For every drug used to treat thrombosis – dangerous clots in blood vessels – the protection comes at the cost of an increased risk of internal bleeding. This grim tradeoff was long assumed to be more or less inevitable.
But a new kind of antithrombotic developed at OHSU appears capable of avoiding bleeding complications. Called xisomab 3G3, it is an engineered monoclonal antibody that binds to a blood component called factor XI, which had attracted little attention until its potential was revealed by Andras Gruber, M.D., a professor of biomedical engineering in the OHSU School of Medicine. Factor XI has since become a hotly pursued target of drug discovery efforts, with dozens of related patents and patent applications during the past five years.
Gruber and his collaborators got a jump on the field with a series of patents filed between 2001 and 2009. And a few weeks ago, the U.S. Food and Drug Administration gave them a green light to begin phase 1 testing of xisomab 3G3 in human subjects.
“Xisomab is the first therapeutic new molecular entity developed in-house at OHSU that has received an FDA go-ahead for human evaluation,” says Gruber. He led the development with OHSU biomedical engineering colleague, Erik Tucker, Ph.D., an adjunct research assistant professor, and David Gailani, M.D., a professor at Vanderbilt University School of Medicine.
Gruber’s interest in factor XI began years ago with musings about the problem of off-target effects. It is relatively easy to develop a drug that acts on a given target in the human body.
“The problem is they’re not disease-specific enough; they also interfere with essential functions,” Gruber says.
Antithrombotic agents well illustrate the problem. They improve survival by stopping the cascade of reactions that trigger the clotting that causes heart attacks, strokes, deep vein thrombosis and other life-threatening conditions. But a rapid clotting cascade is also necessary to prevent uncontrolled bleeding when tissues are damaged.
Warfarin has been mainstay of antithrombotic therapy for more than 50 years. To prevent the risk of major bleeding, it requires ongoing monitoring and adjusting of the dose to maintain effectiveness within a narrow window of safety.
Newer antithrombotic drugs that target thrombin or factor X – key players in the clotting cascade – appear to be safer than warfarin. And these newer drugs can be given in fixed doses that do not require monitoring. Still, all are associated with the life-threatening side effect of internal bleeding. So the need for better antithrombotics remains urgent.
Typically in drug development, researchers seek compounds with a high affinity for the target, and deal with toxicity later. Gruber decided to approach the problem with safety being the first step, says his OHSU colleague Owen McCarty, Ph.D., a professor and interim chair of the Department of Biomedical Engineering.
This led Gruber to focus on factor XI, at the time a poorly understood protein involved in blood clotting. It was known, however, that people with inherited deficiencies in the factor XI gene seem to gain protection from certain types of blood clots. Blood clots can have life-threatening complications, including strokes, myocardial infarction, pulmonary embolism and others. It was also known that people born with factor XI gene deficiencies either have no symptoms or experience less severe bleeding problems than seen in other clotting factor deficiencies.
“It’s usually not a big deal,” Gruber says.
Clotting of blood is a process in which dozens of components interact to drive the reaction forward. There are two main pathways: the so-called extrinsic pathway, activated by trauma that cuts or tears blood vessels; and the intrinsic pathway, activated by damage and inflammation inside the vascular system or by exposure of blood to foreign substances (the surface of an artificial heart valve, for example).
As scientists came to understand the separate pathways, Gruber, and soon others, began exploring the idea that selectively blocking the intrinsic route could provide the long-sought antithrombotic with a low bleeding risk. It would work, as long as it left the extrinsic pathway intact.
Gruber and his colleagues were the first to produce experimental data to show that this could be done by targeting factor XI. Subsequently they developed a monoclonal antibody, xisomab, that binds to a specific site of factor XI. When bound there, it blocks the activation of factor XI by another clotting factor, XII, which interrupts the intrinsic pathway to thrombosis. But the antibody does not stop factor XI from taking part in the extrinsic pathway that is vital for rapid clotting of blood at wound sites.
In studies with mice, treatment with the antibody provided protection from ischemic stroke. Compared with untreated mice in the stroke model, treated mice showed less extensive areas of brain tissue death, greater restoration of blood flow after the stroke, and improved neurological behavior. The antibody-treated mice did not become vulnerable to uncontrolled bleeding. Tests in a primate model had comparable results: protection from thrombosis without increased bleeding.
OHSU in 2012 issued a patent license to Aronora, a startup founded a few years earlier by OHSU and Gruber. Tucker joined the company in 2009, as it began to usher drug candidates through preclinical development, clinical trials and commercialization. Bayer AG has already sublicensed one of the company’s antibodies, and it has an option to sublicense xisomab.
The phase 1 study now underway is a randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of xisomab 3G3 in healthy adult subjects. The company expects to complete the study by April 2018.
Going forward, the antithrombotic agent has many potential applications that could be pursued. It could be tested as a way to prevent or treat surgery-associated deep vein thrombosis, for instance, reduce the mortality of severe infections that are associated with bleeding and blood clots, or prevent or treat strokes in high- -bleeding-risk patients with atrial fibrillation. Or it could be tested in situations where both clotting and bleeding are a danger, for example when blood is exposed to artificial surfaces, such as in hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation.
Gruber says the most urgently needed use would be dealing with the thrombotic and inflammatory complications of severe sepsis, when an overwhelming immune response to infection causes widespread inflammation, blood clots and leaky blood vessels.
In studies using a mouse model of abdominal sepsis, Gruber and colleagues already have shown that factor XI contributes to lethal complications. Animals with sepsis that were treated with the antibody showed less inflammation, clotting, and bleeding, and the treatment improved survival. In July, at the 2017 International Society on Thrombosis and Haemostasis Congress in Berlin, the investigators reported that xisomab could prevent death from lethal Staphylococcus aureus challenge in baboons.
The researchers have a compelling reason to focus on the lethal complications of severe sepsis-associated systemic inflammatory response syndrome.
As it stands, Gruber says, “There is no other treatment.”