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Chemistry: Generation 2+ LICA

IONIS-FXI-LRx is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of Factor XI, a clotting factor produced in the liver that is an important component of the coagulation pathway. High levels of Factor XI increase the risk of blood clot formation inside blood vessels (thrombosis), which can cause heart attacks and strokes. Alternatively, individuals deficient in Factor XI have a lower incidence of thrombosis-related events and little to no increase in bleeding risk. This makes Factor XI an attractive target for an antithrombotic drug because of the potential to separate antithrombotic activity from bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis, these anticoagulants are associated with increased bleeding risk at therapeutic doses, which can lead to major, sometimes fatal bleeding events. In clinical studies evaluating the safety and efficacy of the non-LICA version of IONIS-FL-LRx (IONIS-FXIRx), dose-dependent inhibition of Factor XI activity was demonstrated, which was associated with significant reductions in clotting events and no increase in major bleeding events. These data coupled with data in humans with little to no Factor XI activity provide evidence that IONIS-FXIRx has the potential to be used broadly as an anti-thrombotic in different therapeutic settings for which additional safe and well tolerated anti-thrombotic drugs are needed, especially in patient populations that are at high risk for thrombosis and are also at high risk for bleeding.

About Thrombosis

Thrombosis is the aberrant formation of blood clots inside blood vessels. Blood clots can obstruct blood flow to prevent sufficient oxygen flow to tissues and organs. In addition, clot fragments can break off from the blood clot and travel downstream to occlude other parts of the circulation. Thrombosis is responsible for many heart attacks and strokes and is the leading cause of morbidity and mortality worldwide.

Current antithrombotic treatments include anticoagulants such as warfarin, Factor Xa inhibitors and thrombin inhibitors. Although these drugs are effective at lowering the risk of thrombosis, these drugs place patients at significant risk of serious bleeding because they target factors required for normal coagulation.

Factor XI is a clotting factor produced in the liver that is an important component in the intrinsic pathway of the coagulation process. Factor XI’s role in blood coagulation is in clot stabilization and expansion and not in clot initiation. People with high levels of Factor XI have increased risk of thrombosis while those with deficient Factor XI have a lower incidence of thromboembolic events and minimal risk of bleeding.

Selected Publications

  1. Buller, H.R. et al. (2014) Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. N Engl J Med. Epub ahead of print.
  2. Crosby, J.R. et al. (2013) Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol. 33, 1670-1678.
  3. Younis, H.S. et al. (2012) Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood. 119, 2401-2408.
  4. Lowenberg, E.C. et al. (2010) Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost.8, 2349-2357.
  5. Zhang, H. et al. (2010) Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood. 116, 4684-4692.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.