Improved health and survival rates for patients with malignant brain and prostate cancer, and economic benefit from new chemotherapy treatments.
Submitting InstitutionUniversity of Strathclyde
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Pharmacology and Pharmaceutical Sciences
Summary of the impact
The Cancer Research UK Formulation Unit at the University of Strathclyde
performed the pharmaceutical research and development of new chemotherapy
treatments for malignant brain and prostate cancer (temozolomide and
abiraterone acetate). These two drugs are now marketed globally, with FDA
approval for the US market in 1999 and 2011 respectively, and have
directly improved the quality of life and increased survival rates during
treatment for over a quarter of a million cancer patients annually since
2008. Temozolomide achieved $1 billion sales per annum in 2008, and
Abiraterone global sales reached $1.45 billion by 2013. Both drugs have
produced economic benefit to the charity Cancer Research UK through
Development of a new anti-cancer agent is a long term, team-based process
which takes many years from the isolation of a molecule through extensive
clinical trials to eventual drug delivery to patients. Many scientists and
clinicians were involved in the research for both drugs. For temozolomide
and for abiraterone, the Cancer Research UK Formulation Unit at the
University of Strathclyde performed the pharmaceutical research and
development of new chemotherapy treatments which permitted both the
manufacture of these treatments on a large scale and the optimal
formulation for administration to patients.
Key Research Findings
Temozolomide is a pro-drug of MTIC (3-methyl-(triazen-1-yl)
imidazole-4-carboxamide) a DNA methylating agent which triggers cell
death. Professor M. Stevens was the synthetic chemist based at University
of Aston at the time of the initial drug discovery research and Professor
E. Newlands, Charing Cross Hospital was the lead clinician. During early
clinical studies in the 1980's temozolomide was administered by intra
venous injection in dimethylsulphoxide, which due to solubility and
solvent toxicity issues limited the maximum administrable dose (and hence
biological effect), required patient hospitalisation and was unpleasant.
Temozolomide was initially produced in the relatively small quantities
needed for the lab work at Aston University. Once Phase II clinical trials
started, demand for the drug increased dramatically.
The Unit at Strathclyde conducted pharmaceutical formulation research to
develop an oral capsule formulation (on which the current marketed
formulation is based) determining an optimum blend of starch, lactose and
aerosil, which maximised bioavailability and stability. Capsules at
strengths of 25 mg, 50 mg and 100 mg were developed and manufactured
allowing increasing doses to assess the maximum therapeutic and tolerated
dose, and remove the requirement for parenteral therapy . The ease of
administration and treatment using the oral form assisted the conduct of
Phase II trials, which were critical in determining efficacy and led to
the eventual licensing of temozolomide by Schering-Plough (Woll, P.J., et.
al., (1995) Phase II trial of temozolomide in low-grade non- Hodgkin's
lymphoma. British J. Cancer, 72, 183-184). This pharmaceutical research
was conducted in the Unit between 1993 and 1997.
Abiraterone acetate (CB7630) is a steroid inhibitor of the 17
α-hydroxylase/C17, 20 lyase (CYP17A1) enzyme which is expressed in
testicular, adrenal and prostatic tumour tissue. Abiraterone's chemical
structure is based on a steroid ring system and consequently has very poor
aqueous solubility which limits oral bioavailability. Professors M. Jarman
and I. Judson both from the Institute of Cancer Research were,
respectively, the synthetic chemist and lead clinician in the drug
discovery phase of the research. The Strathclyde Unit conducted the
required pharmaceutical research to increase water solubility and
dissolution to an extent suitable for oral administration, and
subsequently carried out the research to develop formulations for animal
and human trials. The main advance was achieved through particle size
reduction by micronisation, and close control of particle size during
subsequent stages involving manufacture and storage. A suspension
formulation for animal toxicology trials and a capsule formulation for
human phase I dose escalation trials (10 mg, 50 mg, 100 mg and 200 mg) was
researched, developed, tested and prepared. The trial results were
published in 2004  and subsequent clinical trials validated activity,
leading to licensing and final marketing by Johnson and Johnson. This
research was conducted in the Unit between 1995 and 2004 with the majority
of research between 1995 and 2000.
Dr Gavin Halbert, a Senior Lecturer within Strathclyde University and
Director of the CRUK Unit was the principal investigator on the Cancer
Research Campaign/Cancer Research UK grant, which funded this research
from 1992 to 2013. He was the key pharmaceutical scientist involved in the
project teams for both drugs.
References to the research
1. Beijnen, J.H., Flora, K.P., Halbert, G.W., Henrar, R.E.C.,
Slack, J.A. (1995) CRC/EORTC/NCI Joint Formulation Working Party:
Experiences in the formulation of investigational cytotoxic drugs. British
Journal of Cancer, 1995, 72, 210-218.
