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`Abiraterone: a story of scientific innovation and
`commercial partnership
`
`-11
`2014 -
`
`MAY
`
`Abiraterone is one of the ICR's biggest success stories - the first treatment shown to be effective in men
`with advanced prostate cancer. In 2012 it was made available on the NHS, at a stroke transforming the
`options available 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 ICR £10m in royalties, all of which will
`be ploughed back into our research.
`
`But the road from abiraterone's initial concept to today's life-extending treatment was not always smooth
`and highlights the importance of maintaining focus on a critical stage in the ICR's work- the
`commercialisation of the cancer drugs we discover. Without commercialisation, we would fail in an
`essential part of the ICR's mission, in delivering new cancer treatments to patients.
`
`This article details the key stages in abiraterone's almost 20-year history from initial idea to cancer drug
`in the clinic. It draws out some of the key learning points from its discovery and development, so that the
`ICR can not only reproduce the success of abiraterone, but can speed the journey from our next major
`discovery to the clinic.
`
`The initial idea
`
`Abiraterone's journey began in the 1990s, when a team of ICR scientists began to look for ways of
`shutting off 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 blocking its action. Over time most patients'
`cancers stop responding to standard hormone treatments and many scientists believed the cancers had
`learned how to grow without testosterone. The ICR's Professor Mike Jarman, and colleagues Dr Elaine
`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 still be treated by
`disrupting testosterone synthesis.
`
`The team, working in what is now the cancer Research UK Cancer Therapeutics Unit, started with a drug
`called ketoconazole, which they noticed prevented the growth of prostate cancer cells. The drug worked
`by inhibiting an enzyme called CYP17, which is important in the production of male sex hormones.
`Ketoconazole proved to be not very potent, not sufficiently specific and quickly broken down by the body,
`so the team set out to design new more effective inhibitors of the CYP17 enzyme.
`
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`119
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`JANSSEN EXHIBIT 2097
`Amerigen v. Janssen IPR2016-00286
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`Abi raterone: a stay of scientific inmwalion S'ld can mercial partnership - The Institute cl Cancer Research, Londoo
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`101312016
`The search was rewarded when Professor Potter and Dr Barrie designed and evaluated a chemical
`called CB7598, which they called abiraterone. The drug specifically and irreversibly blocked CYP17, and
`prevented testosterone being made anywhere in the body.
`
`Patenting and early commercialisation
`
`The ICR team filed the first of its patents on abiraterone in 1992, 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 rationale as a cancer
`treatment and how it was synthesised.
`
`The decision to patent and its timing were key to the abiraterone success story, and opened the door to
`the drug's commercialisation. The ICR assigned rights for the development of abiraterone to British
`Technology Group, an international specialist healthcare company. Jennifer Hodgson, Business
`Development Manager in the ICR's Enterprise Unit, explains: "The critical step in commercialisation of
`abiraterone was the filing of the two patents from this initial research. A key role for the ICR's Enterprise
`Unit is in deciding when to file a patent. Patents only last for 20 years. If we file too early 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
`intellectual property for licensing is one of the most important roles of the Enterprise Unit and we
`encourage researchers doing work with commercial implications to get in touch at an early stage."
`
`Early studies
`
`The next step for the ICR team was to turn the chemical they had designed into a medicine that could be
`taken by patients. Professor Mitch 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 androgen-dependent organs. These and other early studies were important as
`they demonstrated the drug was safe, effective and ready to be evaluated in patients. Professor Potter
`and Dr lan Hardcastle then scaled up the small amounts of the drug used in the lab into a quantity and
`purity suitable for patient use.
`
`In 1996 BTG out-licensed abiraterone to the German pharmaceutical company Boehringer lngelheim,
`and initial Phase I clinical trials began. Early-stage clinical trials in prostate cancer led by Professor lan
`Judson, with pharmacodynamic studies carried out by Dr Florence Raynaud, showed that abiraterone did
`hit the correct target and lower levels of male hormones. However, early in the drug's development
`concerns were raised about the possible side-effects of blocking CYP17 - in particular about the risk of
`adrenal insufficiency, a potentially life-threatening complication. The developmental progress was further
`hampered by a lack of interest in hormone treatments for prostate cancer. Part of the problem lay 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 led to
`Boehringer withdrawing from the development of abiraterone, with the licence returning to BCG.
