ALnylam 制药公司:ALN-HDV, ALN-HBV, ALN-PDL

StephenW

Treatment of Chronic Hepatitis Delta Virus (HDV) Infection and ALN-PDL for the Treatment of Chronic Liver Infections

Published: Nov 11, 2014 8:00 a.m. ET
– Company Also Remains on Track to Identify Development Candidate (DC) for ALN-HBV, an RNAi Therapeutic in Development for the Treatment of Hepatitis B Virus (HBV) Infection, by End of Year –

CAMBRIDGE, Mass., Nov 11, 2014 (BUSINESS WIRE) -- Alnylam Pharmaceuticals, Inc. ALNY, -0.72% a leading RNAi therapeutics company, announced today that it has expanded its hepatic infectious disease pipeline. Specifically, in a presentation at the American Association for the Study of Liver Diseases (AASLD) meeting, the company announced it has added ALN-HDV, an RNAi therapeutic targeting the hepatitis delta viral (HDV) genome in development for the treatment of HDV infection. Further, it has added ALN-PDL, an RNAi therapeutic targeting hepatocyte-expressed programmed death ligand 1 (PD-L1) in development for the treatment of chronic liver infections. In addition, Alnylam continues to advance its ALN-HBV program, in development for the treatment of hepatitis B viral (HBV) infection; the company remains on track to select a Development Candidate (DC) by the end of the year and expects to file an investigational new drug (IND) application or IND equivalent around the end of 2015.

“Hepatic infectious diseases, such as HBV and HDV infection, are major global health problems, affecting approximately 400 million and 15 million people worldwide, respectively. Significant unmet need exists for novel therapies to treat these infections, as they are the leading causes of fibrotic liver disease and liver cancer worldwide,” said Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence. “We believe that multiple opportunities exist for RNAi therapeutics for hepatic infectious diseases, and our initial focus on HBV will now be expanded to include programs for HDV and liver-specific immune checkpoint blockade by targeting hepatocyte-expressed PD-L1. In both cases, our approach will employ our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, enabling subcutaneous dose administration with high potency and long durability, and a wide therapeutic index. Finally, we remain on track to select our DC for ALN-HBV by end of this year, with the goal of filing an IND or IND equivalent for this program around the end of 2015.”

ALN-HDV, an investigational RNAi therapeutic targeting the HDV genome, is in development for the treatment of HDV infection. HDV is an RNA virus that infects hepatocytes and depends on a co-existing HBV infection to produce the envelope particle which holds its genome. HDV can be acquired at the same time or subsequent to infection with HBV, and is believed to infect between 15 and 20 million people worldwide. Chronic HDV infection results in more severe liver disease as compared to HBV infection alone, with higher risks of cirrhosis and hepatocellular carcinoma. Many chronic HDV patients progress to end-stage liver disease, where liver transplant is the only available treatment1. Alnylam plans to advance ALN-HDV as an ESC-GalNAc-siRNA conjugate combination with ALN-HBV targeting both the HBV and HDV genomes.

In addition, Alnylam is expanding its hepatic infectious disease efforts with ALN-PDL, an investigational RNAi therapeutic targeting PD-L1 in development for the treatment of chronic liver infections. PD-L1 is a cell surface protein that is believed to play a major role in suppressing the immune system in cancer and infection. HBV and HCV infection of hepatocytes is known to lead to increased PD-L1 expression2 which could subdue the immune response against the virus. Further, monoclonal antibodies targeting PD-L1 and its T-cell ligand PD-1 have shown anti-viral effects in pre-clinical and early clinical studies3, but are also associated with systemic toxicities. ALN-PDL is aimed at knocking down liver-expressed PD-L1 to reactivate an immune response against liver viral infection without the systemic toxicities observed with monoclonal antibody therapy. In pre-clinical studies published previously4 by Alnylam and collaborators, an siRNA targeting PD-L1 was shown to increase the endogenous immune response and viral clearance in a mouse model of liver adenovirus infection. Alnylam plans to advance ALN-PDL as an ESC-GalNAc-siRNA conjugate.

