New Blood Thinners Will Prevent Blood Clots Without Causing Bleeding
Several blood thinners are being developed that could prevent the clots that cause heart attacks and strokes—without some of the side effects
Until now, preventing clots has often come at the price of a higher risk of bleeding, ILLUSTRATION: EVA VAZQUEZ A new class of anticoagulant drugs on the horizon is taking fresh aim at one of cardiology’s toughest challenges: how to prevent blood clots that cause heart attacks and strokes, without leaving patients at risk of bleeding.
At least a half-dozen experimental blood thinners are in development that inhibit a protein called factor XI, one of several blood factors that regulate how the body forms clots.
The challenge is this: The body generates two types of clots—good ones that plug holes in blood vessels to stop bleeding caused by external injuries, and bad ones that grow inside arteries and veins. These can block blood flow to critical organs, potentially leading to injury or death.
For decades, drugs developed to prevent the bad clots have targeted proteins involved in forming both types of clots. As a result, preventing clots often comes at the price of a higher risk of bleeding, causing many patients to refuse to take, or stop taking, the medicine.
“Too low of a dose, you clot; too high of a dose, you bleed,” says Dr. Michael Gibson, cardiologist and CEO at the nonprofit Baim Institute for Clinical Research at Harvard Medical School. “Our goal is to keep people from falling off the balance beam. This is what we have been chasing for years.”
Factor XI, it turns out, is crucial for the formation of the bad clots inside blood vessels, what doctors call thrombosis. But researchers now believe that factor XI, unlike other blood factors, plays a minimal role in forming the good clots that stop bleeding. That suggests drugs against it could prevent the bad clots without significantly disrupting the process that causes good clots, and thus minimize excess bleeding associated with anticoagulants and other blood thinners.
Important questions about the effectiveness of factor XI inhibitors have yet to be answered, and success isn’t ensured. Several large-scale or Phase 3 clinical trials are now under way to determine the clinical and economic potential of the new agents. Results are expected later this decade.
At this stage, Factor XI inhibitors “appear to have good safety but maybe not as good efficacy as we would like,” says Richard Kovacs, professor at Indiana University Medical School, Indianapolis, and chief medical officer of the American College of Cardiology, who isn’t involved with the research.
“There isn’t such thing as a free lunch. Maybe that applies here,” he says, adding that more research is needed to determine what role the drugs may play in clinical practice.
A big advance
Any factor XI agent that reaches the market would likely represent an important advance over drugs called factor Xa inhibitors, a blockbuster class of medicines dominated by Eliquis and Xarelto. Since they were approved just over a decade ago, these drugs have supplanted warfarin as the standard-of-care anticoagulant to prevent stroke in patients with the heart-rhythm disorder atrial fibrillation as well as other indications.
Last year alone, Eliquis, marketed by Bristol-Myers Squibb and Pfizer , and Xarelto, from Johnson & Johnson and Bayer, racked up combined worldwide sales of about $19 billion. But while the drugs sharply reduce risk of life-threatening and other serious bleeding, including bleeding in the brain, associated with warfarin, patients taking them remain at risk for such side effects as nosebleeds, bleeding gums and gastrointestinal bleeding that can affect their quality of life or even land them in the hospital.
As a result, studies show, an estimated 40% to 60% of atrial-fibrillation patients refuse to take, stop taking or skip doses of the anticoagulants—or their doctors decide not to prescribe them. That leads to more than 50,000 preventable strokes each year in the U.S. alone.
The factor Xa inhibitors “really changed the landscape” for anticoagulation, “but bleeding is still the major complication,” says Jeffrey Weitz, a professor and coagulation expert at McMaster University in Hamilton, Ontario, who advises several companies developing factor XI drugs. “If we could have something that is at least as effective and safer, that could take us to the next step.”
Testing the possibilities
An important driver of the effort is research showing that people born with low levels of factor XI suffer fewer strokes and other thrombotic events such as heart attacks than those with normal or elevated levels of the protein. They also are less prone to excessive bleeding, for example during surgery, than those with higher levels of factor XI. Moreover, they don’t appear to suffer any ill effects from being deficient in factor XI.
Bristol-Myers and J&J, rivals in the factor Xa market, have joined forces to make a huge bet on factor XI with a twice-a-day pill called milvexian. Their multibillion-dollar program includes Phase 3, or late-stage, trials for stroke prevention in atrial fibrillation and two other major indications—preventing recurrent events in patients who have already had an acute coronary episode such as a heart attack, or a stroke—with plans to enroll more than 46,000 patients. Milvexian targets the activated, or clot-initiating, form of factor XI, called factor XIa. Harvard’s Gibson is leading one of the trials.
