1211912016
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`Abiraterone: a story of scientific innovation and commercial partnership — "the institute of Cancer Research, London
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`Eh
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`- The institute of
`{lancer Researoh
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`ww
`mm
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`iviaking the oisooveries that defeat oanoer
`
`Abireterone: a story of soientitio innovation and
`oornrrieroiai partnership
`
`
`
`Ahiraierone is one ofthe lCR‘s biggest success stories —— the first treatment shown to be etfective in men
`
`with advanced prostate cancer. in 2012 it was made availebie on the Ni~iS, at a stroke transforming the
`options avaiiaoie for the 10,000 men each year diagnosed with aggressive forms of prostate cancer. in the
`current financial year alone. abiraterone is forecast to earn the iC¥< £1 Urn in royalties. all of which will be
`piooghed back into our research.
`
`But the road from abiraterones initial concept to tooay’s lifeexiending treatment was not atways smooth
`and nighiighte the importance of maintaining focus on a criticai stage in the lCFt‘s wort: »» the
`
`cornmerciaiisetion of the cancer drugs we discover. Without cornmerclaiisation, we woiiid fail in an
`essential part of the iCR’s mission, in deiivering new cancer treatments to patients.
`
`This article detaiis the key stages in aoirateronee airnost 20«year history from initial idea to cancer drug in
`the ctinic. it draws out some of the key learning points from its discovery and deveioprnent, so that the K39
`can not oniy reproduce the SLiCCeS$ of abiraterone, out can speed the journey from our next major
`discovery to the clinic.
`
`The initiai idea
`
`Aoiraterones journey began in the iSi90si when a team oi‘ lCR scientists began to took for ways oi‘ shutting
`oil‘ production of male androgen sex hormones. Prostate cancer relies on testosterone to grow. so one of
`the main ways doctors treat the disease is by biocking its action. Over time most patients’ cancers stop
`responding to standard horrrione treatments and many scientists believed the cancers had teamed how to
`grow without testosterone. The ECR’s Professor ti/iike Jarman, and coileagues Dr Eiaine Barrie and
`Professor Gerry Potter; began investigating an alternative theory «« that these prostate cancers were using
`testosterone from elsewhere in body to grow, and might therefore stilt be treated by disrupting testosterone
`synthesis.
`
`the team. working in what is now the Cancer Research UK Cancer Therapeutics Unit, started with a drug
`sailed ketoconazoie, which they noticed preventeizt the growth of prostate cancer oeils. The drug worked by
`inhibiting an enzyi'ne patted CYPW. which is important in ihe production of male sex hormones.
`Ketooonazole proved to be not very potent; not siiiriciently specific and quickiy broken down by the body,
`so the team set out to design new more effective inhibitors of the CYPW enzyme.
`
`Dr Barrie assessed compounds made within Professor Jarmarrs team to work out how suocessfotiy and
`selectivety they woiztd inhibit CYF’1'?i They were aided by three—dimensional models created by Professor
`Stephen hleidle, Dr Charles Laughton and ooiieagues.
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`http:/iwww.icr.ac.uk/news-featuresi'late5t—featuresrahiraterone-a—story-of-scientific-innovation-and-commercial-partnership
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`Abiraierone: a story of scientific innovation and commercial partnership ~ The institute of Cancer Research, London
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`The search was rewarded when Professor Potter and Dr Barrie designed and evaluated a chemicai called
`(387598, which they carted abiraterone. The drug specifically and irreversibly blocked CYP‘l 7, and
`prevented testosterone being made anywhere in the body.
`
`Patenting and early commercialisation
`
`The ECR team filed the first of its parents on abiraterone in 1.992, on the usefulness of the compound as a
`potential cancer treatment. and followed that with a second patent the following year covering its synthesis.
`A year later the team published the first paper describing the drug, its rationaie as a cancer treatment and
`how it was synthesised.
`
`The decision to patent and its timing were key to the alt;-iraterone success story, and opened the door to the
`drugs commercialisation. The SCR assigned rights for the development of abiraterone to eritish Technology
`Group. an iriternationai specialist healthcare company. Jennifer Hodgson. Business Development Manager
`in the |CR‘s Enterprise Unit, explains: “The critical step in commercialisation ofahiraterone was the filing of
`the two patents from this initial research. A key rote for the iCR‘s Enterprise Unit is in deciding when to fits
`a patent. Patents only test for 20 years. it we file too eariy we reduce the number of years we can receive
`royalties because it takes a while for commercialisation to occur. it is because of these initial patents that
`we are now entitled to royalties from abiraterone. Protecting our intetiectoal property for licensing is one of
`the most important roles of the Enterprise Unit and we encourage researchers doing work with comrnerciai
`implications to get in touch at an early stage."
