Ichorcumab: the blood of the gods?

Index Ven­tures re­cently com­pleted an $11M 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 where 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: the pa­tient's 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 $200M 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 US 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 their 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. The pa­tient's 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 Prof. Jim Hunt­ing­ton in the Cam­bridge In­sti­tute for Med­ical Re­search. To­gether the pair of de­tec­tives began an in­ves­tiga­tive jour­ney that would last al­most five 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: the pa­tient 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 Pro­fes­sor 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 $11mil­lion 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 pro­gramme 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 pro­gramme using trusted sup­pli­ers. “With the right part­ners, out-sourc­ing 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 $11mil­lion, 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, PhD) has an in­ter­est in XO1, as in­terim Chief Ex­ec­u­tive Of­fi­cer.