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Hypercholesterolemia

Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S.

Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving target LDL cholesterol (or ‘bad’ cholesterol) goals with statin therapy, including familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe forms of hypercholesterolemia are estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with hypercholesterolemia whose disease is inadequately managed by existing therapies.

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ALN-PCSsc for the Treatment of Hypercholesterolemia

Our collaborators at The Medicines Company are advancing clinical development of ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) that utilizes our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

Inhibition of PCSK9 synthesis through an RNAi mechanism has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher expression of LDL receptor in the liver, and consequently lower LDL cholesterol levels in the blood stream. Lower LDL cholesterol is associated with a decreased risk of cardiovascular disease, including myocardial infarction and stroke. ALN-PCSsc is an investigational PCSK9 synthesis inhibitor that lowers levels of both intracellular and extracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523). Further, RNAi therapeutics can block PCSK9 synthesis across a wide range of plasma PCSK9 levels, which are known to vary widely amongst individuals and are also elevated in association with statin therapy.

In February 2013, we formed an exclusive global alliance with The Medicines Company for the development and commercialization of the ALN-PCSsc program. Alnylam led the program through the completion of Phase 1 and The Medicines Company is responsible for leading and funding development from Phase 2 forward and commercializing the ALN-PCSsc program if successful.

Please read the latest press releases and data presentations for ALN-PCSsc here.

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New Clinical Data from Phase 1 Trial with ALN-PCSsc Confirms Potential for Bi-Annual Dosing

New Clinical Data from Phase 1 Trial with ALN-PCSsc Confirms Potential for Bi-Annual Dosing

Alnylam and The Medicines Company reported updated positive results from the ongoing Phase 1 clinical trial with ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia.  We had previously reported that subcutaneous administration of ALN-PCSsc resulted in an up to 83 percent lowering of LDL-C, with an up to 64 ± 5 percent mean maximum reduction. In new results, the effects of ALN-PCSsc were also found to be highly durable, with clinically significant and clamped reductions in LDL-C that now confirm the potential for a bi-annual subcutaneous dose regimen. An up to 53 percent maximal and 47 percent least squares mean reduction in LDL-C was achieved at day 180 after a single, low volume injection. In addition, ALN-PCSsc was shown to reduce a number of atherogenic lipids, including lipoprotein (a), and total cholesterol, which are associated with increased risk of cardiovascular disease. Importantly, ALN-PCSsc was generally well tolerated with no clinically significant drug-related adverse events to date.



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Positive Initial Clinical Data from Phase 1 Trial with ALN-PCSsc

Positive Initial Clinical Data from Phase 1 Trial with ALN-PCSsc

Alnylam and The Medicines Company reported positive initial results from the ongoing Phase 1 clinical trial with ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia.  Subcutaneous administration of ALN-PCSsc resulted in an up to 83% lowering of LDL-C, with an up to 64 ± 5% mean maximum reduction, comparable to published results for anti-PCSK9 monoclonal antibodies (Zhang XL., et al., BMC Med, 2015).  Similar reductions in LDL-C were seen in patients on and off concomitant statin therapy.  The effects of ALN-PCSsc were highly durable, with clinically significant and clamped reductions in LDL-C maintained for over 140 days, supportive of a once-quarterly and possibly bi-annual subcutaneous dose regimen. Maximal lowering effects on LDL-C were consistently achieved at a dose of 300 mg associated with a low injection volume of 1.5 mL. Importantly, ALN-PCSsc was generally well tolerated with no clinically significant adverse events to date.




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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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