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Arrowhead's ARC-520 Leads to Consistent Immune Reactivation in Chimpanzees with Chronic Hepatitis B Infection
PASADENA, Calif.--(BUSINESS WIRE)-- Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, presented data at HEP DART 2015 showing that in chronically HBV-infected chimpanzees treated with ARC-520 in combination with nucleoside analogs, 7 of 9 (78%) exhibited signs of immune reactivation, which is likely a necessary step for achieving a functional cure of chronic HBV. One chimpanzee also exhibited an on-treatment therapeutic ALT flare and sustained virologic improvements 31 weeks off all treatment. ARC-520 is currently being studied in multiple Phase 2b global clinical trials.
"The hepatitis B virus causes infected cells to produce several proteins that suppress the host immune system, and, therefore, enable chronic viral infection by removing immune control. Our goal with ARC-520 is to reduce expression of those proteins and thereby enable reconstitution of the immune system. We now have shown that ARC-520 can do that, and not just in 1 or 2 infected chimps, but in 7 of the 9 chimps we treated, and this is a big deal," said Christopher Anzalone, Ph.D., Arrowhead president and CEO. "ARC-520 deeply reduces HBV proteins and we believe the elevations in T-cell responsive serum cytokines observed in this study represent a strong proof of principle that ARC-520 can begin the process of immune reconstitution that many believe can lead to functional cure. These data are particularly encouraging when combined with our recent human data. Our Phase 2a clinical trial, which we reported at AASLD last month, showed that ARC-520 can dramatically reduce s-antigen, e-antigen, and core-related antigen in humans after a single dose. During the ongoing Phase 2b clinical trials, we are studying ARC-520 as monotherapy as well as in combination with other agents with the goal of identifying a regimen that leads to consistent functional cures."
Christine Wooddell, Ph.D., director of liver targeting for Arrowhead, presented poster number 152 titled, "Sustained reduction of HBV DNA, RNA and proteins, and HBeAg seroconversion in a chronically HBV-infected chimpanzee treated with nucleoside analog/ARC-520 combination therapy."
In this presentation, Dr. Wooddell and co-authors show that 7 of 9 chimps, HBeAg positive and negative, exhibited indications of an immune response during ARC-520 treatment, as evidenced by elevations in T-cell responsive serum cytokines. Chimp Manetta exhibited deep decreases in HBV DNA, RNA and viral proteins during ARC-520/NUC treatment. The sustained induction of CXCL9 in Manetta was associated with a therapeutic ALT flare (218 U/L) followed by HBeAg seroconversion. Sustained virologic improvements were still observed 31 weeks after all treatment was removed. At this final time point, serum HBV DNA was 5 log10 lower, HBsAg was 1.7 log10 lower, and liver HBV RNA was 99% lower than pre-study.
HBV suppresses the immune system to allow chronic HBV infection. Interferon gamma (IFN-γ) is a key antiviral cytokine critical to innate and adaptive immune responses. IFN-γ produced by natural killer cells and natural killer T cells induces the chemokines CXCL9 and CXCL10 to mediate a T-cell response. An elevation of CXCL9 in the chimps studied is a promising sign of immune system reactivation.
8 out of 9 chimps exhibited episodes of serum cytokine CXCL9 elevation. For 7 chimps these occurred during ARC-520 treatment and in one chimp (Tattoo) these coincided with seroclearance of HBeAg that began prior to study.
To reduce viral replication prior to treatment with ARC-520, chimps were treated for 8-24 weeks with entecavir or in one case (chimp Michele) with entecavir and tenofovir. Following the NUC lead-in period, animals were administered ARC-520 intravenously at 4-week intervals (q4w). Dose levels were 2, 3, or 4 mg/kg ARC-520, along with maintenance doses of entecavir or entecavir and tenofovir. All 9 chimpanzees responded to ARC-520 with HBsAg reductions of 0.5 - 2.7 log10 at nadir, the greater reductions being in HBeAg positive chimps. HBsAg levels in all chimps continued to decrease with repeat dosing. Chimps were monitored for up to 31 weeks off all treatment.
Copies of presentation materials can be accessed by visiting the Events section of the company's website at http://ir.arrowheadresearch.com/events.cfm.
