBV治疗结合目前可直接作用乙肝的抗病毒药物以及其他发展代理商。

“在EASL提供的数据继续建立在科学证据支持SB 9200发展中HBV，HCV和其他病毒疾病的治疗越来越多，”道格拉斯·詹森J.总裁春季银行的首席执行官。 “总的来说，这些数据有助于阐明是基于证据，我们已经在患者组装到今天为止，我们正在推进SB 9200进入II期临床试验的机构，SB 9200我们的研究和开发工作的基础的基本机制今年HBV和评估的机会，合作伙伴，在HCV第二阶段结合研究“。

在会议上提出的春季银行数据的摘要如下：

海报展示

标题：抗病毒疗效和诱导宿主免疫应答与SB 9200，二核苷酸SB 9000的口服药物前体，在慢性乙型肝炎病毒的土拨鼠模型（HBV）感染
日期和时间：周六，4月25日，下午12:30至下午1:00（CEST）
地点：B馆ePoster区
摘要号：PO636
会议：病毒性肝炎：肝炎B＆D - ℃。临床（治疗，新的化合物，电阻）

海报的口头陈述是由史蒂芬博士Menne，研究助理教授，微生物学和免疫学系，乔治敦大学医学中心

摘要：本研究是在两组土拨鼠慢性土拨鼠肝炎病毒（WHV）感染（金标准HBV药物开发）的12周的研究。 WHV载体土拨鼠（N = 5 /组），剂量为15或30mg / kg的口服治疗，每日一次，用SB 9200 12周。终点包括PK和PD，耐受性和功效的变化病毒DNA，表面抗原（WHsAg），和针对WHsAg（抗WHS）抗体的血清水平来确定。效力在肝脏被改变病毒DNA，RNA和抗原的水平进行评价。

治疗用SB 9200在两个选择的剂量水平导致高达4.2和2.2日志10降低血清WHV DNA或WHsAg载荷，分别从治疗前水平。治疗也与WHV DNA复制中间体（RI）的降低的肝水平（高达41％）相关联，WHV共价闭合环状（CCC）的DNA（高达32％），和WHV RNA（高达50％），低级肝表达的WHV芯和表面抗原，并降低肝脏疾病的进展。停止后的SB 9200治疗，WHV复制的复发，观察用15毫克/千克治疗的所有旱獭，而土拨鼠施用30mg / kg的过中的血清WHV DNA和WHsAg复发延迟。抗WHS抗体反应的发展没有任何的土拨鼠的观察。此外，该抗病毒效应用的剂量依赖性诱导型的相关的I型IFN（IFN-α和IFN-β），的ISG（OAS-1，CXCL10，和ISG15）和细胞因子（IL-6）在血液和肝脏。长期SB 9200管理在两个剂量耐受性良好，CBC，血液和血清生化指标经过治疗期间出现的所有正常。

在这项研究中，SB 9200在土拨鼠慢性WHV感染每日一次口服给药导致血清明显减少和病毒DNA，RNA和抗原与被相关联的肝水平（或分别的结果）宿主的诱导免疫应答。这些结果表明，SB 9200可诱导在慢性活性嗜肝病毒感染具有用于治疗慢性乙型肝炎的，最有可能与经批准的抗HBV药物组合的官能固化的潜在的抗病毒免疫应答。

标题：SB 9200，一种新型的免疫调节病毒性肝炎患者：阶段1 MAD研究
患者丙型肝炎病毒（HCV）感染
日期和时间：周六，2015年4月25日，下午3:30至下午4:00（CEST）
地点：B馆ePoster区
会议：晚断路器

摘要：这是第一次在人随机，安慰剂对照，多剂量递增SB 9200在治疗初治，HCV感染的成年人的研究。受试者随机6:2至SB 9200或安慰剂治疗7天。剂量评估为200毫克（N = 8），400毫克（N = 8），900毫克（N = 8的HCV-1，N = 6的HCV-3）。结果表明，增加的SB 9200 AUC 0-T和Cmax分别为与剂量成比例。关于天1端子血浆半衰期（T1 / 2）和7介于0.684至1.07小时的SB 9200，和稍长的代谢物：SP-SB 9000 T1 / 2为4.65-8.90小时，RP-SB 9000 T1 / 2为4.31-5.94小时。 SB 9200的Cmax介于0.531至6.66纳克/毫升在0.817和3.00小时。 SP-SB 9000的Cmax范围为7.13至22.0纳克/毫升，在1.00和12.0小时。 RP-SB 9000的Cmax介于4.32至14.7纳克/毫升为1.00和12.0个小时。从1.5峰个体的病毒载量下降提高到1.9日志10时剂量的增加，从200至400毫克。进一步剂量的增加并不导致响应增加。在抗病毒反应间的个体差异进行了观察。

观察SB 9200 Cmax和第7天HCV RNA最大抑制之间的关系显著（P = 0.015），排除二级学科极端的Cmax值SB 9200七十三不良事件（AE）后，报告了25例（ 83.3％），多为轻度的严重程度。没有剂量限制毒性或全身干扰素样副作用进行观察和无严重不良事件的报告。有发病率之间，严重程度或不良事件的关系和剂量的SB 9200接收或安慰剂没有任何关系。这项研究的结果表明类似于干扰素但没有全身性副作用的抗病毒效果。根据报告的数据HCV，春季银行认为，SB9200的优点与直接作用的抗病毒药物（的DAA）组合试验进一步评估。

关于SB 9200

SB 9200，从春季银行的专有小分子核酸杂交（SMNH）技术平台获得，是一种新型的抗病毒剂，它唯一的作用，通过激活细胞内的前哨蛋白RIG-I和NOD2的调制到病毒感染宿主的免疫反应。 SB 9200正在开发用于治疗慢性乙型和丙型肝炎和其他病毒感染的治疗。

关于春季银行制药

春季银行药业是一家临床阶段的生物制药公司。基于其专有SMNH化学平台上，春季银行正在开发的产品代表一类新的药物的具有广泛应用的管道。这些合理设计分子结合天然存在的核苷酸与经典药物的药物 - 样性质的选择性。所述SMNHs有口服递送，良好的药物动力学曲线，低副作用和易于制造的属性。公司最先进的临床候选，SB 9200，是一个潜在的突破药物用于治疗乙肝，丙肝等病毒性疾病。 SB 9200具有行动涉及在病毒感染的存在的宿主免疫应答的调节的新机制。

注：关于美国国立卫生研究院资助的研究

本新闻稿中提及的某些研究由国家过敏研究所和美国国立卫生研究院在奖号R01AI094469和NIAID的合同实验室传染病被部分支持。本新闻稿中的内容完全是春季银行药品的责任，并不一定代表美国国立卫生研究院的官方意见。

来源：世界银行春季医药

newchinabok

http://adisinsight.springer.com/drugs/800038150

呕卖膏滴

这傻逼SB9200也许不傻，靠谱。配合核苷，表面抗原阻滞剂，效果没的说。单打独斗估计够呛。

齐欢畅2

顶顶。