Finally, Alnylam is also continuing to advance ALN-HBV, an RNAi therapeutic targeting the HBV genome in development for the treatment of HBV infection. HBV infection afflicts 400 million people worldwide, with one to two million people in the U.S., and is a leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide. An RNAi therapeutic targeting the HBV genome could have the potential to achieve a “functional cure” by effectively decreasing expression of tolerogenic hepatitis surface antigen (HBsAg), in addition to inhibiting all steps of the HBV life cycle. In pre-clinical study results presented at the TIDES 2014 meeting, Alnylam reported significant, multi-log reductions in HBsAg and HBV viral titers in chronically infected chimpanzees. Alnylam plans to advance ALN-HBV as an ESC-GalNAc-siRNA conjugate which should enable once monthly subcutaneous dose administration with potent and durable effects, and a wide therapeutic index. The company remains on track to select a DC in late 2014 and plans to file an IND or IND equivalent around year-end 2015.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15™” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the HDV genome for the treatment of HDV infection; ALN-PDL targeting PD-L1 for the treatment of chronic liver infections; and other programs yet to be disclosed. As part of its “Alnylam 5x15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

StephenW

治疗慢性丁型肝炎病毒（HDV）感染与ALN-PDL的慢性肝病感染的治疗

发布时间：2014年11月11日上午08时00 ET
- 公司也保留曲目识别开发候选人（DC）的ALN-HBV，的RNAi治疗的发展为乙型肝炎病毒治疗（HBV）感染，按年结束 -

。马萨诸塞州剑桥市，2014年11月11日（美国商业资讯） -  Alnylam制药公司ALNY，-0.72％，领先的RNAi疗法公司，今天宣布，该公司已经拓展了其肝脏感染性疾病的管道。具体而言，在演示文稿在肝病研究的美国协会（AASLD）会议上，该公司宣布，它已加入ALN-HDV，的RNAi治疗靶向丁型肝炎病毒（HDV）的基因组在开发HDV感染的治疗。此外，还增加了AlN-PDL中的RNAi治疗靶向肝细胞 - 表达程序性死亡配体1（PD-L1）中发展为慢性肝感染的治疗。此外，奥尼拉姆继续推进其ALN -  HBV方案，在发展为乙型肝炎病毒（HBV）感染的治疗;该公司仍有望选择开发候选（DC）到今年年底，预计将提交一份研究性新药申请（IND），或IND相当于2015年左右的末尾。

“肝脏感染性疾病，如HBV和HDV感染，是主要的全球性卫生问题，影响了大约400万美元，1500万世界各地的人分别。显著未满足的需要有新的疗法来治疗这些感染，它们是世界各地纤维化的肝脏疾病和肝癌的主要原因，“劳拉·塞普 -  Lorenzino，博士，副总裁，企业家驻说道。 “我们认为，存在RNAi疗法对肝脏感染性疾病的多种机会，和我们最初的重点是HBV现在将扩大到包括通过靶向肝细胞表达PD-L1的HDV和肝脏特异性免疫检查点封锁计划。在这两种情况下，我们的方法将采用了增强的化学稳定性（ESC）-GalNAc共轭技术，使皮下剂量给药具有高效力和长期耐用性和宽的治疗指数。最后，我们仍然有望在今年年底选择了DC的ALN-HBV，与提交的IND IND或相当于这一计划围绕2015年底的目标“

ALN-HDV，一种研究RNA干扰治疗针对HDV的基因组，是在发展中求HDV感染的治疗。 HDV是一种RNA病毒，感染的肝细胞，并依赖于一个共同存在HBV感染，以产生保持其基因组中的包络颗粒。 HDV可以同时获取或乙型肝炎病毒感染之后，并且被认为是感染15至2000万人全世界。慢性HDV感染导致更严重的肝脏疾病相比，HBV感染单纯，肝硬化和肝癌的风险较高。许多慢性HDV患者进展为终末期肝病，其中肝移植是唯一可用的treatment1。 Alnylam公司计划将推动ALN-HDV与ALN-HBV均配置了HBV和HDV基因组的ESC-半乳糖胺-siRNA的结合物结合。

