Straight Dope on Medicine: Anthos- Too Good to Continue

Author

Scott Ganser
September 25, 2023

The oldest known use of the proverb you can't have your cake and eat it too was in a letter from Thomas, Duke of Norfolk to Thomas Cromwell in 1538.

But sometimes you can.

That is the position Anthos Therapeutics finds itself in due to its smashing success with its lead monoclonal antibody

You see, this agent is a clot buster. What always accompanies clotbusters is the possibility or even inevitability of excessive bleeding

Anthos has found a way around it: clotbusting without bleeding.

How do they phrase it?

Abelacimab, [is] an investigational monoclonal antibody that achieves profound suppression of the novel antithrombotic target Factor XI through dual activity against both Factor XI itself and its activated form, Factor XIa. Abelacimab represents a promising next-generation anticoagulant with the potential to provide ‘hemostasis-sparing anticoagulation’: vital protection from arterial and venous thromboembolic events with a reduced risk of clinically significant bleeding.[i]

Hemostasis means that the body makes a blood clot to stop bleeding.

Rarely, exceedingly rarely, are clinical trials stopped because a prospective drug works too well for the trials to continue. We have to gather the data to support safety and efficacy.

However, when an agent addresses a life-threatening condition, and the evidence is overwhelming that it works, the monitoring group can make the call to end the investigation early because it is deemed “unethical” to withhold said investigational agent from the placebo (control) group.

Anthos has achieved this distinction.

Anthos Therapeutics is ending the Phase II AZALEA-TIMI 71 study ahead of schedule after its investigational monoclonal antibody abelacimab demonstrated an “overwhelming reduction” in bleeding compared to Bayer and Johnson & Johnson’s Xarelto (rivaroxaban), the company announced Monday.

Patients treated with abelacimab saw a sharp reduction in the composite endpoint of major and clinically relevant non-major bleeding events compared with counterparts given rivaroxaban, the current standard-of-care oral anticoagulant.[ii]

Due to the “overwhelming reduction in bleeding” reported in AZALEA-TIMI 71, abelacimab may represent a “paradigm shift” in atrial fibrillation care particularly in the prevention of stroke and other thrombotic conditions, Anthos CMO Dan Bloomfield said in a statement.

Abelacimab is a highly selective and fully human monoclonal antibody that works by inhibiting both Factor XI and its active form Factor XIa. Both proteins play an important role in the coagulation cascade, and high concentrations have been known to promote thrombosis, or pathological clots that impede the flow of blood in veins and arteries.

In a previous study, published August 2021 in The New England Journal of Medicine, abelacimab was able to reduce venous thromboembolism by approximately 80% versus standard of care in patients undergoing knee arthroplasty. The proof-of-concept study gave abelacimab at 30-mg, 75-mg and 150-mg doses, and found that serious adverse events were uncommon across all three dose levels.

Anthos has also demonstrated that at its 150-mg dose, abelacimab can maintain around 98% inhibition of its target proteins over the dosing interval.

Abelacimab is being investigated for two indications: 1) blood clots associated with cancer 2) blood clots in the heart that may lead to stroke.[iii]

More indications will follow. You have to start somewhere.

The Global Clot Busting Drugs Market size is expected to reach $47.7 billion by 2030, rising at a market growth of 7.9% CAGR during the forecast period[iv]

Those aren’t small potatoes

TV Tropes

Anticoagulants would generate more than 40% share of the market by 2030. Cardiovascular diseases (CVDs), which claim approximately 17.9 million lives annually, are the leading cause of mortality worldwide, according to the World Health Organization. Heart attacks and strokes account for more than four out of every five CVD deaths, with premature deaths accounting for one-third of these deaths in those under the age of 70. Unhealthy food, inactivity, cigarette use, and alcohol abuse are the four biggest behavioral risk factors for heart disease and stroke. Raised blood pressure, elevated blood glucose, elevated blood lipids, as well as being overweight and obesity might be symptoms of behavioral risk factors in people.