`
`But the scepticism surrounding the drug was challenged when Professor Johann de Bono joined the ICR
`from San Antonio, Texas, in 2003. Professor de Bono recognised the potential of abiraterone as a
`treatment for men with advanced prostate cancer, and reasoned that late-stage prostate cancer was not
`
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`Abi raterone: a stay of scientific inmwalion S'ld can mercial partnership - The Institute cl Cancer Research, Londoo
`101312016
`Licensing and clinical trials
`
`In 2004, BTG licensed abiraterone to Ortho Biotech Oncology Research and Development, a unit of
`Cougar Biotechnology Inc., granting worldwide exclusive rights to develop and commercialise
`abiraterone. In doing so the ICR gained the financial backing it needed to run the clinical trials now
`required to prove the drug's efficacy and safety.
`
`"Licensing is a critical step in the commercialisation process," explains Toby Richardson, Senior Business
`Development Manager in the Enterprise Unit. ·ucensing 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. Collaborations can take a long time but the ICR has strong
`record of success.
`
`"The ICR has the highest amount of invention income per faculty head in the UK- 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 abiraterone are also entitled to a share of the
`royalties.
`
`With support from Cougar, Professor de Bono, Dr Gert Attard and colleagues began phase I clinical trials
`to test abiraterone's safety and anti-tumour activity.
`
`The first phase I study of abiraterone in patients with advanced prostate cancer was run by the ICR and
`The Royal Marsden. The small 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 levels.
`
`Less than a year later, the results of a larger phase 1/11 study were reported. This study of 54 patients
`confirmed the phase I results, and showed that up to 70 per cent of men responded to abiraterone.
`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 Cougar for just under £600million, gaining access to the drug as it progressed through phase Ill
`evaluation. And in 2010, 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 abiraterone's
`story is an exemplar of how basic molecular studies, followed by collaborations between researchers,
`doctors and industry, can lead to the successful development of effective drugs that can transform lives.
`
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`you are agreeing to our use of cookies on your device as described in our cookie policv. You can change your
`cookie settinas at anytime but parts of our site will not function correctly without them.
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`100120'16
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`Abiral8r<lne: a sby r:l scinfic imwation and ccmmercial partnership- The lnsti . . r:l Cancer R...-ch, London
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`Approval and acceptance by NICE
`
`There was now strong clinical trial evidence for the effectiveness of abiraterone, but there remained
`some significant hurdles in gaining regulatory approval for the drug. The ICR had to play an active role in
`the regulatory process to make sure abiraterone was made available to as many patients as possible.
`
`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 abiraterone's development. Both the ICR and
`BTG received a milestone payment, together with the royalties that followed on worldwide sales of
`abiraterone. •
`
`Later in 2011, the European Medicines Authority also licensed abiraterone. That opened the door to the
`drug being made available in the UK, but accessing it on the NHS continued to rely on local decisions by
`primary care trusts, or access via the Govemmenfs new NHS Cancer Drugs Fund. Abiraterone became
`one of the most requested drugs on the Cancer Drugs Fund, as anticipation grew that it would shortly be
`accepted by NICE.
`
`However, in February 2012, NICE announced that it was minded to reject abiraterone on cost grounds
`unless more data were forthcoming or a better price was offered. The decision came as a significant
`blow to the ICR and to men with prostate cancer across the UK We responded to the NICE appraisal
`
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`you are agreeing to our use of cookies on your device as desaibed in our cookie policy. You can change your
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`Abiraterone: a story of scientific innovation and commercial partnership- The Institute of Cancer Research, London
`1013.12016
`The end-of-life criteria are more lenient guidelines, developed by NICE, which should be followed when
`reviewing treatments which may extend the lives of patients who are terminally ill. The guidelines cover
`drugs which would normally be deemed too expensive for standard NHS use and which are licensed for
`a terminal illness affecting a small number of patients with less than two years to live. Cancer Research
`UK estimated 7,000 men would be eligible for abiraterone and thought this number low enough for the
`drug to be assessed under the end-of-life guidance.
`
`In IVIay 2012, NICE and Janssen finally reached an agreement over cost, and the drug was made
`available on the NHS in England, Wales and Northern Ireland. Since then, abiraterone has gained a
`further licence for the treatment of prostate cancer before chemotherapy, opening up the prospect that it
`will be made available for even more men.
`
`The path from abiraterone's discovery to its commercialisation was long and winding, but it was ultimately
`a major success story for the ICR demonstrating how partnership with industry can deliver real benefits
`for patients.
`
`)I Twoot g+ Snare J
`
`11 Comments
`
`The ICR
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`• Recommend
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`
`Alan Meyer • 2 years ago
`We know that patented drugs have huge and increasing price tags. However no one ever
`explains 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 would argue that, in addition to manufacturing and
`distribution, the money is needed to pay for the high cost of clinical trials and research.
