Alnylam Broadens Pipeline with ALN-AGT, a Subcutaneously Administered RNAi Therapeutic Targeting Angiotensinogen (AGT) for the Treatment of Hypertensive Disorders of Pregnancy (HDP), Including Preeclampsia

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Alnylam Pharmaceuticals, Inc. ALNY, a leading RNAi therapeutics company, announced today that it is broadening its pipeline with ALN-AGT, a subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia, one of the most common complications of pregnancy. Preeclampsia leads to increased risk of maternal mortality, perinatal fetal mortality, fetal pre-maturity, or even the need for late-term abortion to save the mother's life. AGT, which is primarily expressed in the liver, is the protein precursor for angiotensin II, a peptide hormone that promotes vasoconstriction as part of the renin-angiotensin system. Gain-of-function human mutations or variants of AGT are associated with increased risk for hypertension and preeclampsia in pregnant women. Small molecule inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are known to cross the placental barrier and are associated with fetal toxicity. Accordingly, ACE inhibitors and ARBs are contraindicated for the management of hypertension during pregnancy.

In a poster presented at the American Heart Association's High Blood Pressure Research 2014 Scientific Sessions, Alnylam and collaborators at the Charité - Universitätsmedizin in Berlin presented results of an ALN-AGT lead molecule in an established preeclamptic rodent model. The study showed that administration of ALN-AGT resulted in knockdown of maternal AGT in the liver without detectable evidence of fetal drug exposure, significantly improved pregnancy-related hypertension, ameliorated preeclamptic sequelae in the mother such as proteinuria, and improved fetal outcomes.

“At Alnylam, we continue to pursue development of RNAi therapeutics targeting genetically validated, liver-expressed genes involved in the cause or pathway of human disease with high unmet medical need. ALN-AGT, our new cardio-metabolic program targeting angiotensinogen, exemplifies this strategy since human gain-of-function AGT variants are associated with preeclampsia and also more broadly with hypertension. New therapies are clearly needed to prevent or treat HDP, including preeclampsia, since existing small molecule anti-hypertensive drugs readily cross the placental barrier and can cause fetal toxicity,” said Rachel Meyers Ph.D., Vice President of Research and RNAi Lead Development (RLD) at Alnylam. “The new pre-clinical data demonstrate that an RNAi therapeutic targeting AGT ameliorates the clinical sequelae of preeclampsia and improves outcomes for the fetus in an established transgenic rat model. This treatment approach has the potential for selective delivery to the pregnant mother without fetal drug exposure, as our study has confirmed undetectable siRNA levels in the fetus. We look forward to advancing ALN-AGT as a highly innovative approach for the management of HDP and preeclampsia.”

“HDP and preeclampsia represent areas of very high unmet medical need. Today, well over half a million pregnancies in the U.S. and EU are complicated by hypertension; preeclampsia occurs with an incidence of over 250,000 cases per year, and accounts for 10-20% of maternal or fetal perinatal deaths. Early delivery of infants from preeclamptic mothers is associated with prematurity requiring neonatal intensive care and accompanied risks of mortality and morbidity for the newly born infant,” said S. Ananth Karumanchi, M.D., Associate Professor of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School. “Unfortunately, few options exist for management of hypertension-associated pregnancies, and, in the case of preeclampsia, treatment can require early delivery or termination of pregnancy to save the mother's life. These pre-clinical data with ALN-AGT are promising, since new treatment options are clearly needed for the management of these patients.”

Alnylam and collaborators presented results of a pre-clinical study entitled “RNAi Therapeutics Targeting Human Angiotensinogen (hAGT) Ameliorate Preeclamptic Sequelae in an Established Transgenic Rodent Model for Preeclampsia.” A GalNAc-siRNA conjugate targeting human AGT was designed and synthesized using Alnylam's ESC-GalNAc-conjugate delivery platform, which enables subcutaneous delivery of RNAi therapeutics with a wide therapeutic index. In a transgenic rat model of preeclampsia, subcutaneous administration of the lead ALN-AGT molecule resulted in silencing of human AGT in maternal liver by over 90%, reduced mean arterial blood pressure by approximately 20 mmHg, and attenuated proteinuria by greater than 80%; elevated blood pressure and proteinuria are established hallmarks of preeclampsia. ALN-AGT administration also reduced additional manifestations of the preeclamptic phenotype in the mother, including activity levels of agonistic angiotensin 1 receptor autoantibodies and maternal kidney mRNA expression of soluble fms-like tyrosine kinase-1 (sflt-1), which were reduced by approximately 90% and 75%, respectively. Preeclampsia is also known to be associated with abnormal placentation - dysfunction in the interface between mother and fetus - and reduced placental size associated with impaired fetal growth. In the pre-clinical model, administration of ALN-AGT was associated with improved uteroplacental unit weight, increased overall fetal weight, and normalized fetal brain to liver ratio. In aggregate, these results showed that ALN-AGT administration improved fetal outcomes. Finally, quantitative measurements of ALN-AGT drug levels in the maternal and fetal liver were performed. Results showed that while significant levels (>20 μg/g liver) of ALN-AGT could be detected in the maternal liver, levels of ALN-AGT in the fetal liver were below the lower limit of quantitation for the assay (<0.0013 μg/g liver). These results are consistent with published data for large macromolecules such as siRNA, in addition to current company data showing that RNAi therapeutics do not cross the placental barrier.

About Hypertensive Disorders of Pregnancy and Preeclampsia
Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of preeclampsia, one of the most common complications of pregnancy in the U.S. and one of the most common causes of maternal death in developed countries. There are over half a million women in the U.S. and EU who suffer from HDP. Preemclampsia occurs in over 200,000 pregnant women in the U.S. and EU and is associated with increased risk of maternal mortality, perinatal fetal mortality, infant prematurity, neonatal intensive care, and infant morbidity. Presentation with severe preeclampsia before the fetus is viable may necessitate termination of the pregnancy, as delivery is the only known cure to save the mother's life. Hypertensive drugs such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are contraindicated due to side effects to the fetus; patients are typically managed with bed rest and careful monitoring.

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 GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC) GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate technology enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index, and is being employed in several of Alnylam's genetic medicine programs, including programs in clinical development.

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), 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-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; 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; ALN-AGT, an RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; 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 ALN-TTRsc 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.

Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-AGT for the treatment of hypertensive disorders of pregnancy, including preeclampsia, and its expectations regarding its “Alnylam 5x15” product strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to manage operating expenses, Alnylam's ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam's dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation to update any forward-looking statements.