NU172
How NU172 Works |
Potential Therapeutic Applications |
Clinical Trials |
Commercialization Rights | Scientific Publications and Presentations
A Thrombin Inhibitor
NU172 is a short-acting aptamer designed to directly inhibit thrombin's ability to stimulate blood clot formation in the setting of medical procedures where human blood is exposed to foreign materials. Data from the Phase 1 trial and preclinical studies suggest that NU172 has the potential to produce rapid and predictable onset and offset of anticoagulation, work in stagnant blood, avoid thrombocytopenia, and has the potential for non-renal clearance. Due to its short half-life, the effect of NU172 is rapidly reversed without the need for an antidote.
How NU172 Works
NU172 is an aptamer, a single-stranded nucleic acid that forms a well-defined three-dimensional shape conceptually similar to an antibody. Aptamers combine the optimal characteristics of small molecules and antibodies, including high specificity and affinity, and the ability to target protein-protein interactions. In contrast to monoclonal antibodies, aptamers are chemically synthesized rather than biologically expressed.
Potential Therapeutics
NU172 is being studied as a potential short-acting anticoagulant for use in the setting of medical or surgical procedures such as coronary artery bypass graft (CABG) surgery, kidney dialysis and percutaneous coronary interventions (PCI).Approximately 450,000 CABG procedures, 50 million dialysis procedures, and 1.2 million PCIs are performed annually in the U.S. During these procedures, anticoagulants are given to prevent blood clotting. In CABG procedures and often in dialysis, the anticoagulation effect of heparin must be reversed with protamine once the procedure has been completed.
Clinical Trials
We recently completed Phase 1 proof-of-concept development, demonstrating that NU172 rapidly produced and maintained anticoagulation with a rapid return toward baseline after the infusion ended. The single-center, Phase 1b trial examined the safety, tolerability and pharmacokinetics of intravenous bolus plus infusion dosing of NU172 in 24 healthy male volunteers. Volunteers were given a 2 mg/kg bolus dose followed by escalating infusion doses of NU172 for four hours. In all four cohorts, NU172 produced dose-dependent increases in anticoagulation, measured by activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT). The highest infusion dose rate tested, 6.0 mg/kg/hr, resulted in an average ACT per subject ranging from 373 to 414 seconds and an increase of approximately three times baseline. Average PT values per subject ranged from 56 to 92 seconds and had an increase of approximately five times baseline. Average aPTT values per subject ranged from 130 to 178 seconds and had an increase of approximately five times baseline. All measurements were maintained stably throughout the four-hour infusion. Once the infusion ended, the ACT and other coagulation parameters showed a rapid return toward baseline, consistent with the short plasma half-life of NU172 observed in the Phase 1a trial. In addition, NU172 was well-tolerated with no serious adverse events.
We expect to begin a Phase 2 study evaluating NU172 in the fourth quarter of 2008 or the first quarter of 2009.
Commercialization Rights
In August 2006, we entered into a worldwide collaboration with Archemix to develop and commercialize anti-thrombin aptamers. Under the terms of the agreement, Archemix is responsible for discovery of short-acting aptamers for use in acute cardiovascular procedures, and Nuvelo is responsible for development and worldwide commercialization of these aptamers. We paid Archemix an up-front payment of $4.0 million and, under certain circumstances, may invest up to $10.0 million in Archemix's common stock upon an initial public offering. We also agreed to fund Archemix research in the area of short-acting aptamers for three years at a minimum of $5.25 million. In addition, Archemix may receive payments totaling up to $35.0 million per development compound on the achievement of specified development and regulatory milestones, along with potential royalty payments based on sales of licensed compounds. At the initiation of the first Phase 3 study for any licensed compound, Archemix has the option to elect to participate in profits from sales of the compound by funding its pro rata share of prior and future product development and commercialization expenses, in lieu of receiving milestone payments and royalties with respect to that compound.
Scientific Publications
Scientific Presentations
Wagner-Whyte J, Khuri S, Olsen K, Hatala P, Boomer RM, Fraone JM, Brosnan N, Makim A, Lewis SD, Cai L, McCauley T, Hutabarat R, Horvath C, Ganley K, Funk W, Deitcher S, Treanor P, Thatte H, Hussaini BE, Rottman JB, Diener JL. Discovery of an extremely potent aptamer direct thrombin inhibitor. International Society on Thrombosis and Haemostasis (ISTH) Annual Meeting, July 2007, Geneva, Switzerland. [Wagner-White J et al J Thromb Haemost 2007;5(Suppl 1):Number P-S-067.]
Hutabarat RM, McCauley T, Makim A, Lewis S, Olsen K, Wagner-Whyte J, Diener J, Matyugicheva U, Scull J, Levy MD, Deitcher SD, Funk WD, Bouchard P. Pharmacokinetic/pharmacodynamic profile of a novel aptamer direct thrombin inhibitor in cynomolgus monkeys and Yorkshire pigs following a single IV bolus administration. International Society on Thrombosis and Haemostasis (ISTH) Annual Meeting, July 2007, Geneva, Switzerland. [Hutabarat RM et al J Thromb Haemost 2007;5(Suppl 2): P-S-072.]