Conquering blood clots without causing bleeding

For all its iterative precision, science sometimes advances thanks to blind serendipity. In the case of a revolutionary new drug, which may be able to prevent heart attacks and strokes without causing bleeding, the breakthrough came with a doctor’s chance encounter with a patient in A&E who had highly anomalous blood chemistry.

When the patient in question arrived at Addenbrooke’s Hospital A&E in 2008, Prof Jim Huntington and Dr Trevor Baglin had been collaborating for nearly a decade on ways to outwit the blood clots that lead­ to millions of stroke and heart attack deaths every year.

“This patient arrived in A&E with a head injury”, recalls Baglin, the consultant on the case. Testing revealed she had a bruise on the brain, a potentially dangerous condition caused by bleeding. “We rapidly discovered her blood had a degree of anticoagulation consistent with severe haemophilia”, he says. “We thought it might be fatal, but—to our surprise—the bleeding stopped quite normally”. To say this was intriguing would be an understatement.

Routine blood tests showed that Baglin’s patient’s blood was resistant to clotting due to the presence of an inhibitory antibody, ruling out surgery. Baglin walked across the street to Huntington’s office at the Cambridge Institute for Medical Research, and the two set to work to characterise the antibody.

Their analysis revealed that the source of this anticoagulation was an antibody generated by the patient. It bound the key enzyme in the coagulation pathway, thrombin, and proved to be a potent inhibitor.

Despite exceptionally high levels of this inhibitory antibody, resulting in a clotting profile akin to a severe overdose of anticoagulants, the patient recovered without intervention and was discharged from the hospital after ten days.

Baglin and Huntington realised this antibody could help them develop a new anticoagulant drug. Because clots can be deadly, there are drugs are on the market to eliminate them by thinning the blood. But, for many patients, these drugs have dangerous side effects that can make the treatment for clots as perilous as the underlying condition.

What emerged from their work was ‘ichorcumab,’ a synthetic antibody with properties similar to the one found in the patient. It has the potential, observers say, to be one of the best drug candidates to emerge in the last 20 years.

“Undoubtedly higher doses of anticoagulant drugs could prevent the majority of heart attacks and strokes”, says Baglin. “But we can’t give higher doses because the bleeding it would cause would itself be fatal. Ichorcumab has the potential to change all that.”

Cambridge Enterprise was a key player in the development of ichorcumab and led the efforts to find a commercial partner. In the end, a spin-out, X01, was born with funding from Index Ventures and additional investment from Cambridge Enterprise Seed Funds.

“Trevor and I knew nothing about how to develop a new drug”, recalls Huntington. “The early involvement of Cambridge Enterprise was critical.”

In March 2015, X01 was acquired by Janssen Pharmaceuticals, Inc. The antithrombotic market is expected to reach $18 billion annually by 2018, demonstrating the drug’s commercial attractiveness. Several new oral anticoagulants have sales in the region of $1 billion a year each, even though their improvements over generic drugs, such as warfarin, are relatively small.

 

 

 

 

 

 

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