全球领先的RNAi药物开发公司——Alnylam制药8月8日宣布，欧洲药品管理局（EMA）孤儿药品委员会（COMP）已授予RNAi疗法ALN-AT3孤儿药地位，用于A型血有病和B型血友病的治疗。目前，Alnylam正开发ALN-AT3作为一种皮下注射RNAi疗法，靶向抗凝血酶（AT），用于血友病（包括A型血友病、B型血友病、伴有抑制剂的A或B型血友病）及其他罕见出血性疾病（RBD）的治疗。

此前，FDA已于2013年8月授予ALN-AT3治疗A型血友病和B型血友病的孤儿药地位。ALN-AT3采用了Alnylam制药专有的半乳糖胺共轭递送平台（GalNAc-siRNA平台）开发，能够通过皮下注射给药。

临床前数据表明，ALN-AT3能够使凝血酶的生成正常化，并能够改善血友病小鼠的止血，同时还可以完全纠正一种非人类灵长类动物（NHP）血友病"抑制剂"模型中凝血酶的生成。

目前，ALN-AT3正处于I期临床。今年5月在世界血友病联合会2014世界大会上，Alnylam公布了在健康志愿者中开展的研究A部分的积极顶线数据。数据表明，单次低剂量皮下注射ALN-AT3（0.03mg/kg）使抗凝血酶（AT）沉默达28-32%（p＜0.01），使凝血酶生成的峰值取得了统计学意义的显著提高，凝血酶的生成与AT沉默的时间及沉默程度一致。研究中，ALN-AT3的耐受性良好，未出现显著不良事件。根据A部分的积极数据，Alnylam公司已启动B部分研究，预计将于今年年底获得初步临床数据。

今年1月，赛诺菲（Sanofi）扩大与Alnylam的合作，投资7亿美元收购12%股份，支持相关RNAi疗法临床开发。而本月，罗氏耗资4.5亿美元收购Santaris公司，获锁核酸（LNA）平台，继续发力RNA靶向疗法研发。LNA平台是一个创新的RNAi平台，能够克服早期反义RNA技术及siRNA技术的缺陷性，使RNA靶向治疗跨入了一个崭新的时代。这一系列动作表明，制药巨头已对RNA靶向疗法重燃希望，并已重返RNA治疗领域。
关于Alnylam制药

Alnylam是一家生物制药公司，开发基于RNA干扰（RNAi）的新型疗法，该公司开发的GalNAc-siRNA平台在很大程度上客服了RNAi药物输送困难的难题。目前，该公司有多个RNAi疗法处于临床开发，其在研的其他药物还包括：ALN-TTR，开发用于治疗甲状腺素介导的淀粉样变性（ATTR）；ALN-PCS，开发用于治疗严重高胆固醇血症；AlN-HPN，开发用于治疗难治性贫血的治疗。

英文原文：

Alnylam Receives Orphan Drug Designations in the European Union for ALN-AT3, an RNAi Therapeutic in Development for the Treatment of Hemophilia

Alnylam Pharmaceuticals, Inc. (ALNY), a leading RNAi therapeutics company, announced today that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) has granted Orphan Drug Designations for ALN-AT3 as an orphan medicinal product for the treatment of hemophilia A and hemophilia B. Alnylam is developing ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT), for the treatment of hemophilia and other Rare Bleeding Disorders (RBD).

“We are very pleased to have received Orphan Drug Designations from the EMA COMP for ALN-AT3, a key program in our ‘Alnylam 5x15’ product development and commercialization strategy. We believe that our subcutaneously delivered RNAi therapeutic represents an innovative approach for the management of hemophilia and has great potential to make a meaningful impact in the treatment of this often debilitating bleeding disorder,” said Saraswathy (Sara) Nochur, Ph.D., Senior Vice President, Regulatory Affairs and Quality Assurance at Alnylam. “Having announced positive top-line results in adult healthy volunteers earlier this year, we look forward to presenting initial Phase 1 results, including data in hemophilia subjects, later in the year.”

ALN-AT3 is currently being investigated in a multinational Phase 1 trial. At the World Federation of Hemophilia 2014 World Congress held in May, Alnylam presented positive top-line data from Part A of the study performed in adult healthy volunteers. Initial results from the sole dose cohort enrolled (n=4; 3:1, drug:placebo) showed that a single, low subcutaneous ALN-AT3 dose of 0.03 mg/kg resulted in an up to 28-32% knockdown of AT at nadir (p < 0.01 by ANOVA, relative to placebo). This resulted in a statistically significant (p < 0.01) increase in peak thrombin generation, that was temporally associated and consistent with the degree of AT knockdown. ALN-AT3 was found to be well tolerated with no significant adverse events reported. With these data and in light of a dose escalation stopping rule at a 40% level of AT knockdown, the company has transitioned to Part B of the study – an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses, specifically three weekly doses, of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. In this part of the study, dose escalation will be allowed to proceed beyond the 40% AT knockdown level. The company plans to present initial clinical results, including results in hemophilia subjects from Part B of the study, by the end of the year.

Orphan Drug Designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union (EU), and where no satisfactory treatment is available. In addition to a 10-year period of marketing exclusivity in the EU after product approval, Orphan Drug Designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase, and direct access to centralized marketing authorization.

Alnylam will be discussing its progress with the ALN-AT3 program in an RNAi Roundtable webinar to be held at 9:30 a.m. ET today, and can be accessed by clicking here.

About Hemophilia and Rare Bleeding Disorders

Hemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in Factor VIII, and there are greater than 40,000 registered patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered patients in the U.S. and E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 patients worldwide with a severe bleeding phenotype. Standard treatment for hemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of people with severe hemophilia A will develop an antibody to their replacement factor - a very serious complication; these 'inhibitor' patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have co-inherited a prothrombotic mutation, such as Factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. Hemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for Factor VIII or Factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat hemophilia patients.

About Antithrombin (AT)

Antithrombin (AT, also known as “antithrombin III” and "SERPINC1") is a liver expressed plasma protein and member of the "serpin" family of proteins that acts as an important endogenous anticoagulant by inactivating Factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (Factor VIII and Factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., Factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis.

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 5x15TM" 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), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic 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, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; 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. Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection. 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, The Medicines Company, and Genzyme, a Sanofi company. 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, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts.