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Cardio-Metabolic Disease

Cardio-metabolic disease is the number one cause of death in the developed world. Our current pipeline of novel RNAi therapeutics addressing cardio-metabolic diseases is focused on areas such as hypercholesterolemia, hyperlipidemias, and hypertensive disorders.

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 genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetes, 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

We are developing an RNAi therapeutic targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in collaboration with The Medicines Company.  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.

We are advancing ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 that utilizes our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

In August 2015, we presented initial data from a Phase 1 trial of ALN-PCSsc in healthy volunteers with elevated LDL cholesterol (LDL-C). 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 drug related adverse events to date.

We believe that ALN-PCSsc, an investigational first-in-class PCSK9 synthesis inhibitor, has a highly competitive profile as compared with anti-PCSK9 monoclonal antibodies that are labeled for twice-monthly dosing. In particular, we believe that a maximally efficacious and well tolerated quarterly or potentially bi-annual, low volume subcutaneous dosing regimen could address the unmet needs for hypercholesterolemia management in a massive, at-risk, often non-adherent population worldwide.  Moreover, we imagine that ALN-PCSsc has the potential to open new innovation horizons with patients, providers, and payers by linking the temporal cycle of LDL-C monitoring with administration of therapy. Overall, we believe that ALN-PCSsc potentially represents an innovative, differentiated, and well validated approach for the treatment of hypercholesterolemia.

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

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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 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. ANGPTL3 is a liver-expressed, genetically validated target that acts to inhibit lipoprotein lipase and endothelial lipase, and has been shown to increase plasma triglycerides, as well as LDL cholesterol. 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.

At the American Heart Association meeting in November 2014, we presented new data from this program demonstrating that a single dose of a GalNAc-siRNA targeting ANGPTL3 led to robust, dose-dependent knockdown of serum ANGPTL3 protein of up to 99%. In studies performed in an “ob/ob” mouse model of obesity and mixed hyperlipidemia, ALN-ANG treatment as a single 3 mg/kg dose resulted in a greater than 80% reduction in levels of triglycerides and LDL-C. In addition, total cholesterol was reduced up to 68%. These data with ALN-ANG support further advancement of this program for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, which are associated with increased risk of coronary artery disease and/or recurrent pancreatitis.  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.

At the American Heart Association annual meeting in November 2013, Alnylam scientists and collaborators presented new pre-clinical data from our ALN-ANG discovery program. These studies were also performed in an “ob/ob” mouse model of obesity and mixed hyperlipidemia. A single dose of a GalNAc-siRNA targeting ANGPTL3 was found to lead to robust, dose-dependent knockdown of ANGPTL3 protein, with a single dose ED50 of approximately 1 mg/kg. In a multi-dose experiment, subcutaneous doses of 3.0 mg/kg led to a greater than 95% knockdown of ANGPTL3 protein. This ANGPLT3 protein reduction resulted in a greater than 95% reduction in triglycerides, and a more than 85% reduction in LDL-C. In addition, total cholesterol was reduced by greater than 60%.

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ALN-AC3 for the Treatment of Hyperlipidemia

We are also developing ALN-AC3, a subcutaneously delivered RNAi therapeutic targeting apolipoprotein C3 (apoC3) for the treatment of hypertriglyceridemia.  ApoC3 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 apoC3 have been associated with hypertriglyceridemia; specifically a gain-of function leads to higher apoC3 and triglyceride levels, and reduced triglyceride clearance.  ApoC3 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 apoC3 which appear to be cardioprotective (Tachmazidou et al., Nat. Comm, 2013).

At the American Heart Association in November 2014, we presented new pre-clinical data demonstrating that a single 3 mg/kg dose of a GalNAc-conjugated siRNA targeting apoC3 resulted in knockdown of apoC3 levels of up to 94%, with more than 60% knockdown sustained for at least 30 days. In a multi-dose study, results showed that dosing of 3 mg/kg every other week resulted in 96% knockdown of human apoC3 through day 35, the last time point in the study. 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.  We are encouraged that our RNAi-based therapeutic targeting apoC3 expression in the liver reproduced these effects in a mouse model, and plan to continue to conduct additional pre-clinical work in this program to finalize our Development Candidate.

At the Arteriosclerosis, Thrombosis and Vascular Biology 2014 Scientific Sessions in May 2014, we presented data from our ALN-AC3 program for the first time, from a study that was conducted in mouse models that match human genetics.  Specifically, administration of a GalNAc-conjugated siRNA targeting apoC3 resulted in knockdown of apoC3 levels of up to 95% and a reduction in triglyceride levels of up to 68% with durability out to over 20 days. 

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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 the second most common cause 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. We are developing ALN-AGT for the treatment of HDP, including preeclampsia.

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ALN-AGT for the Treatment of Hypertensive Disorders of Pregnancy

ALN-AGT is 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. At the American Heart Association’s High Blood Pressure Research 2014 Scientific Sessions, we presented results for the first time from our ALN-AGT program. The new pre-clinical data 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 has confirmed undetectable siRNA levels in the fetus. ALN-AGT utilizes our proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.  We look forward to advancing ALN-AGT as a highly innovative approach for the management of HDP and preeclampsia.
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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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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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