Notes on quality: General reference to the scope and extent of
scientific research conducted within the Formulation Unit covering the
range of challenges from analytical science to solubility, stability and
formulation. Includes a section on research conducted on temozolomide and
the introduction of the oral formulation. British Journal of Cancer is a
Nature publication, has an impact factor of over 5 and is the key UK based
publication for Cancer Research Campaign/Cancer Research UK funded
2. O'Donnell, A., Judson, I., Dowsett, M., Raynaud, F., Dearnaley, D.,
Mason, M., Harland, S., Robbins, A., Halbert, G., Nutley, B.,
Jarman, M., (2004) Hormonal impact of the 17 alpha-hydroxylase/C-17,C-20-lyase inhibitor abiraterone acetate (CB7630) in
patients with prostate cancer. British Journal of Cancer, 2004, 90(12),
Notes on quality: First clinical paper of the initial phase 1
clinical trial results of abiraterone acetate in prostate cancer patients
conducted using pharmaceutical dosage forms based on the Unit's research
and indicates that the research has led to a viable clinical formulation.
British Journal of Cancer, see notes above.
Other evidence for quality of research (grants, patents etc.).
The Formulation Unit has been funded by Cancer Research UK (previously
Cancer Research Campaign) from the date it was established in 1983 to the
present day. The total peer reviewed grant funding awarded in the period
1993 to 2013 amounts to just over £14 million. The Formulation Unit has
during the period 1993 to 2013 undergone three (1995, 2003 & 2009)
Cancer Research UK Site Visits, external peer review assessments conducted
every 5 years, by panels of leading international and national cancer and
pharmaceutical drug development scientists. The Unit's research was highly
praised during the 1995 review and in both 2003 and 2009 the reviewed
research was rated as Forefront (work which is at the forefront
internationally and which, it is considered will have an important and
substantial impact) with the proposed activities for the next 5
years rated as Competitive Forefront (proposal which is internationally
competitive and will make a significant contribution). Cancer
Research UK's grant rating scale runs from a minimum of 2 to a maximum of
10, Forefront is 8 - 9.99 and Competitive Forefront 5 - 7.99.
Details of the impact
Process from research to impact
The Formulation Unit is funded directly by Cancer Research UK to conduct
pure and applied research [Source 1] across a range of chemical drug and
formulation types, which culminates in the manufacture of an
investigational medicinal product for patient administration in clinical
trial, compliant with EU regulatory requirements. Compounds are selected
by the Cancer Research UK New Agents Committee, which does not operate
with a traditional drug development pipeline. The Unit, therefore, has to
be capable of covering pharmaceutical research ranging across analytical
methods and techniques, utilization of these techniques to understand and
limit chemical degradation and assist stabilization, and the final
development of formulations [Source 2]. The Unit collaborates with
multiple clinical cancer centres in the UK, and nationally and
internationally with multiple cancer drug discovery groups. As the only UK
academic centre capable of conducting this formulation research, the
Unit's research input has played a vital role in the formulation research,
clinical testing and eventual marketing of these two anti-cancer drugs.
Before drugs can be marketed by pharmaceutical companies they must be
tested on patients in clinical trials and approved by regulatory bodies.
In the USA, the relevant body is the Food and Drug Administration (FDA).
In the UK the Medicines and Healthcare Products Regulatory Agency (MHRA)
approves the clinical trial, but this does not necessarily lead to use in
the National Health Service until the National Institute for Health and
Care Excellence (NICE) have assessed the cost benefit calculation and
approved the use of the drug.
Temozolomide was licensed by Cancer Research UK to Schering Plough in
1995, received accelerated FDA approval in 1999 and was approved by NICE
in June 2007 for the treatment of newly diagnosed glioblastoma multiforme
(GBM) and anaplastic astrocytoma [Source 3]. Abiraterone acetate was
licensed by the Institute of Cancer Research via BTG International to
Cougar Pharmaceuticals, and on to Johnson and Johnson. It was FDA approved
for use in castration resistant prostate cancer after chemotherapy in
April 2011; European approval followed in July 2011, with NICE
ratification in England, Wales and Northern Ireland in June 2012 [Source
4]. On December 10, 2012, the FDA approved an expanded indication for
abiraterone acetate (Zytiga Tablets, Janssen Biotech, Inc.) in combination
with prednisone for the treatment of patients with metastatic
castration-resistant prostate cancer [Source 5].
Type of Impact
The research impacts directly on patients with brain and prostate cancers
world-wide, through the provision of better therapies, which improve the
quality of life and increase life expectancy. Sales of these drugs also
produce economic benefits for the pharmaceutical industry at international
level and to the UK economy through royalties.
Benefits for brain cancer patients
Malignant brain cancer accounts for 2% of all new UK cancer cases. There are
around 4,800 new malignant brain tumour cases per annum in the UK with 3,700
deaths and around 240,000 new cases per annum, world-wide [Source 6].