此外，Alnylam公司正在扩大与ALN-PDL，一种研究RNA干扰靶向治疗PD-L1的发展为慢性肝病感染的治疗的肝脏感染性疾病的努力。 PD-L1的是，被认为是抑制免疫系统在癌症和感染中起主要作用的细胞表面蛋白。 HBV和HCV感染的肝细胞是已知的导致增加的PD-L1的表达式可能制伏针对该病毒的免疫反应。另外，针对PD-L1和其T细胞的配体PD-1的单克隆抗体已显示在临床前和早期临床studies3抗病毒效果，但也有全身毒性相关联。 ALN-PDL旨在撞倒肝脏表达PD-L1的重新激活针对肝脏病毒性感染不与单克隆抗体疗法中观察到的全身毒性的免疫应答。在由奥尼拉姆和合作者，靶向PD-L1的一siRNA出版previously4临床前研究已证明能增加肝腺病毒感染的小鼠模型中的内源性免疫应答和病毒清除。 Alnylam公司计划将推动ALN-PDL作为ESC-半乳糖胺-siRNA的结合物。

最后，Alnylam公司还继续推进ALN-HBV，的RNAi治疗针对HBV基因组在开发HBV感染的治疗。 HBV感染折磨着4亿人在全球，有一两百万的人在美国，是肝病和世界各地的肝细胞癌（HCC）的主要原因。的RNAi治疗靶向的HBV基因组可以具有由有效地降低致耐受性肝炎表面抗原（HBsAg）的表达，除了抑制所有步骤的HBV生命周期，实现了“功能性治愈”的潜力。在潮汐2014年会议上提出的临床前研究结果，Alnylam公司报道显著，多日志降低HBsAg和HBV病毒滴度在慢性感染的黑猩猩。奥尼拉姆打算前进的ALN -  HBV作为一个ESC-的GalNAc-siRNA的共轭应使每月一次皮下剂量给药以有效的和持久的效果，并且很宽的治疗指数。该公司仍然有望在2014年年底选择一个DC，并计划提交一份IND IND或相当于绕年末2015年

关于RNAi技术

RNA干扰（RNA干扰）是在生物学革命，代表在了解基因是如何打开和关闭中的细胞，以及一种全新的方法，以药物发现和开发的一个突破。它的发现已被标榜为“一个重大的科学突破，出现这种情况每隔十年左右的时间”，并表示最有前途的和迅速发展的前沿在当今生物学和药物发现被授予2006年诺贝尔生理学或医学中的一个。 RNA干扰是发生在生物体从植物到哺乳动物的基因沉默的自然过程。通过充分利用RNA干扰发生在我们的细胞自然生物过程，创建一个新的重大类药物，被称为RNAi疗法，是在地平线上。小干扰RNA（siRNA），其介导RNAi，并包括Alnylam公司的RNAi的治疗平台分子，通过有力地沉默特定的mRNA，从而阻止引起疾病的蛋白质被制成靶向疾病的病因。 RNAi疗法具有治疗疾病和帮助患者从根本上新的方式的潜力。