`
`Eariy studies
`
`The next step for the ICR tearri was to turn the chemicai they had designed into a medicine that cooid be
`taken by patients. _Professor iviitch Dowsett, Dr Barrie and others showed in animal and cancer cell models
`that the drug worked as expected, blocking synthesis of androgens and reducing their levels in the body
`and the size of androgenoependent organs. "these and other eariy studies were important as they
`demonstrated the drug was safe, effective and ready to be evaiuated in patients. Professor Potter and Dr
`tan tiardcastle then scaled up the small amounts of the drug used in the iah into a quantity and purity
`suitable for patient use.
`
`in 1996 BTG out»-iicensed abiraterone to the German pharmaceutical company Boehringer lngeihetrn, and
`
`initiai Phase l clinical trials began. Early-stage clinical trials in prostate cancer led by Professor lan Judson,
`with pharmacodyriarnic studies carried out by Dr Florence Raynaud, showed that ahiraterone did hit the
`correct target and lower ievels of male hormones. However, eariy in the drugs development concerns were
`raised about the possibte side—etfects of oiocking CYP1?’ —— in particular about the risk of adrenal
`insufficiency, a potentially liiethreatening complication. The developrnentai progress was further hampered
`by a lack of interest in horrnone treatments for prostate cancer. Part of the probiern iay in the name of late-
`stage prostate cancer, which was often referred to as ‘refractory’ disease, implying the cancer became
`resistant to androgens and could progress without them. Many scientists and clinicians argued that
`blocking androgen production at this late stage would be ineffective. These concerns ted to Boehringer
`withdrawing from the deveioprnent of abiraterone, with the licence returning to BCC5.
`
`But the scepticism surrounding the drug was chaiienged when Protessor Johann de Bono joined the ICR
`from San Antonio, Texas, in 2883. Professor de Bono recognised the potentiat of abiraterone as a
`treatment for men with advanced prostate cancer. and reasoned that latestage prostate cancer was not
`‘hormone refractory‘ but ‘castration resistant’, meaning that the turnourwas still dependent on testosterone
`but was slots to progress because it could get androgens from elsewhere ~— perhaps even from the prostate
`cancer itself. He also reasoned that adrendai insufficiency would not he an issue with abiraterone, since
`children born with inherited deficiency of {3YP‘l 7 do not suffer from it. The FCR was ready to take
`abiraterone back into clinical trials.
`
`http:.l.'www.icr.ac.ukfnews-featuresiiatest-featLiresiabiraterone-a-story-of-scientific-innovation-and-commerciaispartnership
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`Abiralerone: a story of scientific innovation and commerciat partnership - ?'he institute of Cancer Research, London
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`Licensing and oiinioal trials
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`in 2004, BTG licensed abiraterone to Onho Bioteoh Onooiogy Research and Development. a unit of
`
`Cougar Biotechnology lno, granting worldwide exctusive rights to develop and commercialise abiraterone.
`in doing so the ECR gained the financial backing it needed to run the clinical trials now required to prove the
`drugs efficacy and safety.
`
`“Licensing is a critical step in the commercialisation process," explains Toby Richardson, Senior Business
`Development Manager in the Enterprise Unit. "Licensing gives a company permission to own our property.
`Our number one goal is to ensure patients benefit as quickly as possible from our innovations. The
`Enterprise Unit has good links with a range of companies and has cover 40 years of collective experience
`and expertise in negotiating. Cotletzioratioris can take a tong time but the ECR has strong record ofsuccess.
`
`"the K3}? has the highest amount of invention income per faculty head in the UK w more than twice the
`organisation in second place. But it's not only the iCR who benefits. The Rewards for innovators Scheme
`means that the researchers involved in the development of ahiraterone are also entitled to a share of the
`royalties.
`
`With support from Cougar. Professor de Bono, Dr Gert Attard and colleagues began phase l clinicai triais to
`test abiraterones safety and anti-tomour activity.
`
`"the first phase E study of abiraterone in patients with advanced prostate cancer was run by the iCR and
`the Royai Niarsden. The smail study involved 21 men and found that the drug appeared safe in humans
`and that the majority of patients who took it experienced both significant: tumour shrinkage and dramatic
`falls in PSA ievels.
