Contributions
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:45 to 14.06.2015 09:00
Location: Room Stolz 2
Background
Uncontrolled complement activation plays a pivotal role in a variety of disorders such as PNH and aHUS.
Aims
ALN-CC5 is a subcutaneous (S.C.) investigational RNAi therapeutic targeting complement C5 (C5) with the purpose of decreasing terminal complement activity and thereby protects against intravascular hemolysis and complement mediated tissue damage.
Methods
Preclinical studies in rat and non-human primate (NHP) models were used to investigate the ability of ALN-CC5 to reduce complement C5, inhibit complement-mediated hemolytic activity and complement alternative- and complement classic pathway (CAP and CCP). Furthermore, ALN-CC5 was investigated in a rat membranous nephropathy model, the anti-collagen antibody induced arthritis model and in a passive myasthenia gravis model.
A placebo controlled double blind phase 1 clinical study in healthy volunteers and patients with PNH is ongoing. Several cohorts in part A, a single ascending dose study have been completed and Part B, a multiple ascending dose study is currently ongoing. Part C will be a multiple dose study in patients with PNH. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, reduction of circulating C5, reduction in hemolytic and CAP as well as CCP activity.
Results
Pre-clinical studies demonstrated that ALN-CC5 resulted in mean 98.4 ± 0.7% reduction of C5 levels in NHPs, mean 88 ± 6.1%% reduction in hemolysis and mean 95.1 ± 0.93% reduction in CAP with every-other week or monthly S.C. dosing. Furthermore, ALN-CC5 significantly reduced proteinuria in a rat membranous nephropathy model, reduced disease activity in the mouse arthritis model and reduced clinical disease score and improved grip strength in the myasthenia gravis model. ALN-CC5 reduced disease manifestation comparable to treatment with C5 monoclonal antibody.
In Part A of the phase 1 study, human volunteer subjects were randomized (3:1) to placebo or a starting single subcutaneous dose of 50 mg ALN-CC5 and followed for at least 70 days. Following safety review, additional single ascending dose cohorts were authorized. Part B multiple ascending cohorts are planned to start in parallel to Part A. Up-to-date results on safety, tolerability and C5 knockdown, changes in CAP, CCP and hemolytic activity from study will be presented.
Summary
Collectively, these data suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement mediated diseases. The subcutaneous route of administration and infrequent dosing make this a particularly encouraging potential therapy.
Keyword(s): Complement, PNH, RNA interference (RNAi)
Session topic: Biology and clinics of bone marrow failure syndromes and PNH
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:45 to 14.06.2015 09:00
Location: Room Stolz 2
Background
Uncontrolled complement activation plays a pivotal role in a variety of disorders such as PNH and aHUS.
Aims
ALN-CC5 is a subcutaneous (S.C.) investigational RNAi therapeutic targeting complement C5 (C5) with the purpose of decreasing terminal complement activity and thereby protects against intravascular hemolysis and complement mediated tissue damage.
Methods
Preclinical studies in rat and non-human primate (NHP) models were used to investigate the ability of ALN-CC5 to reduce complement C5, inhibit complement-mediated hemolytic activity and complement alternative- and complement classic pathway (CAP and CCP). Furthermore, ALN-CC5 was investigated in a rat membranous nephropathy model, the anti-collagen antibody induced arthritis model and in a passive myasthenia gravis model.
A placebo controlled double blind phase 1 clinical study in healthy volunteers and patients with PNH is ongoing. Several cohorts in part A, a single ascending dose study have been completed and Part B, a multiple ascending dose study is currently ongoing. Part C will be a multiple dose study in patients with PNH. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, reduction of circulating C5, reduction in hemolytic and CAP as well as CCP activity.
Results
Pre-clinical studies demonstrated that ALN-CC5 resulted in mean 98.4 ± 0.7% reduction of C5 levels in NHPs, mean 88 ± 6.1%% reduction in hemolysis and mean 95.1 ± 0.93% reduction in CAP with every-other week or monthly S.C. dosing. Furthermore, ALN-CC5 significantly reduced proteinuria in a rat membranous nephropathy model, reduced disease activity in the mouse arthritis model and reduced clinical disease score and improved grip strength in the myasthenia gravis model. ALN-CC5 reduced disease manifestation comparable to treatment with C5 monoclonal antibody.
In Part A of the phase 1 study, human volunteer subjects were randomized (3:1) to placebo or a starting single subcutaneous dose of 50 mg ALN-CC5 and followed for at least 70 days. Following safety review, additional single ascending dose cohorts were authorized. Part B multiple ascending cohorts are planned to start in parallel to Part A. Up-to-date results on safety, tolerability and C5 knockdown, changes in CAP, CCP and hemolytic activity from study will be presented.
Summary
Collectively, these data suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement mediated diseases. The subcutaneous route of administration and infrequent dosing make this a particularly encouraging potential therapy.
Keyword(s): Complement, PNH, RNA interference (RNAi)
Session topic: Biology and clinics of bone marrow failure syndromes and PNH