关于Alnylam制药

Alnylam公司是一家生物制药公司，开发基于RNA干扰或RNAi的新疗法。该公司是领先的RNAi的翻译作为一类新的带芯专注于RNAi疗法的基因药物，包括方案作为公司的“Alnylam公司的5x15™”产品战略的一部分，创新药物。 Alnylam公司的基因药物项目是指向了严重的，危及生命的疾病的病人和他们的照顾者有限的治疗选择治疗基因定义的目标RNAi疗法。这些包括：patisiran（ALN-TTR02）靶向运甲状腺素蛋白（TTR），用于在患者的家族性淀粉样多神经病（FAP）的TTR介导的淀粉样变性（ATTR）的治疗; revusiran（ALN-TTRsc）靶向TTR对ATTR的患者的TTR心脏淀粉样变，包括家族性淀粉样变性心肌病（FAC）和老年性系统性淀粉样变性（SSA）的治疗; ALN-AT3靶向抗凝血酶（AT）用于治疗血友病的和罕见的出血性疾病（RBD）; ALN-CC5靶向补体成分的C5为的补体介导的疾病的治疗; ALN-AS1针对氨基乙酰丙酸合成酶-1（ALAS-1）肝卟啉症，包括急性间歇性卟啉病（AIP）的治疗; ALN-PCS靶向PCSK9的高胆固醇血症的治疗; ALN-AAT靶向α-1抗胰蛋白酶（AAT），用于AAT缺乏症相关的肝脏疾病的治疗; ALN-HBV针对乙型肝炎病毒（HBV）基因组HBV感染的治疗; ALN-TMP的靶向TMPRSS6为β-地中海贫血和铁过载疾病的治疗; ALN-ANG靶向血管生成素样3（ANGPTL3）的遗传形式的混合型高脂血症和高甘油三酯血症重症治疗; ALN-AC3靶向载脂蛋白C-III（载脂蛋白CIII）用于高甘油三酯血症的治疗; ALN-AGT靶向血管紧张素原（AGT）怀孕（HDP），包括子痫前期高血压疾病的治疗; ALN-GO1针对乙醇酸氧化酶（GO）的原发性高草酸盐1型（PH1）的治疗; ALN-HDV针对HDV基因组HDV感染的治疗; ALN-PDL针对PD-L1的慢性肝脏感染的治疗;和其他程序尚未披露。作为其“Alnylam公司5x15”战略的一部分，在2014年初更新的，该公司预计将有六到七遗传医学候选产品处于临床开发阶段 - 包括在第3阶段至少有两个方案5〜6与概念的人证明方案 - 到2015年底该公司的明确承诺RNAi疗法，使之形成与领先的公司，包括默克，美敦力，诺华，Biogen Idec公司，罗氏，武田，协和发酵麒麟，立体派，葛兰素史克，Ascletis，孟山都大联盟，和Medicines公司。在2014年初，Alnylam公司和Genzyme公司，赛诺菲公司，形成了罕见病领域Alnylam公司的基因药物项目多产品的地理联盟。具体来说，Alnylam公司将引领开发和商业化，在北美和欧洲的计划，而Genzyme公司将开发和商业化产品在世界其他地方。此外，Alnylam公司和Genzyme公司将共同开发并在北美和欧洲共同市场化revusiran。在2014年3月，收购了Alnylam公司siRNA治疗，默克公司的全资子公司。此外，Alnylam公司持有轩辕治疗公司的资产状况，公司专注于发现微RNA疗法，开发和商业化。 Alnylam公司的科学家和合作者发表了他们对RNAi疗法的研究超过200同行评审的论文，其中包括许多世界顶尖的科学期刊，如自然，自然医学，自然生物技术，细胞，新英格兰医学杂志和柳叶刀。公司成立于2002年，Alnylam公司保持总部设在马萨诸塞州剑桥市。欲了解更多信息，请访问www.alnylam.com。

hao2014

值得等待
希望快点

001话梅

看不懂！

hao2014

看得懂也没办法
毕竟要等

StephenW

回复 001话梅 的帖子

哪些部分你不明白?

001话梅

回复 StephenW 的帖子

内容看不懂说是乙肝有什么进展吗？

StephenW

回复 001话梅 的帖子

Alnylam公司正在发展3项HBV药物:
1. ALN-HDV - 利用RNAi技术沉默HDV与HBV基因, 治疗HDV
2. ALN-PDL - 利用RNAi技术沉默降低肝表达的PD-L1, 以重新激活抗肝病毒感染的免疫反应.
3. ALN-HBV - 利用RNAi技术沉默HBV基因, HBV.

咬牙硬挺

感谢分享