Ichorcumab: the blood of the gods?

By David Grainger

Index Ventures recently completed an $11 million Series A investment in XO1, an asset-centric company established with the sole objective of developing the monoclonal antibody ichorcumab under license from Cambridge University.

The story of its discovery has striking similarity with Alexander Fleming's discovery of penicillin--combining luck and skill in equal measure when a patient displaying a unique blood-clotting profile arrived in a hospital emergency room. But, fortunately, not just any hospital. This patient arrived at Addenbrooke's Hospital in Cambridge and into the clinical care of Trevor Baglin--a clinician with a unique depth of knowledge on the inner workings of blood clotting derived from parallel interests in research and patient care. As he observed his patient over a period of several weeks, the full significance of what he was witnessing began to dawn on him. 

Yet his biggest asset was his friendship and collaboration with Professor Jim Huntington, a structural biologist with a particular penchant for the coagulation cascade (an area in which Cambridge University has led the world for two decades, among other things elucidating the "mousetrap" mechanism of serpin inhibition of proteases in the clotting cascade--an early achievement on Professor Huntington's CV).

Together, they pieced together the story of this singular patient: her blood contained an antibody against the exosite 1 of thrombin that conferred unique properties--anticoagulation without any propensity to bleed.

The investment--which comes from the €150 million Life Sciences fund Index launched with Johnson & Johnson and GlaxoSmithKline in 2012 to accelerate new drug discovery--is one of the largest-ever Series A investments in a preclinical stage, single-asset company certainly in Europe. Indeed, it ranks as a significant deal even by U.S. standards. But that is entirely appropriate: Ichorcumab is a very special antibody.

Current anticoagulants (including the much heralded novel oral anticoagulant drugs, such as the direct thrombin inhibitor Pradaxa™ (dabigatran) and the Factor Xa inhibitors like Eliquis™ (apixaban), as well as older drugs such as warfarin, heparin and anti-platelet agents) cause bleeding at the same doses they deliver anticoagulation.

In fact, so many drugs show this profile that it has long been assumed that dissociating undesirable bleeding from beneficial anticoagulation was impossible.

That was until this patient arrived at Addenbrooke's Hospital.

In Greek mythology, ichor was the ethereal fluid in the blood of the gods that conveyed their immortality. It is early days, but ichorcumab (a monoclonal antibody with the same binding characteristics as this patient's natural antibody) has the potential to offer, if not immortality, then at least a chance to save millions of lives.

"A Five Year Journey"

It was August 2008, when a patient in her fifties presented at the emergency room of Addenbrooke's, the teaching hospital of Cambridge University, with a head injury. A CT scan revealed a small haematoma, and in preparation for any possible need to drain it if it worsened, the surgeons ordered a routine clotting screen.

The results shocked the consultant haematologist on duty, one Dr Trevor Baglin. Her blood was essentially unable to clot.  Alarm bells immediately rang--a bleed on the brain and blood that cannot clot are invariably a fatal mix.

However, hours, then days, passed and far from suffering a fatal bleed, the haematoma spontaneously resolved without intervention. Fascinated, and slightly perplexed as to what could cause such a phenotype with total anticoagulation in the test tube, but no propensity to major bleeding complications (the holy grail for anticoagulant drugs), Dr Baglin contacted his friend and collaborator Professor Jim Huntington in the Cambridge Institute for Medical Research.

Together the pair of detectives began an investigative journey that would last almost 5 years and culminate in the founding of XO1.

The unusual clotting profile of this patient, it turned out, was down to a million to one chance: she had developed an IgA paraprotein that reacted with thrombin. And reacted with thrombin in a very special way that allowed clots to form and stabilize--so preventing bleeding--but not to expand into the intravascular space and so also preventing thrombosis.

Being structural biologists, Professor Huntington and his team crystallized the antibody:thrombin complex and elucidated the structure, showing the precise binding site in the exosite 1 region of the thrombin molecule. This clearly contributes to the attractive profile of the antibody, since exosite 1 is disordered in prothrombin, preventing the antibody from binding to and clearing the zymogen, an effect that would certainly cause bleeding.

The elegant mechanistic details that confer the lack of bleeding risk with this particular antibody have not yet been published, but they provide a unique insight into the molecular physiology of coagulation--as well as providing the first agent with the potential to dissociate bleeding from anticoagulation.

As DrugBaron has noted previously, even the recently introduced oral anticoagulants such as Pradaxa™ dabigatran from Boehringer Ingelheim and Eliquis™ Apixaban from BMS, distinguish bleeding and anticoagulation little better than warfarin. As Dr. Baglin puts it, "They are more convenient than warfarin, but they are not fundamentally better".

If you didn't have to worry about bleeding risk, the degree of anticoagulation could be significantly increased with substantial benefits in terms of reduced cardiovascular morbidity and mortality. And that's where ichorcumab comes in.

Using the structural data from the complex of the patient IgA with thrombin, the Cambridge team designed an IgG4 to bind to the same site, in the same way. BioLayer Interferometry confirms that this synthetic antibody has exactly the same binding characteristics as the patient's own IgA, and preclinical studies suggest it displays similar dissociation between anticoagulation and bleeding.

"Being on a hinge-stabilized IgG4 framework, this synthetic ichorcumab has ideal pharmacokinetics," explains Huntington. "And because there appears to be no bleeding risk, it's possible it could be administered monthly or even less frequently to achieve sustained and powerful anticoagulation."

"Maintaining complete anticoagulation without bleeding risk could in principle eliminate the risk of heart attack and ischemic stroke. That's why we named the monoclonal antibody after the blood of the gods--with this agent in your veins you may not achieve immortality but you might not die prematurely of cardiovascular disease, stroke or pulmonary embolism" he says.

The goal now is to get ichorcumab into the clinic as fast as possible, to see whether the extraordinary promise it shows in preclinical models is reflected in man. "Almost uniquely, though, we already have a lengthy clinical trial, albeit in a single patient" says Dr. Kevin Johnson, partner at Index Ventures and a director at XO1. "It's not sufficient proof, but it's more evidence of the clinical profile of a preclinical drug than we usually have".

It is also the perfect example of an asset-centric opportunity. In founding XO1 in Cambridge to develop this single asset, the objective is simple: to move it to clinical trials as quickly as possible and unlock its potential.

"You may not associate a $11 million Series A financing with asset-centric deals," said Johnson, "but then again in this case we felt we really had a straight-forward, and relatively low risk path forward. We are absolutely true to our model: every cent will be invested in driving the lead program to the clinic."

Not surprisingly, therefore, XO1 is following the tried-and-tested asset-centric formula of virtual development. Despite the headline investment figure, the company will operate with only a couple of employees--experienced drug developers guiding an out-sourced program using trusted suppliers. 

"With the right partners, outsourcing is not about saving money--though it does that too--but about smarter, quicker drug development," Johnson adds. "Ichorcumab will be the poster-child for the asset-centric virtual development model."

So this antibody may dissociate good from bad in more than one way: anticoagulation dissociated from bleeding risk, but also high quality development from high costs. If, as XO1 plans, they can take this agent into the clinic and obtain the first demonstration of its profile in man with a Series A investment of $11 million, then the future for modern biotech, as well as patients with cardiovascular disease, is set to be far brighter than it is today.

Note that DrugBaron (David Grainger, Ph.D.) has an interest in XO1 as interim Chief Executive Officer. He is also a venture partner at Index Ventures. Read his blog.

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