`
`Less than a year tater. the results of a larger phase till study were reported. This study of 54 patients
`confirmed the phase l results. and showed that up to 70 per cent of men responded to ahiraterone. These
`men experienced significant benefits for an average of eight months with scans showing their tumours
`decreased in size and their PSA levels dropped substantially.
`
`Following these very positive results. the giant US pharmaceutical company Johnson & Johnson agreed to
`buy Gouger for just tinder £8GOmillion, gaining aooess to the drug as it progressed through phase Etl
`evaluation. And in 2030. a pivotal phase ill trial showed that patients given abiraterone lived on average
`15.8 months longer, compared with 11.2 months for men taking a placebo. This part of abirateronels story
`is an exemplar of how basic molecutar studies. followed by ootlahorations between researchers. doctors
`and industry, can lead to the successful development of effective drugs that can transform lives,
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`http:.'lwww.ior.ao.uklnewswfeaturesllatest-featureslabiraterone«a-slory—of-scientlfic-innovalion~and-cornmerciai-partnership
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`Abiraierone: a story of scientific innovation and commercial partnership - The Institute of Cancer Research, London
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`iaoorovai and acceptance by i‘~diCE
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`There was new strong clinical trial evidence for the effectiveness of aeiraterone, but there remained some
`significant hurdles in gaining regulatory approval for the drug. The ICR had to play an active role in the
`reguietory process to make sure abiraterorie was rnade available to as many patients as possibie.
`
`The first step was the submission to a new drug application to the US Food and Drug Administration,
`leading to the approval of abiraterone in the US.
`
`Hodgson says: "Approval in the US was a significant step in abiraterones development. Both the ICLR and
`BTG received a milestone payment, together with the royeities that ‘ioiiovved on worldwide sates of
`abiraterone."
`
`Later in 201i, the European Medicines Authority atso licensed abiraterone. That opened the door to the
`drug being made available in the UK) but accessing it on the NHS continued to reiy on iocal decisions by
`primary care trusts, or access via the Government's new i\iHS Cancer Drugs Fund. Aoiraterone became
`one of the most requested drugs on the Cancer Srugs Fund. as anticipation grew that it would shortly be
`accepted by NKEE.
`
`However, in February 2Gt2, l\§iCE announced that it was minded to reject abiraterone on cost grounds
`uniess more data were forthcoming or a better once was offered. The decision came as a significant blow
`to the ECR and to men with prostate cancer across the UK. We responded to the NICE appraisal
`consoitation document highlighting our concerns about certain aspects of the process underiéng the NECE
`decision, and asking it to reconsider its position. The ICR calied for NiCE to reexamine fuiiy the ootentiai
`for abiraterone to be costmeffective in a subgroup of patients for whom it appeared to be particuiariy
`effective, and to foilow its own ‘end-ofuiife criteria’ for deciding whether drugs should be made availabie.
`
`http:!fvwvw.icr.ac.uklnews-featuresllatest-featores.'abiraterone—a—stoiy—of—scientific-innovation—and—commerciat-partnership
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`Abiraterone: a story of scientific innovation and commerciai partnership ~ The Institute of Cancer Research, London
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`the end—ot-life criteria are more lenient guidelines, developed by NECE, which should be toliowed when
`reviewing treatments which may extend the iives of patients who are terminally ill. The guideiines cover
`drugs which would riotrnaiiy be deemed too expensive for standard NHS use and which are iicensed for a
`terrniriai iiiness affecting a small number of patients with tess than two years to live. Cancer Research UK
`estimated Y,€)GG men would be eligible for abiraterone and thought this number low enough for the drug to
`be assessed under the end-of—lite guidance.
`
`in ivlay 2012, NiCE and Janssen finally reached an agreement over cost. and the drug was made availabie
`on the i\tl-iS in England, Wales and Northern ireiand. Since then. abiraterone has gained a further licence
`for the treatment of prostate cancer before chemotherapy, opening up the prospect that it wili be made
`avaiiabie for even more men.
`
`The path from abiraterones discovery to its corornerciaiisation was long and winding. but it was uitirnateiy a
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`major success story for the Kit? demonstrating how partnership with industry car‘: deliver real benefits for
`patients.
`'
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`
`
`Ti Comments
`
`The ECR
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`V Recommend
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`['12 Share
`
`Join the discussion...
