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Aln-CC5, an Investigational RNAi Therapeutic Targeting C5 for Complement Inhibition

Anna Borodovsky, Kristina Yucius, Andrew Sprague, Nirmal K Banda, V. Michael Holers, Akshay Vaishnaw, Martin Maier, Rajeev Kallanthottathil, Klaus Charisse, Satya Kuchimanchi, Muthiah Manoharan, David J Salant, Kevin Fitzgerald, Rachel Meyers and Benny Sorensen

Abstract

Excessive complement activation plays a pivotal role in a variety of disorders. Complement component C5 is a clinically validated therapeutic target for treatment of both paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome.

We developed a robust RNAi therapeutics platform for the delivery of siRNAs to the liver using trivalent GalNAc conjugates, enabling specific silencing of hepatocyte-expressed genes following subcutaneous (SC) injection. The liver produces essentially the entirety of C5 and other complement pathway proteins. We are developing ALN-CC5, an investigational RNAi therapeutic targeting human, primate and rodent C5. C5 silencing and complement activity inhibition were examined in rodents and primates. Multi-dose SC ALN-CC5 treatment resulted in sustained lowering of cyno serum C5 with ≤3% residual protein remaining. C5 reduction was associated with >90% and >95% inhibition of classical and alternative complement pathways as measured by ELISA-based assays. Additionally, >80% lowering of complement serum hemolytic activity was observed. ALN-CC5 was safe and well tolerated in both rat and non-human primate toxicology studies. In addition to wild type animals, ALN-CC5 was tested in several animal models of disease in which complement activation plays a prominent role. Silencing of murine C5 was highly efficacious in a model of anti-collagen antibody-induced arthritis with a disease modifying activity equivalent to that of an anti-C5 antibody. Furthermore, C5 silencing was effective at reducing proteinuria in a rat model of membranous nephropathy. Up-regulation of C5 expression, observed in both models, had no effect on the extent of C5 silencing, suggesting that ALN-CC5 could be efficacious in the context of inflammation. These data demonstrate a prominent role for circulating, liver-derived C5 in mediating pathology at extrahepatic sites and the potential utility of an RNAi therapeutic targeting C5.

In summary, RNAi-mediated silencing of liver-derived C5 is a promising novel therapeutic approach for inhibiting systemic complement activity, with the potential to enable, low volume, subcutaneous treatment for patients with PNH and other disorders where complement activation plays a role in disease progression.

Disclosures Borodovsky: Alnylam: Employment. Yucius: Alnylam: Employment. Sprague: Alnylam: Employment. Banda: Alnylam: Research Funding. Holers: Alnylam: Research Funding. Vaishnaw: Alnylam Pharmaceuticals: Employment, Equity Ownership. Maier: Alnylam: Employment. Kallanthottathil: Alnylam: Employment. Charisse: Alnylam: Employment. Kuchimanchi: Alnylam: Employment. Manoharan: Alnylam: Employment. Salant: Alnylam: Honoraria. Fitzgerald: Alnylam: Employment. Meyers: Alnylam: Employment. Sorensen: Alnylam Pharmaceuticals: Employment, Equity Ownership.

  • * Asterisk with author names denotes non-ASH members.