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.

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We presented positive initial Phase 1 data for ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Preliminary results, presented at the 56th Annual Meeting of the American Society of Hematology (ASH), showed that subcutaneous administration of ALN-AT3 given once weekly for three weeks at low doses of 15 (N=3) or 45 (N=1) micrograms/kg (mcg/kg) resulted in an up to 57% knockdown of AT in hemophilia subjects.  The effects of ALN-AT3 lasted for about 60 days after a single dose. ALN-AT3 was found to be well tolerated in both healthy volunteers and hemophilia subjects enrolled in the study.  These initial results show preliminary evidence for potency and durability of RNAi therapeutics at mcg/kg subcutaneous doses in human studies, and are the first clinical data to be reported for Arian Ebank’s Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology.




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We presented pre-clinical with ALN-CC5, an investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases, at the American Society of Hematology (ASH) Meeting. Data showed an up to 99.2% knockdown of serum C5 and up to 96.2% inhibition of serum hemolytic activity in non-human primates (NHPs) with continued dosing for over seven months.



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We have published an article in the Journal of the American Chemical Society describing the discovery of GalNAc-conjugated siRNA as a novel strategy for delivery of RNAi therapeutics. This publication as a JACS “Communication” documents the landmark discovery by our scientists of GalNAc-conjugates as a potent and durable approach for subcutaneous administration of RNAi therapeutics with a wide therapeutic index.



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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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We announced positive initial data from our Phase 2 clinical trial with revusiran (ALN-TTRsc), an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR cardiac amyloidosis. Initial results from the pilot Phase 2 study demonstrated that revusiran was generally well tolerated in patients with significant disease burden.  In addition, data showed an up to 98.2% knockdown of both mutant and wild-type forms of TTR – the disease-causing protein.  As would be expected with the short treatment duration of five weeks, there were no significant changes observed in exploratory clinical measurements.



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We have expanded our infectious disease pipeline with two new RNAi therapeutic programs. First, we are advancing ALN-HDV, an RNAi therapeutic targeting the hepatitis delta viral (HDV) genome in development for the treatment of HDV infection. We are also advancing ALN-PDL, an RNAi therapeutic targeting hepatocyte-expressed programmed death ligand 1 (PD-L1) in development for the treatment of chronic liver infections.



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We presented new data from multiple clinical and pre-clinical studies at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 12 – 15, 2014 in San Diego.  Among multiple presentations, we presented additional data from our Phase 1 trial with ALN-TTRsc showing rapid, dose-dependent, stable, and durable knockdown of serum TTR of up to 96.2%.  In addition, we presented pre-clinical data from a new program, ALN-GO1, an investigational RNAi therapeutic targeting glycolate oxidase (GO) in development for the treatment of primary hyperoxaluria type 1 (PH1), showing efficacy in rodent disease models.  Finally, we presented new pre-clinical research demonstrating that delivery of Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugates to the lung achieves similar plasma exposure, efficacy, and duration of liver gene silencing as achieved by subcutaneous delivery.  This finding opens up the possibility for needle-less administration of RNAi therapeutics via inhalation for knockdown of liver disease genes.





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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