(Bloomberg Businessweek) -- Blood clots are estimated to cause about 1 in 4 deaths worldwide, and the leading blood thinners prescribed to prevent them are among the most widely used medicines. Known under the brands Eliquis and Xarelto, the drugs are called Factor Xa inhibitors for the enzyme they block in the body's natural clotting process. In rare cases, however, switching off Factor Xa can cause unintended consequences, ranging from bruising easily to life-threatening internal bleeding, limiting who can take the medicines. Now drugmakers are working on alternatives that act on a different enzyme to dramatically reduce those risks.
If the emerging treatments are proven safe and effective, they'll allow pharmaceutical companies to target the roughly eight applications where Eliquis and Xarelto can't be used, including, critically, preventing strokes in people who've already had one, says Andrew Baum, an analyst at Citigroup Inc. It will take a few more years before any of them become available: Three of the experimental drugs that have generated buzz—from Bayer, Bristol-Myers Squibb and its partner Johnson & Johnson, and Anthos Therapeutics, a biotech that launched in 2019 using technology from Novartis—are in late-stage trials. And none would have meaningful sales until around 2028, after Eliquis and Xarelto are set to lose patent protection, Baum says. But the long-term potential is huge. He estimates the new drugs could become a $55 billion category by around 2035.
Even with just a handful of use cases, Eliquis and Xarelto are big moneymakers: Eliquis brought in almost $11 billion of sales for Bristol-Myers Squibb Co. last year, and J&J and Bayer AG's Xarelto recorded more than $8 billion. Among the conditions they can treat is atrial fibrillation, which results in an irregular heartbeat that can produce clots and is thought to affect 37 million people globally. Should the drugs work as well as the current treatments without the risk of bleeding, “that would be a game changer,” says Leslie Lake, president of the National Blood Clot Alliance, a nonprofit advocacy group, and the co-founder and managing director of New York City-based Invus Financial Advisors. “That's a really, really big deal.”
Clots act like a dam in a blood vessel, stopping oxygen-rich blood from flowing to critical organs. They're caused by a malfunctioning of the so-called coagulation cascade—how the body stops blood from pouring out when you scrape your arm or cut yourself shaving. Scientists have been tinkering with blood thinners for more than a century; early breakthroughs included heparin and warfarin—drugs that are still in use. Factor Xa inhibitors, approved about a decade ago, are the most targeted approaches developed to date. Yet the Factor Xa enzyme's centrality makes blocking it risky: Doing so opens a spigot and introduces the possibility that the flow may not shut off.
Blood thinners send older adults to the emergency room from complications at a higher rate than any other group of medications, according to the US Centers for Disease Control and Prevention. Before prescribing Eliquis or Xarelto, doctors weigh how much a person might benefit from the blood thinner against how much risk the side effects could introduce. For example, a lumberjack or sushi chef with atrial fibrillation wouldn't be a good candidate, because one wrong move at work could cause them to bleed out, says John Jefferies, a cardiologist at the University of Tennessee Health Science Center. “Anything you can do to put someone on a blood-thinning medication without the risk of bleeding is huge,” he says.
Genetics have been key to helping scientists identify a different blood-clotting enzyme to target: Factor XIa. People who lack the enzyme bleed slightly more than normal but not as badly as those with other forms of hemophilia. Research showed these people were at a lesser risk of stroke, giving drugmakers confidence to try replicating the phenomenon. Getting the medicines to their final phases of development has taken decades.
Bristol started its earliest work in 1999, and refining the chemistry to create a potent pill took 10 years alone. Today, Bristol and J&J are testing the molecule, called milvexian, in humans. Over the past year, the companies presented results from a few midstage trials. Bayer generated excitement in April when a study of its own compound targeting Factor XIa, asundexian, produced 67% less bleeding than Eliquis.
Most recently, Bristol and J&J shared data from a study examining whether milvexian could prevent another stroke in people who'd recently suffered one. The trial failed its main goal but gave the companies enough confidence to advance milvexian to the final round of tests, with executives pointing to a 30% reduction in stroke risk without a worrisome risk of bleeding. Bayer's asundexian also failed to meet its primary objective, but the company said it would keep going. Anthos Therapeutics Inc. started enrolling patients in late-stage trials of its monoclonal antibody, abelacimab, in May.
Importantly, the results suggest the experimental drugs are living up to their promise of being safer than the existing treatments, says Geoffrey Barnes, a heart and blood vessel doctor at the University of Michigan. “But I do think we all need to tamper down some of the enthusiasm in case they're not able to be quite as efficacious as hoped, and we won't know that until we conduct large Phase III studies,” says Barnes, who's consulted for Bristol, J&J, and Pfizer Inc.
Patients are rooting for all the drugs in the pipeline, says Lake, 58, who's taken Xarelto since doctors found multiple blood clots in her lungs in 2018. Because of the risk of unwanted bleeding, her doctors ordered her to give up hobbies like cycling through Manhattan and riding horses. “This could change the way people live their lives,” she says.
It will take years for the companies to complete the final studies they need to conduct to prove the drugs work. Thousands of people around the world will need to be recruited and monitored, a massive undertaking. For Bristol Chief Executive Officer Giovanni Caforio, the looming loss of exclusivity for Eliquis is an important consideration, but the treatment opportunity has always made the company's search for a safer blood-clot drug pressing: “The sense of urgency has always been there to develop milvexian rapidly,” he says, “because we know that there are patients that are waiting.”
(Adds detail about blood thinner risks in fifth paragraph. A previous version of the story corrected the relationship between Anthos and Novartis in second paragraph.)
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