title: M118--a rationally engineered low-molecular-weight heparin designed specifically for the treatment of acute coronary syndromes.
abstract: The initial choice of anticoagulant therapy administered in emergency departments for acute coronary syndromes (ACS) has important consequences for subsequent patient care, as neither unfractionated heparin (UFH) nor low-molecular-weight heparin (LMWH) are ideally suited for all potential clinical treatment pathways. UFH remains widely used for surgical interventions because of the ability to rapidly reverse its anticoagulant activity. However, the unpredictable pharmacokinetic profile of UFH presents safety issues, and the low subcutaneous bioavailability limits the utility of UFH for patients who are medically managed. LMWH has superior pharmacokinetic properties, but its anticoagulant activity cannot be effectively monitored or reversed during surgery. There is an unmet medical need for a baseline anticoagulant therapy that addresses these shortcomings while retaining the beneficial properties of both UFH and LMWH. We describe here M118, a novel LMWH designed specifically for use in the treatment of ACS. M118 shows broad anticoagulant activity, including potent activity against both factor Xa (~240 IU/mg) and thrombin (factor IIa; ~170 IU/mg), low polydispersity, high (78%) subcutaneous bioavailability in rabbits, and predictable subcutaneous and intravenous pharmacokinetics. Additionally, the anticoagulant activity of M118 is monitorable by standard coagulation assays and is reversible with protamine. M118 demonstrates superior activity to conventional LMWH in a rabbit model of abdominal arterial thrombosis without increasing bleeding risk, and is currently being evaluated in a phase II clinical trial evaluating efficacy and safety in patients undergoing percutaneous coronary intervention.
authors.affiliation: Momenta Pharmaceuticals, Inc, Cambridge, MA 02142, USA. kkishimoto@momentapharma.com
authors.forename: Takashi Kei
authors.initials: TK
authors.lastname: Kishimoto
authors.forename: Yi Wei
authors.initials: YW
authors.lastname: Qi
authors.forename: Alison
authors.initials: A
authors.lastname: Long
authors.forename: Ishan
authors.initials: I
authors.lastname: Capila
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
authors.forename: Luis
authors.initials: L
authors.lastname: Guerrero
authors.forename: Ian
authors.initials: I
authors.lastname: Fier
authors.forename: James
authors.initials: J
authors.lastname: Roach
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkataraman
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001012:Aorta, Abdominal; D001018:Aortic Diseases / Q000188:drug therapy*; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D001682:Biological Availability; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D006470:Hemorrhage / Q000139:chemically induced; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use / Q000633:toxicity; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007413:Intestinal Mucosa / Q000737:chemistry; D008297:Male; D011817:Rabbits; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D013917:Thrombin