`
`The drug company argument is at least partially valid. Clinical trials and other startup costs
`are expensive, though in more and more cases the actual research is paid for by government
`agencies like the NCI in the US and ICR in the UK, from taxes on all 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 will bear. This is normal capitalism and it works well for computers and cars, but it
`doesn't work so well when the product is not something that people can elect to buy or not, or
`to buy from this vendor or that. What is being sold is life. The alternative is death.
`
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`you are agreeing to our use of cookies on your device as described in our cookie oolicv. You can change your
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`101312016
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`Abi raterone: a stay of scientific inmwalion S'ld can mercial partnership - The Institute cl Cancer Research, Londoo
`
`they could come up with something better than an unregulated free market.
`3 ""
`• Reply • Share>
`v
`
`Stephen B. Strum • 2 years ago
`,.
`I agree with DavidS. As a medical oncologist in the PC {prostate cancer) field since 1983,
`there is also a glaring omission of a trial that compares the efficacy of HDK {high-dose
`ketoconazole) at a cost of $180 per month with abiraterone acetate {Zytiga) at a monthly cost
`on average of $7,700. Both work on the adrenal axis, both lower testosterone, but HDK also
`has been shown to have a direct cytotoxic effect, whereas I do not believe any study
`involving Zytiga has shown this. Moreover, there are publications showing that ketoconazole
`blood levels are associated with tumor response. It always amazes me how the "almighty"
`dollar seems to dominate so much of our "civilized" world.
`1 ""
`• Reply • Share>
`v
`
`Lucy Mendoza~ Stephen B. Strum • 2 years ago
`,.
`I am writing you from Mexico City. My husband is 81 years old with prostate cancer
`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
`the future. It is TERRIBLY expensive I understand. Perhaps the Insurance Co., might
`pay for it but in your commentary you talk about HDK which perhaps sounds much
`more amicable to his system. I will keep your information Stephen and give it to our
`doctor. I agree with you and with David B, it is amazing what the costs of these
`medicines amount to. God bless you all. Lucy Mendoza.
`1 ""
`• Reply • Share >
`
`v
`
`DavidB • 2 years ago
`,.
`The issue that this article does not discuss is the high price of abiraterone. I'm immensely
`lucky that my health insurer is paying for me, but I believe that others (especially people
`without insurance) have not been so fortunate. What's the point of having such a great
`treatment if it's restricted to a fortunate few?
`2 ""
`• Reply • Share>
`
`v
`
`,.
`
`willstai n ~ DavidB • 1 0 months ago
`Especially as it was developed by public contributions to the ICR from the British
`public. Medicine is no longer the caring institution that it once was, now it's all about
`cost & profit. (I'm on abiraterone by the way, it's just starting to be ineffective after 22
`months.)
`• Reply • Share >
`
`""
`
`v
`
`DavidB ~ willstain • 10 months ago
`
`,.
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`101312016
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`Abi raterone: a stay of scientific inmwalion S'ld can mercial partnership - The Institute cl Cancer Research, Londoo
`How long did it take to stop working?
`• Reply • Share >
`
`v
`
`A
`
`DavidB ~The Guv • 9 months ago
`Abiraterone worked for about a year before my PSA started to rise,
`which is better than the 8 months average in the trials.
`• Reply • Share >
`v
`
`A
`
`Alan Meyer~ The Guv • 9 months ago
`Guv,
`
`,.
`
`,.
`
`The article above says that clinical trials demonstrated an average
`response of eight months to the drug. Individual responses however
`can vary quite a bit. Some men get no benefrt at all while others may
`benefit for a year or several years. I 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 down
`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 all of the known pathways in all of
`the different cells that can synthesize testosterone. It is therefore more
`effective than the older LHRH agonists like Lupron, Zoladex, Eligard,
`etc. However, some scientists hypothesize that prostate tumor cells
`can and, given a long enough time, will, mutate to resume cell division
`and metastasis even in the absence of all testosterone.
`
`Hopefully, we will continue to develop anti-cancer drugs that work in
`ways other than testosterone suppression, thus extending life for men
`who have become "castration resistant".
`
`Best of luck to you.
`• Reply • Share >
`v
`
`A
`
`The Guv ~Alan Meyer • 9 months ago
`Thanks for the info. I am 2 months into Abiraterone treatment for
`mCRPC 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
`• Reply • Share >
`v
`
`A
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`10012016
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`AblraarClfl8: a sb-y ar sdanllllc lrnMIIIon and commS'Cial partnership· Tha lnslltutB r:l Canca' Raselrch, l..ondcn
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`-------------->~----------------------------------------------------
`Re-inventing the finger
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