About ARC-520
Arrowhead's RNAi-based candidate ARC-520 is being investigated in the treatment of chronic HBV infection. The small interfering RNAs (siRNAs) in ARC-520 intervene at the mRNA level, upstream of the reverse transcription process where current standard of care nucleotide and nucleoside analogues act. Arrowhead is investigating ARC-520 specifically to determine if it can be used to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without seroconversion. Arrowhead is conducting Phase 2b multiple dose and combination studies in chronic HBV patients. Approximately 350-400 million people worldwide are chronically infected with the hepatitis B virus, which can lead to cirrhosis of the liver and is responsible for 80% of primary liver cancers globally.
About Arrowhead Research Corporation
Arrowhead Research Corporation is a biopharmaceutical company developing targeted RNAi therapeutics. The company is leveraging its proprietary Dynamic Polyconjugate™ delivery platform to develop targeted drugs based on the RNA interference mechanism that efficiently silences disease-causing genes. Arrowhead's pipeline includes ARC-520 and ARC-521 for chronic hepatitis B virus, ARC-AAT for liver disease associated with alpha-1 antitrypsin deficiency, ARC-F12 for hereditary angioedema and thromboembolic diseases, and ARC-HIF2 for renal cell carcinoma.
For more information please visit http://www.arrowheadresearch.com, or follow us on Twitter @ArrowRes. To be added to the Company's email list and receive news directly, please visit
http://ir.arrowheadresearch.com/alerts.cfm.
Safe Harbor Statement under the Private Securities Litigation Reform Act:
This news release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties, including our ability to finance our operations, the future success of our scientific studies, our ability to successfully develop drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, and the enforcement of our intellectual property rights. Arrowhead Research Corporation's most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q discuss some of the important risk factors that may affect our business, results of operations and financial condition. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances.
DYNAMIC POLYCONJUGATES is a trademark of Arrowhead Research Corporation.
Source: Arrowhead Research Corporation
箭头的ARC-520信息一致的免疫重新激活的黑猩猩慢性乙型肝炎病毒感染
