Arrowhead Presents New Clinical Data Demonstrating a Sustained Host Response in Hepatitis B Patients Following RNAi Therapy
Arrow Introduces New Clinical Data Shows Sustained Host Response to Hepatitis B Patients After RNAi Therapy
- a decrease of 5.0 log10 in HBsAg was observed; data at HEP DART 2017 show -
Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) provided new data on the company's Phase II clinical study from patients receiving multiple doses of ARC-520, a previous generation based on Clinical candidates for RNAi fight against chronic hepatitis B infection (HBV). The maximum baseline reduction of 5.0 log10 of HBV surface antigen (HBsAg) at 7 months after the last dose of ARC-520 was applied, with the lowest absolute level just above the lower limit of quantitation of HBsAg. These data were presented at the 22nd Biennial HEP DART meeting held December 3-7 in Kona, Hawaii, suggesting that multiple doses of RNAi-based therapies may lead to sustained host response after treatment is over.
Bruce D. Given, Ph.D., COO and Head of Research and Development at Arrowhead Pharmaceuticals, said: "We believe that functional therapy to achieve chronic hepatitis B infection will require sustained host response that may be immune-mediated, In clinical studies, a persistent decrease in the number of key HBV markers seen in multiple patients over a long period of time following the discontinuation of ARC-520 therapy represents the first clinical evidence that RNAi-based approaches may lead to favorable sustained host response consistently It is possible to achieve this result with the ARC-520, which is not designed to incorporate anti-HBV antigens produced by DNA integration, giving us the confidence that our new RNAi-based compound ARO -HBV is designed to silence the production of all HBV gene products, including transcriptional products derived from integrated DNA, and offers a good opportunity for therapies for therapies aimed at treating chronic HBV combinations.
In an oral report entitled "Reviewing Next-Generation Next Gene RNAi Design for HBV," Dr. Given first found two (66.7%) HBeAg positive patients and five (40%) HBeAg positive patients in two Negative patients achieved a sustained response to host therapy with RNAi-based therapy. It is characterized by the continuous reduction of various HBV markers including HBsAg and consistent with the increased circulation of liver enzyme alanine aminotransferase (ALT), indicating a host response. The latest figures from Heparc-2001 show that the company was more than seven months after the last dose of ARC-520 after the second phase of the ARC-520 open-label study and the entecavir combination of eight patients, the last time Points are currently available.
Of the 4 patients that appeared to have a sustained host response, a reduction in HBsAg was observed of 5.0, 3.1, 2.4 and 0.6 log 10 relative to baseline. In addition, these patients achieved absolute levels of HBsAg of 58, 2.6, 0.36 and 0.051 IU / ml. The lower limit of quantitation for HBsAg is 0.05 IU / ml, below which serum clearance will be considered. These patients also reduce HBV DNA below quantitative levels and have a profound reduction in core-associated antigens (HBcrAg) and HBeAg, many of which are at or below their respective lower limit of quantitation.
Given also presented some preclinical data for ARO-HBV, ARO-HBV is a new treatment that utilizes the company's next generation of chronic HBV patients targeting the RNAi molecule (TRiM ™) platform. Notably, 3 doses of ARO-HBV in wild-type pHBV mice resulted in a 3.44log10 reduction in HBV DNA, with both HBsAg and HBeAg falling below the lower limit of quantitation (greater than 3.0 log10 and greater than 2.2 log10, respectively).
In addition, the arrow creates a mutant pHBV mouse model that eliminates the HBx trigger site and mimics HBV patients with high levels of HBV DNA integrated with cccDNA. In this model, a single dose of ARO-HBV resulted in a 2.95 log10 reduction in HBsAg. The effect lasted for a long time and a reduction in HBsAg of about 2.0 log10 was still observed at 8 weeks after dosing.
ARO-HBV is designed to silence the production of all HBV gene products, including transcripts derived from integrated DNA, with the goal of reaching the level at which the patient's immune system can be rebuilt, resulting in a sustained host response and ultimately functional cure. Arrow Company knowledge gained from various clinical studies of the previous compounds ARC-520 and ARC-521, as well as extensive non-clinical studies done in a variety of species, including chronically chimpanzees, has led to the rapid development of ARO-HBV . The results of ARC-520 do not necessarily predict the outcome of ARO-HBV.
GLP-toxicology studies are being conducted and Arrowhead is manufacturing the drug supply necessary to begin clinical studies of ARO-HBV. The company anticipates filing a Clinical Trial Application by the second quarter of 2018.
Slides from Dr. Given's presentation may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.
About Arrowhead Pharmaceuticals
Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead's RNAi-based therapeutics leverage this natural pathway of gene silencing.
For more information, please visit www.arrowheadpharma.com, or follow us on Twitter @ArrowheadPharma. To be added to the Company's email list and receive news directly, please visit http://ir.arrowheadpharma.com/alerts.cfm. 作者: StephenW 时间: 2017-12-6 20:19
Arrowhead制药公司首席运营官兼研发主管Bruce D. Given博士表示：“我们相信，实现慢性乙型肝炎感染的功能性治疗需要持续的免疫介导的宿主反应。在临床研究中，在停止ARC-520治疗后长时间内在多个患者中观察到的关键HBV标志物数量持续下降，这代表了第一个临床证据，即基于RNAi的方法可以持续地导致有利的持续宿主反应。有可能为了达到这个结果，ARC-520不是用来整合由DNA整合产生的抗HBV抗原，使我们相信我们新的基于RNAi的化合物ARO-HBV被设计用于沉默所有HBV基因产物的产生包括来源于整合DNA的转录产物，并且为治疗慢性HBV组合治疗提供了良好的机会。