Date: 2014-06-09
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the 7th International Conference on Complement Therapeutics being held June 6 – 11, 2014, in Olympia, Greece.
Company: Isis Pharmaceuticals (USA)
Product: ALN-CC5
Action
mechanism: RNAi. ALN-CC5 is an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases. The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in 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. Complement component C5, which is predominantly expressed in liver cells, is a genetically and clinically validated target; loss of function human mutations are associated with an attenuated immune response against certain infections and intravenous anti-C5 monoclonal antibody therapy has demonstrated clinical activity and tolerability in a number of complement-mediated diseases. A subcutaneously administered RNAi therapeutic that silences C5 represents a novel approach to the treatment of complement-mediated diseases.ALN-CC5 utilizes Alnylam\'s ESC-GalNAc conjugate technology which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
Disease: complement-mediated diseases
Therapeutic area: Immunological diseases
Country:
Trial details:
Latest
news: * On June 9, 2014, Alnylam Pharmaceuticals, a leading RNAi therapeutics company, announced new pre-clinical results with its Development Candidate (DC) for ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases. These results were presented at the 7th International Conference on Complement Therapeutics being held June 6 – 11, 2014, in Olympia, Greece. New data demonstrate that ALN-CC5 led to an up to 98.7% knockdown of serum C5 and an up to 96.8% inhibition of complement activity in non-human primates (NHP) with weekly subcutaneous dose administration. Alnylam believes that ALN-CC5 – part of the company’s “Alnylam 5x15” product strategy – could represent a novel approach for the treatment of complement-mediated diseases, with a potentially competitive profile compared with intravenously administered anti-C5 monoclonal antibody therapy. ALN-CC5 utilizes the company’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. ESC-GalNAc conjugates are a clinically validated platform based on recent preliminary Phase 1 study results from the company\'s ALN-AT3 program in development for the treatment of hemophilia. In a presentation titled “RNAi-Mediated C5 Silencing for Complement Inhibition,” Alnylam scientists presented new pre-clinical data with ALN-CC5. In NHP studies, weekly subcutaneous doses of ALN-CC5 at 5 mg/kg led to serum C5 knockdown of up to 98.7% (mean of 97.9 +/- 0.7%), as well as inhibition of complement activity of up to 91.3% (mean of 84.9 +/- 7.1%) by serum hemolytic activity assay and up to 96.8% (mean of 94.6. +/- 1.8%) by complement alternative pathway (CAP) ELISA. Based on early human translational data for ESC-GalNAc conjugates, weekly dosing at less than 1 mg/kg is expected to result in similar effects in humans. The observed inhibitory effect toward complement activity is notable since an over 80% level of complement inhibition has been shown to yield clinical benefit in paroxysmal nocturnal hemoglobinuria (PNH) based on published data with eculizumab, an intravenously administered monoclonal antibody that binds to serum C5 (Hillmen et al., N Engl J Med 2004,350:552-559). The company is continuing dosing in the primate study to explore twice-monthly and once-monthly subcutaneous dosing regimens, and expects to report additional pre-clinical data later this year. In addition, in vitro reconstitution studies in human serum were performed to evaluate the potential anti-C5 monoclonal antibody (anti-C5 mAb) dose sparing effects of ALN-CC5. Specifically, in serum in which C5 was reduced to 5% of normal (i.e., a level corresponding to 95% C5 knockdown with RNAi), the concentration of anti-C5 mAb required to achieve 80% inhibition of hemolytic activity was found to be reduced approximately 20-fold. This lower concentration requirement could reduce frequent dose requirements and the high costs of anti-C5 antibody therapy. Finally, results were presented from a study comparing subcutaneous doses of ALN-CC5 to a high, intravenously administered dose of an anti-C5 mAb in a mouse anti-collagen antibody induced arthritis (CAIA) model. Results showed that C5 knockdown with ALN-CC5 was as effective as the anti-C5 antibody in reducing clinical disease activity, with both treatments resulting in an approximately 80% reduction in clinical disease activity score. Moreover, ALN-CC5 maintained its knockdown effect toward C5 following lipopolysaccharide (LPS) treatment, showing the ability of RNAi to blunt induction of C5 as part of an inflammatory response. These results demonstrate that knockdown of liver-derived C5 should be fully sufficient to achieve a therapeutic effect, and show the absence of a significant role for local complement production in this disease model.The company is on track to file its ALN-CC5 IND or IND equivalent in late 2014, and is now guiding that it expects to present initial clinical results in mid-2015.
