Un­der the mi­cro­scope

Ire­land miss­ing out on huge drugs dis­cov­ery mar­ket:

The Irish Times - Tuesday - Health - - Front Page - Seán Duke

For decades now, Ir­ish gov­ern­ments have courted big pharma and en­cour­aged them to come here and man­u­fac­ture their drugs. This has cre­ated in­dus­try jobs for sci­en­tists, but there has been no ap­petite to en­cour­age drug dis­cov­ery – a risky busi­ness that de­mands huge in­vest­ment at an early stage.

The IDA, which is re­spon­si­ble for the at­trac­tion and de­vel­op­ment of for­eign direct in­vest­ment, has drawn most of the big pharma names here, and en­sured a steady stream of the spe­cialised sci­ence and med­i­cal grad­u­ates they re­quire even as their needs changed.

In­ter­est­ingly, Ire­land is the world’s leader in the man­u­fac­ture of so-called bi­o­logic drugs. These are hard to make – far harder than mak­ing an as­pirin tablet, for ex­am­ple – as they are com­plex and de­signed to bi­o­log­i­cally in­hibit the parts of our im­mune sys­tem that can turn against us and cause dis­eases such as rheuma­toid arthri­tis. The bi­o­log­ics are cash cows for the drug in­dus­try, with the global mar­ket set to reach an es­ti­mated $272 bil­lion (¤240 bil­lion) in 2017.

Ire­land is, thus, known around the world for the qual­ity of its sci­en­tists and abil­ity to make dif­fi­cult drugs. Yet there must be a ques­tion mark over why that kind of sci­en­tific tal­ent has not been en­cour­aged to en­ter into the re­ally valu­able field of drug dis­cov­ery.

This is a strate­gic mis­take, ac­cord­ing to ex­perts such as Luke O’Neill, pro­fes­sor of bio­chem­istry at TCD and founder of Op­sona Ther­a­peu­tics in 2004 and In­fla­zome in 2016. The aim of In­fla­zome is to de­velop new drugs for arthri­tis, type 2 di­a­betes, Alzheimer’s and Parkin­son’s.

“Blue skies re­search is es­sen­tial,” says O’Neill. “That is where the big­gest value is. Ire­land has to be par­tic­i­pate in this be­cause we could have a guy or a woman who will make the big break­through. You have to fund re­search here be­cause you never know: we might crack it.”

A dis­cov­ery lead­ing to a new drug could be worth $1 bil­lion or more to the Ir­ish econ­omy. But O’Neill says this won’t hap­pen by fund­ing re­search that sim­ply changes a nu­ance here or there.

Lab work

Since at least the 1980s, the cru­cial ini­tial work that led to the pro­duc­tion of new drugs has al­most al­ways been done in a univer­sity lab­o­ra­tory, first through the iden­ti­fi­ca­tion of drug tar­gets that might al­le­vi­ate dis­ease. This has been fol­lowed by enor­mous in­vest­ment by big pharma to get the drug through rig­or­ous clin­i­cal tri­als and onto the mar­ket.

A case in point are TNF-in­hibit­ing drugs, which were de­vel­oped to com­bat rheuma­toid arthri­tis. In 1986, in work funded by the UK Arthri­tis Foun­da­tion, pro­fes­sors Ravin­der Maini and Marc Feld­man found that TNF (tu­mour necros­ing fac­tor) was slosh­ing around in large quan­ti­ties in­side the rheuma­toid knee. TNF is a pro­tein made by the body’s im­mune sys­tem dur­ing in­fec­tion.

The pharma in­dus­try noted their re­search and funded work to block or in­hibit TNF. This led to the man­u­fac­ture of a drug called Rem­i­cade, which cures rheuma­toid arthri­tis in 50 per cent of pa­tients. Rem­i­cade acts by slow­ing down the ero­sion of joints and the crip­pling twist­ing of fin­gers. The drug is shared by John­son & John­son and Merck, and its an­nual sales value in the US along hov­ers around $5 bil­lion. It is one of the most valu­able drugs of all time, and is now also used to treat Crohn’s dis­ease.

No sur­prise, given the suc­cess of Rem­i­cade, that there are now six anti-TNF drugs avail­able on pre­scrip­tion, in­clud­ing one called Hu­mira, which is man­u­fac­tured in Sligo for Ab­b­vie. The firm earns about $6 bil­lion a year on the drug. So all of this value in mon­e­tary and hu­man terms come from one dis­cov­ery.

Tax­payer ex­po­sure

Most would agree that the huge risks in­volved with fund­ing drug dis­cov­ery, where a mul­timil­lion in­vest­ment can evap­o­rate fol­low­ing ad­verse re­sults in a clin­i­cal trial, is not some­thing that Ir­ish tax­payer should be ex­posed to. But there is a solid ar­gu­ment for gov­ern­ment cre­at­ing an at­mos­phere that en­cour­ages more pri­vate in­vest­ment in dis­cov­ery work.

