Date: 2014-09-16
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the 25th International Complement Workshop being held September 14 - 18, 2014, in Rio de Janeiro, Brazil
Company: Alnylam Pharmaceuticals (USA - MA)
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, membranous nephropathy, 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 (mAb) 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 September 16, 2014, Alnylam Pharmaceuticals announced new pre-clinical results with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases. These results were presented at the 25th International Complement Workshop being held September 14 - 18, 2014, in Rio de Janeiro, Brazil . Amongst other results, new positive data were reported from non-human primate (NHP) studies evaluating a monthly subcutaneous ALN-CC5 dose regimen, and from a rodent model of primary membranous nephropathy (MN) - a complement-mediated progressive disease of the kidney with high unmet need - where anti-C5 monoclonal antibody (mAb) therapy has demonstrated incomplete effectiveness (Cunningham et al., J Am Soc Nephrol2005, 16:1214-1222). The new research findings included data on ALN-CC5 activity in NHP and results in a rodent model of MN. New NHP studies were performed to evaluate a monthly or twice-monthly subcutaneous dosing regimen as compared with previously reported results with weekly dosing. With either a monthly or twice-monthly dosing regimen, ALN-CC5 administration at 5 mg/kg led to potent, clamped knockdown of serum C5 of up to 98.7% (mean of 98.2 +/- 0.8%), 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. Results were presented for a period of 100 days from the ongoing study. Based on human translational data for ESC-GalNAc conjugates, dosing at less than 1 mg/kg and less than 1 mL/injection are expected to result in similar effects in humans. The observed inhibitory effect toward complement activity in these pre-clinical studies 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 mAb that binds to serum C5 (Hillmen et al., N Engl J Med 2004, 350:552-559). In addition, new pre-clinical results were reported for ALN-CC5 in the rat passive Heymann nephritis model of MN (as described in Salant et al., J Clin Invest 1980, 66:1339-1350). In the model, nephritis is induced by administering a sheep anti-rat kidney fraction antiserum that results in complement-mediated renal damage similar to that reported in the human MN disease. As compared with placebo, ALN-CC5 administration was associated with a statistically significant (p < 0.05) reduction by over 70% in the proteinuria associated with complement-mediated renal damage. These results demonstrate pre-clinical efficacy for ALN-CC5 in the setting of renal impairment, where clinical results with anti-C5 mAb therapy have shown limited effects. Finally, as previously presented, results in a mouse anti-collagen antibody induced arthritis (CAIA) model showed that C5 knockdown with ALN-CC5 was as effective as an anti-C5 mAb 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. New data presented today show that RNAi-mediated C5 knockdown preserves joint histology and prevents C3 deposition as effectively as inhibition with an anti-C5 mAb. These results demonstrate that knockdown of liver-derived C5 is sufficient to achieve a therapeutic effect, and show the absence of a significant role for local complement production in this disease model. The company remains on track to file its ALN-CC5 Clinical Trial Application (CTA) in late 2014 and expects to present initial clinical results in mid-2015.
