Preclinical potential

Alnylam’s investigational RNAi therapeutic demonstrates up to 98.7-percent knockdown of serum C5

Kelsey Kaustinen
CAMBRIDGE, Mass.—RNAi therapeutics company Alnylam Pharmaceuticals Inc. has released preclinical results regarding its development candidate for ALN-CC5, a subcutaneously administered investigational RNAi therapeutic that targets complement component C5. The compound is currently being developed for the treatment of complement-mediated diseases.
 
ALN-CC5 engendered an up to 98.7-percent knockdown of serum C5 and an up to 96.8-percent inhibition of complement activity in non-human primates (NHPs) when administered subcutaneously on a weekly basis. RNAi-mediated knockdown of C5 was shown to be equally effective as an anti-C5 monoclonal antibody in reducing clinical disease activity in a mouse model of arthritis. In addition, ALN-CC5 maintained its knockdown effect toward C5 after lipopolysaccharide treatment, proving that RNAi can blunt induction of C5 as part of an inflammatory response. Based on early human translational data for the ESC-GalNAc conjugates, it is expected that weekly dosing at less than 1 mg/kg will produce similar effects in humans. Alnylam will continue dosing in its primate study to evaluate once- and twice-monthly subcutaneous dosing regimens, with the expectation of reporting additional preclinical data later this year.
 
The compound uses Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which allows for subcutaneous dosing while offering increased potency and durability as well as a wide therapeutic index. GalNAc-siRNA conjugates are Alnylam’s proprietary delivery platform, designed to enable targeted delivery of RNAi therapeutics to hepatocytes by way of uptake by the asialoglycoprotein receptor.
 
“These new preclinical data with our recently selected development candidate for ALN-CC5 demonstrate potent C5 knockdown and robust inhibition of complement activity in NHPs with weekly subcutaneous dosing. We believe that these are promising results, since an over 80-percent inhibition of complement activity has been shown to be associated with clinical benefit. Further, comparative studies in a mouse arthritis model showed ALN-CC5 to be as effective as an anti-C5 antibody in reducing disease activity, demonstrating a necessary and sufficient role for liver-expressed C5 in localized complement-mediated disease,” Dr. Akshay Vaishnaw, executive vice president and chief medical officer of Alnylam, commented in a news release.
 
“ALN-CC5 employs our ESC-GalNAc-siRNA conjugate platform that has recently been validated in preliminary data from human studies and where we observe a further tenfold increase in potency as compared with studies in NHPs,” Vaishnaw continued. “Accordingly, we believe we are seeing the emergence of a compelling therapeutic profile for ALN-CC5, which could make it competitive with anti-C5 monoclonal antibody therapy.”
 
Alnylam expects to file an Investigational New Drug (IND) or IND-equivalent application late this year, with an eye toward presenting initial clinical results in mid-2015.
 
Complement component C5, which is largely expressed in liver cells, is a genetically and clinically validated target, and intravenous anti-C5 monoclonal antibody therapy has shown clinical activity and tolerability in several complement-mediated diseases. As noted on a supplement page from Davidson College’s website, “the complement system consists of a series of plasma protein interactions which mediate direct attack on pathogens and induce inflammation … C5 plays a significant role in vital immunological pathways as well as contributing to several human diseases.” It adds that C5 is known to play a role in or have the potential to worsen several conditions, including septicemia, systemic lupus erythematosus, Leiner’s disease and possibly liver fibrosis.
 
“The complement system evolved as part of the innate immune system and plays a key role in host defenses. Dysregulation of the complement system can lead to serious complications in a wide range of human diseases, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and neuromyelitis optica,” said Dr. Anita Hill, consultant hematologist for Leeds Teaching Hospitals NHS Trust in the United Kingdom and honorary senior lecturer at the University of Leeds. “I am very encouraged by these preclinical data showing potent and durable knockdown of serum C5 with robust inhibition of complement activity using a subcutaneously administered RNAi therapeutic. If these results can be extended to the clinical setting, I believe that they could represent an attractive therapeutic strategy and potential new treatment option for patients with complement-mediated diseases.”

Kelsey Kaustinen

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