Break­throughs in Ire­land would help off­set the huge ex­pense of new drugs such as Orkambi for cys­tic fi­bro­sis. This is not likely to be a once-off; we are go­ing to see more Orkambi sit­u­a­tions as big pharma pro­duces drugs that cure dis­eases but are hugely ex­pen­sive.

Another ex­am­ple is the drug so­fos­bu­vir, pro­duced by Gilead against hep­ati­tis C. Many women in Ire­land con­tracted hep C from re­ceiv­ing anti-D dur­ing preg­nancy in the 1970s and 1980s. With­out treat­ment, the women be­came chron­i­cally sick, got liver can­cer, and died. There was no treat­ment, but Gilead came up with a vac­cine that has a 98 per cent cure rate but costs ¤45,000-¤55,000 per pa­tient. The price is jus­ti­fied not only morally but eco­nom­i­cally, as a per­son with hep C re­quires a lot of health­care re­sources, while a liver trans­plant op­er­a­tion costs about ¤1 mil­lion.

It is clear why the pharma firms want to de­velop block­buster drugs that can bring bil­lions of dol­lars in sales rev­enue around the world. What is less clear is why some of them at least want to in­vest sig­nif­i­cantly in so-called “or­phan drugs” – ones that ben­e­fit only small group of pa­tients.

One such or­phan dis­ease is Muck­leWells syn­drome, an ex­tremely rare ge­netic con­di­tion that causes the eyes, skin, joints, kid­ney and liver to be­come in­flamed. About 15 years ago it was found that a gene called NLRP3 is de­fec­tive in peo­ple with this con­di­tion. Then, in 2015 a group of sci­en­tists in­clud­ing Prof O’Neill found a drug, called MCC950, that could block the dam­aged gene.

Drug com­pa­nies are in­ter­ested in de­vel­op­ing MCC950 be­cause the gene is also de­fec­tive in com­mon con­di­tions such as arthri­tis. For those with the con­di­tion, the drug works but it costs about ¤200,000 a year.

This ex­am­ple of how a drug is de­vel­oped for or­phan dis­eases is highly rel­e­vant as we move to­wards a per­son­alised model of med-

Blue skies re­search is es­sen­tial, that is where the big­gest value is. Ire­land has to be par­tic­i­pate in this be­cause we could have a guy, or woman, who will make the big break­through

icine, where fu­ture drugs might be de­signed for 1,000 pa­tients, or less. Sci­en­tists un­der­stand that the body’s im­mune sys­tem is com­plex and dif­fer­ent for each in­di­vid­ual, and finding a bro­ken cog in a sys­tem of per­haps 10,000 parts could lead to new drugs in the fu­ture.

If Ire­land is to fi­nally move into the drug dis­cov­ery arena, its res­i­dent tal­ent must be funded to do the work. This has hap­pened up to now, says O’Neill, as the fo­cus has been on fund­ing ap­plied med­i­cal re­search, which can pro­vide se­cure, but far less valu­able, re­turns for pa­tients and in­vestors.

“It is like you have a foot­ball team and you are in­vest­ing in the for­wards and ex­pect­ing the other team’s mid­field to pass to you,” he says. “If all we in­vest in is for­wards, we’ll never score a goal and that is why we need to in­vest in ba­sic med­i­cal re­search.”

Clin­i­cal tri­als

The re­cent up­side of med­i­cal re­search in re­cent years is the in­creas­ing num­ber of clin­i­cal tri­als tak­ing place for pa­tients with a range of con­di­tions. For ex­am­ple, un­der the UCD Clin­i­cal Re­search Cen­tre um­brella there are tri­als un­der­way led by Prof Glen Do­herty into IBD; Prof Fion­nu­ala McAuliffe in­ves­ti­gat­ing the role of the mi­cro­biome in the health of preg­nant women; and Prof Peter Kelly, who is run­ning a trial on stroke.

“The UCD CRC is im­pact­ing pa­tient’s lives and help­ing to trans­form the Ir­ish health­care land­scape, by en­sur­ing that novel treat­ments are de­vel­oped and dif­fused into rou­tine clin­i­cal prac­tice,” says the cen­tre’s di­rec­tor, Dr Peter Do­ran.

“We have cre­ated an en­vi­ron­ment that is sup­port­ive of in­ves­ti­ga­tors, recog­nised by reg­u­la­tors and at­trac­tive to pa­tients, an en­vi­ron­ment which has seen a huge in­crease in the vol­ume and im­pact of clin­i­cal re­search be­ing con­ducted at our part­ner hospi­tals – the Mater, St Vin­cent’s and [the Na­tional Ma­ter­nity Hos­pi­tal at] Holles Street.”

If break­throughs were hap­pen­ing in Ire­land, then it would help to off­set the huge ex­pense of new drugs such as Orkambi for cys­tic fi­bro­sis

PHO­TO­GRAPH: GETTY

Sci­en­tific tal­ent: Ire­land is known around the world for the qual­ity of its sci­en­tists.

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