`
` Aianfiiiayer == 2 years ago
`
`
`
`50" *3)? Newest
`
`‘
`
`We know that patented drugs have huge and increasing price tags. However no one ever
`' expiains why? is the drug difficult to manufacture? Does a month's supply of the drug cost
`something close to $7,000 to manufacture’? Or is it $700, or even $70? The drug
`
`manufacturers would never say and wouid argue that, in addition to manufacturing and
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`distribution, the money is needed to pay for the high cost of ciinicai trials and research.
`
`The drug company argument is at ieast partialiy vaiid. Ciinicai trials and other startup costs
`
`are expensive. though in more and more cases the actual research is paid for by
`government agencies iike the NCI in the US and iCR in the UK, from taxes on aft of us. But
`drug companies, like computer companies and car companies and all other commercial
`companies, are in business to make money - which requires charging the highest price that
`the market wiii bear. This is normal capitaiism and it works welt for computers and cars, but
`
`it doesn't work so welt when the product is not something that peopie can eiect to buy or
`
`not, or to buy from this vendor or that. What is being sold is life. The alternative is death.
`
`i think that in the US, UK, and other capitalist countries we need a new modei tor regulated
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`drug pricing. it shouid be one that ensures that drug companies can do their job of
`deveioping drugs, but also ensures that public health needs are served. 3 don't have a plan
`in my pocket that would achieve that, but I'm pretty sure that if knowiedgeabie people put
`http:ilwww.icr.ac.ukinews-featuresilatest-fealuresiabiraterone~a-story-of—scientific-inrsovation-and-commerciai-partnership
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`Abiraterone: a story of scientific innovation and commerciai partnership - The institute of Cancer Research. London
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`their minds to it they could come up with something better than an unregulated free market.
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`3 A
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`V =1 Reply a Share»
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`Stephen B. Sitram =* 2 years ago
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`W
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`I agree with DavidB. As a medical oncoiogist in the PC (prostate cancer) field since 1983,
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`there is also a giarirtg omission of a trial that compares the efficacy of HDK {high~ciose
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`ketoconazole) at a cost of $180 per month with ahiraterone acetate (Zytiga) at a monthly
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`cost on average of $7700. Both work on the adrenai axis, both lower testosterone, but
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`HDK aiso has been shown to have a direct cytotoxic effect, whereas I do not believe any
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`study involving Zytiga has shown this. ivioreover, there are publications showing that
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`ketoconazoie blood levels are associated with tumor response. it aiways amazes me how
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`the "almighty" doiiar seems to dominate so much of our "civi|i2ed“ world.
`
`1
`
`xx
`
`V 6 Reply « Share >
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`
`
`Lucy Mendoza #9’ Stephen B. Strum » 2 years ago
`
`'
`
`‘“”
`
`i am writing you from Mexico City. My husband is 81 years old with prostate cancer
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`since 2001. He has good quAlity life now, but is what they call refractary to the
`ZOLADEX treatment he was having before. this drug Zytiga was recommended for
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`the future. it is TERRIBLY expensive E understand. Perhaps the insurance C0,.
`
`might pay for it but in your commentary you talk about HDK which perhaps sounds
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`much more amicabie to his system. I wilt keep your information Stephen and give it
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`to our doctor. i agree with you and with David B,
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`it is amazing what the costs of
`
`these medicines amount to. God bless you all. Lucy Mendoza.
`1 A
`v ~ Reply e Share >
`
`
`I
`M WA\,;:g§
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`i)aviciB = 2 years ago
`
`"*""
`
`The issue that this artists does not discuss is the high price of abiraterone. l‘m immenseiy
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`iucky that my health insurer is paying for me, but I believe that others (especialiy people
`
`without insurance) have not been so fortunate. What's the point of having such a great
`treatment if its restricted to a fortunate few?
`
`2 A
`
`v » Reply « Share)
`
`M“
`I
`wiiistain rt Davidi3 =* a year ago
`' Especiaily as it was deveioped by public contributions to the iCR from the British
`
`2
`
`public. Medicine is no Eonger the caring institution that it once was, now it's all about
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`cost & profit. (i‘m on abiraterone by the way, it's just starting to be ineffective after
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`22 months.)
`
`A
`
`V « Reply = Share>
`
`°"“’
`a year ago
`Dayidfl A? wilistain
`Sadly abiraterone stopped working for me, and the next expensive drug
`
`M
`
`(enzalutamide) didn't work at ail, so I‘ve just started chemo.
