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.
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.
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.