Feb. 26, 2013, 9:00 a.m. EST
Arrowhead Data Demonstrates RNAi Candidate ARC-520 Silences Hepatitis B Virus
Single injection induces multi-log repression of viral RNA, proteins, and viral DNA
PASADENA, Calif., Feb 26, 2013 (BUSINESS WIRE) -- --Long duration of effect lasting over 30 days
--Regulatory submissions planned for Q2 2013
Arrowhead Research Corporation ARWR +10.05% , a targeted therapeutics company, today announced the publication of data demonstrating multi-log reductions in hepatitis B viral DNA and proteins lasting over 30 days after a single injection in animal models. This suggests that Arrowhead's RNAi-based candidate ARC-520 has the potential to treat chronic hepatitis B virus infection in a fundamentally different manner, with the goal of achieving a functional cure. The paper, entitled "Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection," by Wooddell et al, was published online ahead of print in the journal Molecular Therapy (doi:10.1038/mt.2013.31).
In the publication, Arrowhead scientists describe the use of a novel Dynamic PolyConjugate (DPC) technology to deliver small interfering RNAs (siRNAs) designed against the hepatitis B virus (HBV). This DPC technology incorporates a biodegradable peptide composed of naturally occurring amino acids and a liver-targeted molecule that is co-injected with a cholesterol-conjugated siRNA (chol-siRNA). In proof-of-concept studies, utilization of this DPC to deliver chol-siRNA targeting Factor 7 to non-human primates results in >99% knockdown of target gene expression and >80% knockdown for over one month after a single injection. Multi-dose studies in mice showed no diminution of knockdown activity or toxicity upon repeated injection at therapeutic doses. In transient and transgenic mouse models of HBV infection, a single co-injection of DPC with chol-siRNA targeting HBV sequences resulted in multi-log knockdown of HBV RNA, proteins and viral DNA with long duration of effect.
"This publication is important because it speaks to a specific product and a broader platform," said Dr. Christopher Anzalone, President and Chief Executive Officer. "These data suggest that ARC-520 could be a powerful therapy for chronic HBV infection, a disease with 350 million infected people worldwide and no cure. We are on schedule to file with regulatory authorities next quarter to begin first-in-human studies. During phase 1 we will be able to measure the drug's ability to knock down production of new infectious virus as well as viral proteins, including s-antigen, e-antigen, and the core protein that forms the capsid. The ability to substantially knock down these viral proteins is what is unique about ARC-520 and what many in the field believe will be necessary to revive the host immune response and potentially provide a functional cure, which no other current therapy can reliably do. More broadly, this paper reports on a delivery system capable of extremely efficient gene silencing that can be used for a variety disease targets."
About Arrowhead Research Corporation
Arrowhead Research Corporation is a clinical stage targeted therapeutics company with development programs in oncology, obesity, and chronic hepatitis B virus infection. The company is leveraging its platform technologies to design and develop peptide-drug conjugates (PDCs) that specifically home to cell types of interest while sparing off-target tissues, create targeted drugs based on the gene silencing RNA interference (RNAi) mechanism, and work with partners to create improved versions of traditional small molecule drugs. 作者: StephenW 时间: 2013-2-26 23:20
Arrowhead Receives Notice of Patent Allowance for New Protease Sensitive Masking Chemistry for DPC siRNA Delivery System
PASADENA, Calif. - February 28, 2013 - Arrowhead Research Corporation, a targeted therapeutics company, today announced that it has received a Notice of Allowance from the U.S. Patent and Trademark Office for U.S. Patent Application Number 13/336,028 entitled, "In Vivo Polynucleotide Delivery Conjugates Having Enzyme Sensitive Linkages." This new IP expands the Dynamic Polyconjugate (DPC) platform, broadly protecting Arrowhead's next generation DPC polymer masking technology. Using this masking technology, DPCs can be engineered for long circulation times and improved tissue-targeting characteristics. In addition, hepatocyte-targeted DPCs formulated using this new masking technology have shown to be highly potent upon subcutaneous administration. The company has previously reported target gene knockdown of 99% in monkeys after a single subcutaneous injection of 1 mg/kg, with >80% knockdown for 3 months. Additional data will be reported at upcoming scientific conferences and through peer-reviewed publications.
"This patent protects a new masking chemistry that broadens the reach of DPC-enabled RNAi therapeutics. It enables efficient subcutaneous delivery of siRNA and opens up new therapeutic area targets including oncology," said Dr. Chris Anzalone, President and CEO of Arrowhead. "Arrowhead scientists continue to discover innovative solutions for siRNA delivery and we look forward to providing updates on how these technologies are being deployed to create new drug candidates."
1. Mycrludex - 阻塞乙肝病毒的肝细胞受体 -只能防止肝细胞重新感染. Mycrludex + Entecavir/Tenofovir 可能完全阻止任何重新感染. 过了一段时间，cccDNA的数量可能会减少
2. REP9AC - 抑制乙肝表面抗原释放 - 不会阻止新的病毒颗粒的释放 - 它也需要干扰素或日达仙，以提高乙肝表面抗体的生产.
3. GS9620 - Gilead's TLR7 agonist ("口服干扰素") - 干扰素单治疗很少能够治愈所有的患者.
4. ARC-520 - RNAi - 疗效未知 - 应该能够减少新的病毒和病毒蛋白质生产，包括表面抗原的，e抗原，核心蛋白形成衣壳, 衣壳, 因此重振宿主的免疫反应能力.
5. GI-13020 - 治疗性疫苗 - 疗效未知.
Studyforhope
的评论:
As a stand alone therapy it is likely to fail, like all other therapeutic vaccines so far. In the presence of high or moderate surface antigen concentrations it has almost no chance to ignite an effective TCell response. Furthermore, most long standing cases of chronic hepatitis B have mutations in several epitopes to adapt to the immune pressure. To elicit Tcell responses against epitopes that do not exist anymore is not very effective.
作为一个独立的治疗很可能失败，像所有其他治疗性疫苗到目前为止。在高或中等的表面抗原浓度的存在下，它具有几乎没有机会来点燃一个有效的T细胞反应。此外，慢性乙型肝炎的最久的案件在几个表位的突变，以适应的免疫压力。为了激发T细胞应答的抗原表位不存在了，是不是很有效。