Temozolomide is currently available as a treatment in 39 countries
worldwide. Before the availability of temozolomide, approximately 29% of
adult patients with malignant brain tumours survived one year after
diagnosis and 13% at five years. Treatment was only offered to robust
patients using surgical excision followed by radiotherapy, providing a 4 to
5 month increase in median survival but with a high percentage (70%)
recurring locally, leading to a rapid deterioration in quality of life.
Further chemotherapy options were limited and would only provide a further
median increase in survival of around 2 months. By making temozolomide
available orally, it is easier to administer than standard chemotherapy
regimes and, in relapsed cases, increased progression-free survival at 6
months from 8% on previous therapy to 21%, and survival from 44% to 60%.
Other studies have indicated that in malignant glioma about 10% of patients
on temozolomide therapy show a complete response, 25% a partial response and
30% exhibit periods of stable disease. In addition, temozolomide
significantly improves quality of life prior to disease progression. The
Strathclyde research made these benefits possible.
The CRUK website states that "the standard of care for glioblastoma
multiforme — also known as glioma - includes chemotherapy during and after
radiotherapy. The use of temozolomide both during radiotherapy and for six
months post radiotherapy is now the gold standard treatment for most cases
of the disease." [Source 4].
Benefits for patients with prostate cancer:
Prostate cancer accounts for 12% of all new UK cancer cases, and 25% of
new cancers in men. In the UK around 37,000 men are diagnosed with
prostate cancer per annum with around 10,200 dying from the disease — a
figure that expands to 258,000 worldwide deaths annually with around
50,000 castrate resistant [Source 6]. Around 20 to 30% of men with primary
prostate cancer present with metastatic disease (for which surgery and/or
radiotherapy treatments are inappropriate). Hormone treatment will
increase median survival by around two and a half years and provide
symptomatic relief. However, metastatic prostate cancer will nearly always
become refractory to hormone therapy (castrate resistant) with the only
remaining treatment option being chemotherapy, with docetaxel and steroids
only recommended for robust patient groups. In metastatic castrate
resistant patients who have progressed after chemotherapy, abiraterone
significantly increased median survival from 10 to 15 months and median
prostate specific antigen progression from 6 to 10 months.
Wider benefits of these anti-cancer drugs: The use of temozolomide
in other malignancies, for example melanoma, is currently under active
research. The clinical use of abiraterone is also expanding with potential
extension into third or even second line metastatic prostate cancer
therapy. In addition the method of action of abiraterone is applicable in
certain breast cancers, and clinical studies in this indication are
on-going [Source 7].
Economic benefits: Annual sales of temozolomide reached $1 billion
in 2008, providing profits to Schering Plough and economic impact in the
UK through royalty payments to Cancer Research UK. The Chief Executive of
CRUK notes on their website "The royalties we receive from the sales of
temozolomide go straight back into the pot to fund further research to aid
the development of even more drugs to help in our fight against the
disease." [Source 8]. Merck and Schering Plough merged in 2009, and in the
US temozolomide is sold as Temodar until the licence expires in August
2013. Temodar's estimated global sales for 2012 amount to $882 million
BTG plc received an undisclosed milestone payment following the licensing
of abiraterone acetate (Zytiga) in the EU, together with a royalty on
worldwide sales [Source 10]. Annual sales of abiraterone in the USA for
the years 2011, 2012 and 2013 were 221.1, 462.2 and 730.4 million US
dollars, respectively. In Europe, sales for these years were 96.0, 465.5
and 721.4 million US dollars, respectively, giving an overall total of
$1.45 billion dollars worldwide for this drug [Source 11].
Sources to corroborate the impact
http://www.cancerresearchuk.org/cancer-info/news/archive/pressrelease/2003-04-25-scotland-to-be-uk-leader-in-anticancer-drugs Role of the CRUK
Formulation Unit in drug delivery
- Document: Newell, D.R., Searle, K.M., Westwood, N.B., Burtles, S.S.,
on behalf of the Cancer Research UK Phase I/II Clinical Trials Committee
(2003) Professor Tom Connors and the development of novel cancer
therapies by the Phase I/II Clinical Trials Committee of Cancer Research
UK. British J. Cancer 89, 437-454.
- The story of temozolomide, Cancer Research UK, shows role of
Strathclyde Formulation Unit.
- Prostate cancer drug abiraterone launched in UK,
Abiraterone gains FDA approval
New diagnosis of cancer rates in the UK (2010 figures)
Abiraterone being trialled for breast cancer treatment
- 2008 figures on sales of temozolomide
2012 sales of temozolomide
Economic benefits of abiraterone acetate (Zytiga)
- Document with data requested from http://www.decisionresourcesgateway.com
will confirm abiraterone sales figures.