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Alnylam Scientists Present Pre-clinical Data with ALN-CC5, an RNAi Therapeutic

Published: Friday, June 21, 2013
Last Updated: Friday, June 21, 2013
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New research demonstrates potent, dose-dependent, and durable silencing of serum C5 for the treatment of complement-mediated diseases.

Alnylam Pharmaceuticals, Inc. announced that it has presented new pre-clinical data with ALN-CC5, an RNAi therapeutic targeting complement component C5. These data were presented at the 6th International Conference on Complement Therapeutics being held June 18 - 23, 2013 in Kos, Greece. The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in serious, life-threatening complications in a broad range of human diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis optica, amongst others. C5 is a genetically and clinically validated target; loss of function human mutations are associated with an attenuated immune defense against certain infections and intravenously administered anti-C5 monoclonal antibody therapy has demonstrated clinical activity and tolerability in a number of complement-mediated diseases. In a presentation titled “Development of an RNAi Therapeutic Silencing the C5 Component of Complement,” Alnylam scientists presented pre-clinical results showing potent, dose-dependent, and durable RNAi-mediated knockdown of serum C5 and inhibition of complement-mediated hemolytic activity of approximately 90% with a subcutaneously administered RNAi therapeutic. Alnylam believes that ALN-CC5 – part of the company’s “Alnylam 5x15” product strategy – represents a novel approach for the treatment of complement-mediated diseases; the company expects to nominate a development candidate for clinical advancement in late 2013.

“C5 is a genetically and clinically validated target that exemplifies the potential of Alnylam’s ‘5x15’ product strategy for innovative new medicines. First, C5 is predominantly expressed in liver, where we have established clinical activity and tolerability for RNAi therapeutics. In addition, our clinical development plan for an RNAi therapeutic targeting C5 will be facilitated by serum biomarkers in Phase I trials and a relatively streamlined and focused path for advanced development,” said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead Development at Alnylam. “Indeed, we believe that a subcutaneously administered RNAi therapeutic targeting C5 could represent an important advance for the treatment of a broad range of complement-mediated diseases.”

New data presented at the scientific meeting showed that a GalNAc-siRNA conjugate targeting the C5 mRNA resulted in potent, dose-dependent, and durable silencing of C5 liver mRNA, knockdown of C5 serum protein levels, and inhibition of complement-mediated hemolysis activity. Specifically, a prototype GalNAc-siRNA conjugate targeting C5 showed a single dose ED50 for C5 knockdown of approximately 0.6 mg/kg in rodent models. In multi-dose experiments, subcutaneous administration of the GalNAc-siRNA conjugate resulted in approximately 90% knockdown of serum C5 levels at doses of ≥1.25 mg/kg. Additional multi-dose experiments showed that the current lead candidate siRNA could achieve an approximately 90% inhibition of complement-mediated hemolytic activity in the rat at subcutaneous doses of 5 mg/kg; these effects were rapid, dose-dependent, and durable for weeks after cessation of treatment. The company is performing additional optimization of the GalNAc-siRNA conjugate lead molecule and expects to nominate its ALN-CC5 development candidate in late 2013.

“The complement system plays a central role in immunity as part of host defense. However, dysregulation of this pathway can lead to life-threatening complications in a wide range of human diseases including PNH, aHUS, myasthenia gravis, neuromyelitis optica, amongst others,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer at Alnylam. “We are excited about these pre-clinical data showing potent, dose-dependent, and durable knockdown of serum C5 with about 90% inhibition of hemolysis activity using a subcutaneously administered RNAi therapeutic. We believe that if these results can extend in the clinical setting, they could represent a very promising therapeutic strategy and new treatment option for patients with complement-mediated diseases.”

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