Animation

anthostherapeutics.com/wp-content/uploads/2023/06/AOS101_abelacimab_MoA_Animation_HD_220612-4.mp4

Stroke

Not so long ago, headlines trumpeted Alteplase.

A new clot busting drug developed by scientists at the University of Manchester is able to effectively break down blood clots in the brains of mice that are resistant to current drugs, according to research we’ve funded and published in the journal Blood. The scientists say that the findings could open the door for a safer and more effective stroke treatment.[v] 

Researchers found that the drug they’ve developed, called caADAMTS13, was effectively able to break down blood clots in the brains of mice who had had a stroke. They also found signs that it may have a beneficial effect on the immune response that a stroke triggers.

Alteplase is currently the only clot busting drug approved to treat patients who have an ischaemic stroke. While it works for many patients, it’s less able to break down clots which are rich in Von Willebrand Factor, a protein that plays a crucial role in blood clot formation. Around 50 per cent of clots are rich in Von Willebrand Factor.

The drug also prevented neutrophils, a type of white blood cell, from entering the brain tissue that had been starved of oxygen. This process is thought to damage brain cells, so preventing this from happening could further help to reduce the amount of damage a stroke causes.

“With over 100,000 strokes in the UK each year, new treatments are sorely needed to improve outcomes for patients. These promising findings suggest that drugs that target Von Willebrand Factor (VWF) have the potential to safely and effectively dissolve blood clots that resist currently available therapies.

This distinction has Alteplase on track to earn $2 billion by 2030.

Stroke statistics

  • In 2021, 1 in 6 deaths from cardiovascular disease was due to stroke.1

  • Every 40 seconds, someone in the United States has a stroke. Every 3 minutes and 14 seconds, someone dies of stroke.[vi]

  • Every year, more than 795,000 people in the United States have a stroke. About 610,000 of these are first or new strokes.

  • About 185,000 strokes—nearly 1 in 4—are in people who have had a previous stroke.

  • About 87% of all strokes are ischemic strokes, in which blood flow to the brain is blocked.

  • Stroke-related costs in the United States came to nearly $56.5 billion between 2018 and 2019. This total includes the cost of health care services, medicines to treat stroke, and missed days of work.

  • Stroke is a leading cause of serious long-term disability. Stroke reduces mobility in more than half of stroke survivors age 65 and older.

The Clotbusting market is estimated to double by 2032.[vii]

Conclusion

Anthos has hit on the two critical categories: critical unmet medical need and overwhelming effectiveness. They are off to the races.

Barring strategic FDA corruption, of course.

One time when I was discussing property issues with my mobile mechanic, who owned homes, the scourge of property inspectors. He said that they are ALL on the take. One time when he first began his rental business, he dropped a $100 on the ground. The property inspector picked it up and said, “You dropped a $100.” The mechanic said, “It isn’t mine.” The inspector put it in his wallet. From that point forward, the mechanic said, “He was in my pocket.”

Suddenly the “property issues” disappeared.

Maybe these biotechs need to drop a $100 on the ground.

However, we probably shouldn’t be accommodating corruption, or playing along with it, but rooting it out and eliminating it.

We’d all be better off.

Jean Connors, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, all based in Boston, Massachusetts, USA, began by establishing that a key patient population in particular need of safe and effective anticoagulation is the AF (Atrial Fibrillation) population, which represents 65–70% of the 3,600 patients cared for by the Brigham and Women’s Hospital anticoagulation management service in Boston. Connors highlighted the high and growing global prevalence of AF, which amounts to over 37 million cases, and is predicted to increase by as much as 60% by 2050.[viii] The size of this population means that the burden of complications exerts a significant impact on healthcare provision, and society in general. Since AF is well known to greatly increase the risk of stroke, anticoagulant protection is especially important in this population.

Anthos is delivering one.