`
`A
`
`v 2 Reply » Share>
`
`
` :_A\;
`httpzlrwww.icr.ac.ukinews-featuresilatesbfeaturesiabiraterone-a-story-of-scientific-innovation-ano-commercial-partnership
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`‘The Guy *9 DavidB = a year ago
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`W
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`iznsifzoi 5
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`Abitaterone: a story of scientific innovation and commercial partnership - The institute of Cancer Research, London
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`How tong did it take to stop working?
`
`A
`
`v at Repiy a Share:
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`
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`Davida e? The Gov = a year ago
`
`‘W
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`Abiraterone worked for about a year before my PSA started to rise,
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`which is better than the 8 months average in the triais.
`
`A
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`v ~ Reply : Share>
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`fitiantifieyer »-it The Gov it a year ago
`
`M’
`
`Guv,
`
`The article above says that ciinical trials demonstrated an average
`
`response of eight months to the drug. tndividuai responses however
`
`can very quite a bit. Some men get no benefit at all white others may
`
`benefit for a year or several years. t have seen reports by several
`
`men that Zytiga seemed to stop working for them Their PSA went up
`
`but they kept taking the drug and, to their surprise, the PSA went
`
`Clown again. Different patients can have quite different tumor
`
`characteristics and drugs have different effects on them.
`
`As i understand it, Zytiga interferes with a chemical reaction that is
`
`involved in testosterone synthesis in alt otthe known pathways in ail
`
`of the different ceils that can synthesize testosterone. It is therefore
`
`more effective than the otcier LHRH agonists like Lupron, Zoiadex,
`
`Eiigard, etc. However, some scientists hypothesize that prostate
`
`tumor ceils can and, given a tong enough time, wiii, mutate to resume
`Celt division and metastasis even in the absence of all testosterone.
`
`Hopefoliy. we will continue to develop anticancer drugs that work in
`
`ways other than testosterone suppression, thus extending iife for
`men who have become "castration resistant".
`
`Best of tuck to you.
`
`A
`
`v «= Reply e Share)
`
`
`
`the Guy I? Alanlvieyer -’ a year ago
`
`““
`
`Thanks for the info.
`
`I am 2 months into Abiraterone treatment for
`
`mci’-{PC and was just curious how long it can be effective before one
`
`has to switch to other treatments. As you say it seems to depend on
`
`the person. The experience of others in the same boat would be
`welcome
`
`A
`
`v « Repiy « Share)
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`
`
`wiitstain -+ DavidB '« a year ago
`
`'
`
`it looks like l‘ll be joining you! There is a new drug which is on triai at
`
`the ICR/Royai ivlarsden, it's called Oiaparib. To get on the trial you
`have to have had chemo, so iust maybe i couict be a candidate
`
`http:h'www.icr.ac.ukinews-features.'Iatest—features/abiraterone»a~story-of-scientific—innovation-and-commerciahpaitnership
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`further down the line. By ihe {Nay theldrug didrft stop working, the
`cancer just got smarter! Good Luck.
`A
`v R F-?ranIu 9 Sharp )
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`
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`Previous
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`Next
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`%eiete§ feeigires eriieiee
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`ivieving away iirem ‘$18 ‘ene fraction size fits aii‘ appreeeh “re
`radiotherapy
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`Researchers are ciisccivering bioiogica! markers that can predict the sensitivity of tumours to radiotherapy.
`with the gsoteriiiai to taiior dosing to individuai patients, finds Liz Buriaiiy.
`
`
`
`Re~invenۤrig the finger
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`http://w\.vw.icr.ac.ukinews-featuresllaiesbfeaturesiabiraierone-a-story-of-scientific-innovation-and-commercial-partnership
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`in ‘me first of five articles shortlisted for the E{3R‘s Mei Greaves Scienca Writing Prize 2815, the winner Dr
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`Hugh Harvey writes about re-inventing an age-mic: test for prostate cancer.
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`
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`Using the seeds 3‘? cancar ta guide tféatmemfi atrategies
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`Circuiaiing tumour cells can act as ‘seeds’ «- bieaking away from the piimary tumour and coionésing other
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`sites in ihe body. But they are also becoming an increasmgty usefui too; in cancer medicine — measuring a
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`patients state of disease.
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`http:i‘iwww.icr.ac.uk!news-ieaturesllatesbfeatisresfabiraterone-a-siory—of-sciemific-innovaiion-and—commerciaE~par1nership
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