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`Abiraterone: a story of scientific innovation and commercial partnership
`
`
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`11
`
`MAY
`2014
`
`Abiraterone: a story of scientific
`innovation and commercial
`partnership
`
`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
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`WCK1102
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
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`

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`Abiraterone: a story of scientific innovation and commercial partnership - The Institute of Cancer Research, London
`
`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.
`
`Dr Barrie assessed compounds made within Professor Jarman’s team to work out how
`successfully and selectively they would inhibit CYP17. They were aided by three-dimensional
`models created by Professor Stephen Neidle, Dr Charles Laughton and colleagues.
`
`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.
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`http://www.icr.ac.uk/news-features/latest-features/abiraterone-a-story-of-scientific-innovation-and-commercial-partnership[4/19/2017 3:30:42 PM]
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`Abiraterone: a story of scientific innovation and commercial partnership - The Institute of Cancer Research, London
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`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 Ian 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
`Ingelheim, and initial Phase I clinical trials began. Early-stage clinical trials in prostate cancer
`led by Professor Ian 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 ‘hormone refractory’ but ‘castration resistant’, meaning
`that the tumour was still dependent on testosterone but was able to progress because it could
`get androgens from elsewhere – perhaps even from the prostate cancer itself. He also
`reasoned that adrendal insufficiency would not be an issue with abiraterone, since children
`born with inherited deficiency of CYP17 do not suffer from it. The ICR was ready to take
`abiraterone back into clinical trials.
`
`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. “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.
`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
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`Abiraterone: a story of scientific innovation and commercial partnership - The Institute of Cancer Research, London
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`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 I/II 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 III evaluation. And in 2010, a pivotal phase III 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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`Abiraterone: a story of scientific innovation and commercial partnership - The Institute of Cancer Research, 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 Government’s 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 consultation document highlighting our concerns about
`certain aspects of the process underling the NICE decision, and asking it to reconsider its
`position. The ICR called for NICE to re-examine fully the potential for abiraterone to be cost-
`effective in a subgroup of patients for whom it appeared to be particularly effective, and to
`follow its own ‘end-of-life criteria’ for deciding whether drugs should be made available.
`
`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 May 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
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`Abiraterone: a story of scientific innovation and commercial partnership - The Institute of Cancer Research, London
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`can deliver real benefits for patients.
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