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X01 Cracks Coagulation Conundrum, Raises $11M

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By Catherine Shaffer
Staff Writer

When Trevor Baglin, a hematologist at Addenbrooke's Hospital at Cambridge University had a head injury patient with a much better-than-expected outcome, he did something unusual. He got very curious.

Physicians had found in the patient a degree of anticoagulation consistent with severe hemophilia, and yet the patient's bleeding stopped normally.

Rather than writing it off as good luck, Baglin teamed up with Jim Huntington, of the Cambridge Institute for Medical Research, to design a synthetic version of an antibody in the patient's blood that caused the anticoagulation effect without excessive bleeding. That discovery became the central asset for a new company, X01 Ltd., based in Cambridge, formed by Index Ventures, which has now raised $11 million to develop the antibody, ichorcumab, as an alternative to currently marketed anticoagulants, which carry a major risk of excessive bleeding.

The revelation that clotting could be blocked without resulting in bleeding was a huge surprise. According to X01 acting CEO David Grainger, understanding what was going on required testing new theories of how clotting works. X01 execs contended that clotting happens in two stages, a clot formation stage and a slow expansion stage. Ichorcumab may block that second stage.

"The field, almost simultaneously with this discovery, is beginning to figure out that it's a two-step process," Grainger told BioWorld Today.

X01 was formed by Index Ventures. Grainger said it took "about 20 seconds" to realize that the research by Baglin and Huntington had potential. However, there was no team and no business plan around it. "It was nothing but a naked asset," Grainger said.

Index built a company around that asset, and has funded it to the tune of $11 million. Grainger said that Index recognized the potential of ichorcumab because it is unprecedented in the field of antithrombotic drugs to separate the anticoagulation effect from the bleeding side effect. He noted that even the new factor Xa inhibitors do not separate those effects any better than warfarin.

"Clearly there's a huge amount of potential," Grainger said. "What's really unique is the way in which it was found, in a patient with an antibody at very high levels in the blood for many years." Essentially, the product has already had a long-term, high-dose clinical trial in one patient. "That's something you never have for a preclinical asset," Grainger said.

The $11 million cash infusion is expected to get the product to the end of a first time in human study, taking between two and 2.5 years, with investigational new drug filing after about 18 months.

Next steps after that would include raising a Series B round to complete Phase I testing, and launching a Phase IIa study in knee surgery.

Grainger said that knee surgeries tend to have spontaneous clot formation as a complication, and although it's generally not terribly dangerous for the patient, it makes a convenient model of clotting efficacy vs. bleeding risk.

"It's a well-trodden pathway for drugs recently through that process," he noted.

In the short term, X01 will be working with the antibody in animals to confirm its profile of anticoagulation without bleeding risk. After that, the company will begin doing toxicology work and other studies necessary to prepare for human trials.

The company will operate in virtual mode, outsourcing its activities to other organizations in order to maintain flexibility and speed development.

Antithrombotics, particularly Factor Xa inhibitors, have been hot commodities in the drug development world, as a need exists for more effective therapies with less dangerous side effects.

A Factor Xa inhibitor, betrixaban, is the star asset in Portola Pharmaceuticals Inc.'s portfolio, which it leveraged to make an initial public offering in May, to raise $122 million. It also reported safety and efficacy data from a Phase II proof-of-concept study of approved Factor Xa inhibitor Eliquis (apixabn) in healthy volunteers showing that it results in a rapid, sustained, dose-related reversal of anticoagulant activity with no serious adverse events.

Perosphere Inc., of Mount Kisco, N.Y., recently received FDA clearance of its investigational new drug application to start clinical testing of PER977 to reverse anticoagulant activity of unfractionated heparin low-molecular-weight heparins, fondaparinux and Factor Xa- and IIa inhibitors. Perosphere initially will test the ability of PER977 to reverse the anticoagulant activity of edoxaban, a Factor Xa inhibitor sold by Tokyo-based Daiichi Sankyo Co. Ltd., which is co-sponsoring the Phase I trial.

>Thus far, however, none of the Factor Xa inhibitors on the market or in development have shown the characteristic of stopping clotting without bleeding as a side effect.

Index Ventures has been very active in the biotech space, based on its model of building a virtual company around a single asset. It has recently funded Gensight Biologics and Versartis Inc. (See BioWorld Today, Jan. 16, 2013, and April 10, 2013.)

Index's goal is to invest in first-in-class or best-in-class products that are based on novel science and meet unmet medical need. The fund aims to attenuate risk by putting cash into small companies that have only one or two assets, reducing the amount of money that goes into building corporate infrastructure and putting the focus on finding out if the molecules work or not. (See BioWorld International, Oct. 17, 2013.)