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.


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.

Author notes


Asterisk with author names denotes non-ASH members.

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