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Hyperlipidemia

Mixed hyperlipidemia is a genetically inherited condition characterized by very high levels of cholesterol and triglycerides in the blood, both of which are known to increase the risk of coronary artery disease, the leading cause of death in the U.S.

It is estimated that as many as 1 out of every 100 individuals have mixed hyperlipidemia and are at increased risk of developing cardiovascular disease. Some forms of mixed hyperlipidemia can be managed through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation), and medicines such as statins or fibrates; however, a large portion of mixed hyperlipidemia patients are unable to reach either their LDL cholesterol (or ‘bad’ cholesterol) and/or triglyceride goals with the current standard of care.

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ALN-ANG for the Treatment of Hyperlipidemia

We are developing ALN-ANG, an RNAi therapeutic targeting the gene angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. Exome sequencing studies have identified a statistically significant relationship of loss-of-function mutations in ANGPTL3 with decreased levels of triglycerides and LDL-C (N. Engl. J. Med (2010) 363:2220-2227). A subcutaneously administered RNAi therapeutic that inhibits ANGPTL3 synthesis and lowers both LDL-C and triglycerides represents a potential novel approach to the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. ALN-ANG utilizes our proprietary GalNAc conjugate delivery platform enabling subcutaneous dose administration.

ALN-ANG utilizes our proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

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ALN-AC3 for the Treatment of Hyperlipidemia

We developing ALN-AC3, a subcutaneously delivered RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia. ApoCIII is a component of lipoprotein particles in the blood, and inhibits lipoprotein lipase and hepatic lipase and reduces hepatic uptake of triglyceride-rich particles. Polymorphisms in apoCIII have been associated with hypertriglyceridemia; specifically a gain-of function leads to higher apoCIII and triglyceride levels, and reduced triglyceride clearance. ApoCIII loss-of-function results in greater triglyceride hydrolysis into free fatty acids and increased triglyceride clearance; heterozygous individuals have lower triglycerides and lower very low density lipoprotein (VLDL). Recent studies have identified rare loss of function variants in apoCIII which appear to be cardioprotective (Tachmazidou et al., Nat. Comm, 2013; Bochem et.al., Clin Genet., 2014).

ALN-AC3 utilizes our proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

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Alnylam R&D Day 2014 Webcast and Presentations

Alnylam R&D Day 2014 Webcast and Presentations

On December 12, we hosted an R&D Day in New York City. Alnylam management and key opinion leaders discussed the latest progress as well as plans for the future development of our RNAi therapeutics pipeline. At this event, we announced our pipeline growth strategy for development and commercialization of RNAi therapeutics across three Strategic Therapeutic Areas (STArs): Genetic Medicines, Cardio-metabolic Disease, and Hepatic Infectious Disease.



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New Pre-Clinical Data on RNAi Therapeutic Programs for Cardio-Metabolic Diseases

New Pre-Clinical Data on RNAi Therapeutic Programs for Cardio-Metabolic Diseases

We presented pre-clinical data from our investigational RNAi therapeutic programs toward genetically validated targets in development for the treatment of cardiovascular metabolic diseases, including: ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AC3 targeting apolipoprotein C3 (apoC3) for the treatment of hypertriglyceridemia; and ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia.  The data, presented at the American Heart Association (AHA) Scientific Sessions 2014, included new pre-clinical multi-dose data in non-human primates (NHPs) with over six months of dosing for ALN-PCSsc, showing robust and clamped knockdown of PCSK9 of up to 92% and reductions in LDL-C of up to 77% with a once-monthly subcutaneous dosing regimen.  These studies confirm the potential for a once-monthly, and possibly once-quarterly, low volume subcutaneous dose regimen, thus highlighting the emerging profile of our ESC-GalNAc conjugate delivery technology. We believe that ALN-PCSsc represents an innovative, differentiated, and well-validated approach for the treatment of hypercholesterolemia.



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Pre-Clinical Data with ALN-AGT for Treatment of Hypertensive Disorders of Pregnancy, Including Preeclampsia

Pre-Clinical Data with ALN-AGT for Treatment of Hypertensive Disorders of Pregnancy, Including Preeclampsia

We announced a new program, ALN-AGT, an RNAi therapeutic targeting angiotensinogen (AGT) in development for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia. Pre-clinical data were presented at the American Heart Association’s High Blood Pressure Research 2014 Scientific Sessions, held September 9 – 12, 2014, in San Francisco. Data from experiments in an established rat model of preeclampsia demonstrated that an RNAi therapeutic targeting AGT ameliorates the clinical sequelae of preeclampsia and improves outcomes for the fetus.  This treatment approach has the potential for selective delivery to the pregnant mother without fetal drug exposure, as our study confirmed undetectable siRNA levels in the fetus.




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