Capella

Capella—the Online Voice of Progress in RNAi

Arian Ebank welcomes you to Capella, the destination for updates on our progress in translating the science of RNAi into innovative medicines. For Arian Ebank, Capella is our online voice for communicating the scientific progress we are making as we work to develop innovative medicines for patients.

To view our corporate presentation, click here.

We announced six-month clinical data from our ongoing Phase 2 open-label extension (OLE) study with patisiran (ALN-TTR02) for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP).  Data were presented at the American Neurological Association’s 2014 Annual Meeting held October 12 – 14, 2014 in Baltimore.  Results showed a mean 0.95 point decrease in modified Neuropathy Impairment Score (mNIS+7) at six months in 19 patients.  This decrease in neuropathy progression compares favorably with the 7-to-10 point increase in mNIS+7 at six months that can be estimated from historical data sets in untreated FAP patients with similar baseline characteristics.  In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for over nine months, with an up to 89.6% knockdown achieved between doses.  Patisiran was found to be generally well tolerated in this study out to one year of therapy, with no drug-related serious adverse events to date, and all 27 patients enrolled in the study continue to receive drug treatment.   Infusion-related reactions were infrequent (14.8%), mild in severity, and did not result in any discontinuations.  All other reported adverse events were mild to moderate, and there were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.




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We presented pre-clinical data with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases, at the 25th International Complement Workshop held September 14 – 18, 2014, in Rio de Janeiro, Brazil. Data demonstrated potent and clamped C5 knockdown as well as robust inhibition of complement activity in non-human primates for up to 100 days with a subcutaneous, monthly dosing regimen. Further, in a rat model of membranous nephropathy, ALN-CC5 administration resulted in a significant reduction in proteinuria due to complement-mediated disease activity in the kidney.



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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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We presented pre-clinical data with our Development Candidate for ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases, at the 7th International Conference on Complement Therapeutics, held June 6 – 11, 2014, in Olympia, Greece.  These data demonstrate that ALN-CC5 led to an up to 98.7% knockdown of serum C5 and an up to 96.8% inhibition of complement activity in non-human primates (NHP) with weekly subcutaneous dose administration.



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We presented positive top-line data from our Phase 1 clinical trial with ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD). In “Part A” of the Phase 1 study, we gave a single dose of drug to healthy volunteers to evaluate the drug’s safety and tolerability. Importantly, we had a dose escalation stopping rule at a maximum of 40% AT knockdown. Initial results, presented at the World Federation of Hemophilia (WFH) 2014 World Congress held May 11 – 15, 2014 in Melbourne, Australia, show that a single, low subcutaneous dose of ALN-AT3 at 0.03 mg/kg resulted in an up to 28-32% knockdown of AT at nadir relative to placebo (p <0.01 by ANOVA) and a temporally associated increase in peak thrombin generation (p <0.01). ALN-AT3 was found to be well tolerated with no significant adverse events reported.  With these results in hand, we have now proceeded to “Part B” of the Phase 1 study.



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We presented pre-clinical data with ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection, at the TIDES 2014 meeting held May 12 – 15 in Providence, Rhode Island. Specifically, we reported significant, multi-log reductions in HBV surface antigen (HBsAg) and HBV viral titers, and showed evidence for an immune-mediated therapeutic effect in chronically infected chimpanzees.



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We are presenting key scientific data on our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform at the TIDES 2014 meeting held May 12 – 15, 2014 in Providence, Rhode Island. This technology enables subcutaneous dosing of RNAi therapeutics with increased potency and durability, and a wide therapeutic index.  Data show that chemical modifications of siRNA that enhance in vitro stability result in higher liver exposure in vivo and lead to a significantly increased potency and durability of effect in pre-clinical studies. As compared with the “standard template chemistry” (STC)-GalNAc-conjugate approach used in our ALN-TTRsc program for the treatment of transthyretin (TTR) cardiac amyloidosis, ESC-GalNAc-siRNA conjugates demonstrated a 10-fold increased potency in non-human primate (NHP) studies, and a durability of effect that supports once-monthly or possibly even less frequent subcutaneous dosing regimens.



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We presented new pre-clinical data supporting the advancement of a Development Candidate (DC) for ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease. Data were presented in a Late-Breaking Abstract Session at Digestive Disease Week (DDW), held May 3 – 6, 2014 in Chicago. As previously presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, “The Liver Meeting”) in November 2013 and as updated at DDW, studies were performed in transgenic mice overexpressing the human Z-AAT protein. Subcutaneous administration of a GalNAc-siRNA targeting AAT led to rapid, potent, dose-dependent, and durable knockdown of AAT of greater than 95%, as well as a significant reduction in fibrosis and the incidence of liver tumors.



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We have presented new pre-clinical data from our growing pipeline of RNAi therapeutics for the treatment of cardiovascular metabolic disease, including ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia, and a newly named program, ALN-AC3 targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia.  The data were presented in an oral presentation at the Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2014 Scientific Sessions held May 1-3, 2014 in Toronto, Ontario.



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We have presented pre-clinical data with RNAi therapeutics targeting TTR for the treatment of TTR-mediated amyloidosis (ATTR).  These data were presented at the International Symposium on Amyloidosis (ISA) held April 27 – May 1, 2014.  These data showed that the degree of TTR knockdown in a mouse disease model was highly correlated with regression of TTR tissue deposits.  Further, comparative studies performed with the TTR stabilizer tafamidis and a TTR-specific antisense oligonucleotide (ASO) showed RNAi therapeutics targeting TTR to have superior pharmacologic profiles.



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