加利福尼亚州帕萨迪纳 - （BUSINESS WIRE） - 箭头研究公司（纳斯达克股票代码：ARWR），一家生物制药公司开发有针对性的RNAi疗法，数据呈现在高能物理DART 2015年显示出与ARC-520联合治疗慢性HBV感染的黑猩猩与核苷类似物，9（78％）7表现出免疫激活，这很可能是对实现慢性HBV的官能固化的必要步骤的迹象。一个黑猩猩也显示出对治疗治疗ALT耀斑和持续病毒学改进31周了所有的治疗。 ARC-520目前正在研究中的多个阶段2b全球临床试验。
“乙型肝炎病毒引起感染的细胞，以产生几种蛋白质抑制宿主的免疫系统，并且因此，通过除去免疫控制使慢性病毒感染。我们与ARC-520的目标是减少那些蛋白质的表达，从而使重构免疫系统。现在，我们已经表明，ARC-520能做到这一点，而不是仅仅在1或2感染的黑猩猩，但在7月9日的黑猩猩，我们处理了，这是一个大问题，“克里斯托弗Anzalone，pH值表示。四，箭头总裁兼首席执行官。 “ARC-520深受降低乙肝病毒的蛋白质，我们认为在本研究中观察到的T细胞反应的血清细胞因子的升高代表原则上有力地证明了ARC-520可以开始免疫重建的过程中，许多人认为会导致功能治愈。这些数据尤其令人鼓舞，当我们人类最近的数据结合起来。我们的阶段2a临床试验，这是我们上个月报道AASLD，表明ARC-520可以大大降低表面抗原，e抗原，并在人类中的核心相关抗原单次剂量后期间正在进行的阶段2b临床试验中，我们正在研究的ARC-520作为单一疗法以及与其他药剂与识别的方案，导致一致的官能固化的目标结合“。
恭Wooddell，博士，肝靶向的箭头主任介绍海报编号152题为“在慢性HBV感染的黑猩猩持续减少HBV DNA，RNA和蛋白质，而HBeAg血清转换与核苷类似物/ ARC-520处理组合疗法“。
在这份报告中，Wooddell博士及其合作者显示，7月9日的黑猩猩，HBeAg阳性和阴性，显示出迹象时ARC-520治疗的免疫反应，就证明了T细胞反应细胞因子升高。黑猩猩Manetta期间ARC-520 / NUC治疗表现出乙型肝炎病毒DNA，RNA和病毒蛋白深减小。持续感应CXCL9在Manetta用治疗的ALT耀斑（218 U / L），接着加入血清转换相关联。持续的病毒学改善仍可观察到31周被删除的所有治疗。在这最后的时间点，血清HBV DNA是5日志10时，乙肝表面抗原为1.7日志10下，与肝乙肝病毒RNA比前研究降低99％。
HBV抑制免疫系统，以允许慢性HBV感染。干扰素γ（IFN-γ）是一个关键的抗病毒细胞因子的先天和适应性免疫反应的关键。通过自然杀伤细胞和天然杀伤T细胞产生的IFN-γ诱导的趋化因子CXCL9和CXCL10介导的T细胞应答。 CXCL9在研究黑猩猩的海拔是免疫系统激活一个令人鼓舞的迹象。
8出9只黑猩猩表现出血清细胞因子CXCL9升高发作。对于7黑猩猩在ARC-520处理这些发生在一个黑猩猩（纹身）这些正好与e抗原转阴的研究之前开始。
为了减少病毒复制治疗前与ARC-520，黑猩猩进行了8-24周的治疗恩替卡韦或在一种情况下（黑猩猩米歇尔），恩替卡韦和替诺福韦。继NUC导入期，动物施用的ARC-520静脉内，在4周的时间间隔（q4w）。剂量水平2，3，或4毫克/公斤的ARC-520，以及维持剂量恩替卡韦或恩替卡韦和替诺福韦。所有9黑猩猩回应ARC-520与乙肝表面抗原削减0.5 - 2.7日志10在最低点，更大的降低HBeAg阳性黑猩猩之中。 HBsAg水平在所有黑猩猩持续减少与重复给药。黑猩猩进行了监测最多31周的时间，所有治疗。
介绍材料的副本可通过访问该公司网站的事件部分在http://ir.arrowheadresearch.com/events.cfm访问。
关于ARC-520
箭头的基于RNAi的候选ARC-520正在调查慢性HBV感染的治疗。小干扰RNA（siRNA）的ARC-520介入在mRNA水平，反转录过程，其中护理核苷酸的目前标准和核苷类似物起作用的上游。箭头正在调查的ARC-520特异性以确定它是否可用于实现一个功能治愈，这是其特征在于，乙肝表面抗原阴性血清有或没有血清转化的免疫clearant状态。箭头正在进行阶段2b在慢性乙型肝炎患者多剂量和联合研究。全世界大约350-400百万人慢性感染了乙肝病毒，它可导致肝硬化并负责全球80％的原发性肝癌。
关于箭头研究公司
箭头研究公司是一家生物制药公司，开发有针对性的RNAi疗法。该公司利用其专有的动态Polyconjugate™传输平台开发基于能够有效地沉默致病基因RNA干扰机制的靶向药物。箭头的管道包括ARC-520和ARC-521为慢性乙型肝炎病毒，ARC-AAT用于与α-1抗胰蛋白酶缺乏，ARC-F12为遗传性血管水肿和血栓栓塞性疾病，和ARC-HIF2为肾细胞癌相关的肝脏疾病。
欲了解更多信息，请访问http://www.arrowheadresearch.com，或关注我们的微博@ArrowRes。要添加到公司的电子邮件列表，并直接接收新闻，请访问：
http://ir.arrowheadresearch.com/alerts.cfm。
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本新闻稿中包含的1995年。这些声明的私人证券诉讼改革法案中有关“安全港”条文所界定的前瞻性声明是基于我们目前的预期，仅截至本新闻稿发布日的发言。公司的实际业绩可能会与不利所表达的任何前瞻性陈述的各种因素和不确定性，包括我们资助我们的业务，我们的能力，成功开发候选药物的能力，我们的科学研究的未来的成功结果，启动和完成临床试验，在我国市场的快速技术变革的时机，以及我们的知识产权执法。的Form 10-Q表格10-K和其后的季度报表箭头研究公司的最新年度报告讨论了一些可能会影响我们的业务，经营及财务状况造成的重要危险因素。我们不承担更新或修改前瞻性声明以反映新的事件或情况。
动态POLYCONJUGATES是箭头研究公司的商标。
资料来源：箭头研究公司
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发表于 2015-12-8 10:02