Also in the mix is Anthos Therapeutics, a startup launched in 2019 by Blackstone Life Sciences, a unit of the private-equity firm Blackstone Group, to develop an antibody called abelacimab against factor XI. Anthos obtained rights to the drug from Novartis, which retains a royalty interest in it.
Merck, Ionis Pharmaceuticals and closely held Aronora have agents earlier in development aimed at various clot-related ailments.
Anthos provided a boost for agents against factor XI at the annual scientific meeting of the American Heart Association in November. There, researchers reported that abelacimab showed a striking 67% reduction in bleeding risk when tested against Xarelto in a study of 1,287 patients with atrial fibrillation at moderate to high risk of a stroke.
Such an advantage on bleeding against a factor Xa inhibitor “was really a game changer,” says Dr. Christian Ruff, director of general cardiology at Brigham and Women’s Hospital, Boston, who led the trial.
Moreover, patients treated with abelacimab, delivered once a month by injection, had a 93% reduction in gastrointestinal bleeding compared with those taking Xarelto. GI bleeding accounts for about three-quarters of bleeding events that lead to hospitalization for atrial-fibrillation patients.
But while the reduction in bleeding indicates the drug is safer than a factor Xa inhibitor, the trial wasn’t large enough to show whether abelacimab was at least as effective in preventing stroke as Xarelto, leaving the efficacy question unanswered.
A week later, Bayer, a third contender in the factor XI race, stunned cardiologists with the announcement that a Phase 3 study of its factor XIa inhibitor asundexian was stopped early for lack of efficacy in preventing stroke in atrial-fibrillation patients when tested against Eliquis.
Pressing ahead
Weitz believes asundexian was ineffective because the dose in the study was too low. Bristol-Myers, J&J and Anthos say they remain confident in prospects for their respective agents. For its part, Bayer says it is reviewing data from its study and plans to publish its findings “in due time.” It is continuing a Phase 3 trial of the drug to prevent recurrent stroke and weighing its options for other indications, including in atrial-fibrillation patients.
“We continue to believe in the promise of factor XIa inhibitors, and in asundexian,” the company says.
In any event, the failure of the asundexian study means just two factor XI agents have emerged as front-runners in a race to reach the market for stroke prevention in atrial-fibrillation patients—a total market in the U.S. of six million patients that the U.S. Centers for Disease Control and Prevention expects to grow to 12.1 million by 2030.
Anthos, which had the big bleeding win in a study against Xarelto, is enrolling about 1,900 patients in a Phase 3 trial testing abelacimab against placebo among some atrial-fibrillation patients. The study is targeting only the estimated 40% to 60% of atrial-fibrillation patients who, because of bleeding risk or fear of bleeding, aren’t taking a factor Xa inhibitor or another anticoagulant such as warfarin or the antithrombin drug dabigatran. The strategy could narrow its market for the drug, at least initially, but the company believes it will have no trouble proving efficacy in preventing stroke against placebo. Results could come in 2025.
“Those are the patients who really need an anticoagulant that’s safer,” says Dr. Dan Bloomfield, Anthos’s chief medical officer. Essentially “placebo is what they’re taking anyway.” Results could come as early as next year. Anthos is also testing abelacimab in certain cancer patients with a blood-vein clotting condition called venous thromboembolism.
Bristol-Myers and J&J are testing milvexian in a 15,500-patient head-to-head trial against Eliquis. The challenge is to show the drug is at least as effective in preventing stroke as Eliquis with a significantly lower bleeding risk. Results are expected in 2027.
If the trials are successful, the timing in both cases suggests the drugs could reach the market just as Eliquis and Xarelto lose patent protection and cheaper generic versions become available. Drugs will likely have to show a significant benefit against factor Xa inhibitors to gain traction against generic competition, researchers say.
Low bleeding risk could also make factor XI inhibitors candidates to help prevent recurrent events in patients who have already suffered a stroke or an acute coronary event such as a heart attack—a potentially huge new market for anticoagulants. Standard of care for such patients are antiplatelet drugs such as clopidogrel, ticagrelor and aspirin, regimens that have sharply limited or ruled out adding anticoagulants that increase a patient’s bleeding risk. Bristol-Myers and J&J could see the results of their studies in these indications in 2026.
“It’s an exciting hope that we can find drugs that will prevent [stroke] associated with atrial fibrillation without increasing the bleeding,” says Dr. Mariell Jessup, chief science and medical officer at the American Heart Association, who isn’t involved in the research. “If this is efficacious, it will change many, many things” about treatment of cardiovascular disease.