Transcript Lecture 7. The implications of the Screening Hypothesis.

Lecture 7 – NPs and The
Pharmaceutical Industry
Artemisinin treats multi-drug
resistant strains of malaria. It is a
sesquiterpene lactone fom the
shrub Artemisia annual.
Apparently it is only produced
when the plant is subjected to
certain conditions.
Wikepedia
Artemisinin
Lecture 7 – NPs and The
Pharmaceutical Industry
Learning Outcomes - at the end of the lecture you should:
1.
Appeciate the importance of NPs as pharmaceutical agents
2.
Understand what we mean by Bioprospecting
3.
Appreciate why some environmentalists got excited by this possible means
of funding conservation
4.
Appeciate
4.1 Why the potential of bioprospecting may have been greatly overplayed
4.2 Why the screening hypothesis questions the underlying scientific
rationale
4.3 Why the behaviour of pharmaceutical companies supports this analysis
4.4 How “bioprospecting” might be done in future
Company
Pfizer
GlaxoSmithKline
Merck
AstraZeneca
J&J
Sales (m$)
$28,288
$27,060
$20,130
$17,841
$17,151
R&D
$5,176
$4,108
$3,957
$3,069
$3,235
Aventis
Bristol-Myers Squibb
Novartis
Pharmacia
Wyeth
$16,639
$14,705
$13,547
$12,037
$10,899
$2,799
$2,746
$2,677
$2,218
$2,359
Lilly
Abbott
Roche
Schering-Plough
Takeda
$10,385
$9,700
$9,355
$8,745
$7,031
$2,080
$2,149
$1,562
$1,425
$1,304
$7,045
$5,369
$4,509
$3,074
$2,845
$1,152
$1,020
$1,014
$896
$641
Sanofi
Boehringer-Ingelheim
Bayer
Schering AG
Sankyo
FORDMOTOR
PFIZER
DAIMLERCHRYSLER
TOYOTA MOTOR
SIEMENS
GENERALMOTORS
MATSUSHITA ELECTRIC
IBM
GLAXOSMITHKLINE
JOHNSONandJOHNSON
SONY
MICROSOFT
NOKIA
INTEL
VOLKSWAGEN
USA
USA
Germany
Japan
Germany
USA
Japan
USA
UK
USA
Japan
USA
Finland
USA
Germany
7,500
7,131
6,689
6,210
6,084
5,700
5,272
5,068
4,910
4,684
4,683
4,659
4,514
4,360
4,233
Finding new drugs - which is the way ahead?
Preserving biodiversity
Combinatorial chemistry
Rational drug design
OR
Finding new NPs
Exploiting ethnobotanical knowledge
High throughput screening
Throughout the 1990s this was
the approach adopted by most
companies – but has it failed?
Exploiting ecological knowledge
Many environmentalists and some
environmental economists say that
the future lies with NPs BIOPROSPECTING
Finding new drugs – BIOPROSPECTING?
Google finds 58000 references to
Bioprospecting ( 2005) and
489,000 now!
Bioprospecting – money for conservation?
 World sales of pharmaceuticals are currently about $400 billion annually
(25% in these sales are in LDC and 75% in the others)
 25-50% of pharmaceutical drugs contain natural products or compounds
derived from natural products
 Balick & Mendelsohn (1992), studying the harvesting of medicinal plants
from a rain forest estimated that annual revenues of $16-61 per ha could be
achieved.
 Pearce & Puroshothamon (1995) estimated that OECD countries might
suffer an annual loss of £25 billion if 60,000 threatened species were actually
lost as a medicinal resource.
 Merck & Co. entered into a bioprospecting agreement ($1 million) with the
National Institute for Biodiversity (INBio) in Costa Rica in 1991 and Eli Lilly
made an investment in Shaman Pharmaceuticals
Bioprospecting – money for conservation?
G C Rausser & A A Small (2000) J Political Economy, 108, 173-206
“Numerical simulation results suggest that, under plausible
conditions, the bioprospecting value of certain genetic
resources could be large enough to support market-based
conservation of biodiversity”
G C Rausser & A A Small (2000) J Political Economy, 108, 173-206
However, their analysis is too simplistic.
Total cost of drug (T) = Drug Discovery (A)
+ clincal studies (B) + safety testing (C) + drug manufacture (D)+ IPR (E)
+ etc.
A1. obtaining chemical samples
A2. testing the samples for a useful biological effect
B. efficacy of the drug in clinical trials (e.g. does the effect found in the test
tube translate into a positive outcome for the patient?)
C. safety testing (e.g. are there adverse side effects due to the chemical
having more than one effect?). Will include metabolism studies and long term
animal studies.
D. manufacturing methodologies (e.g. can the chemical be extracted,
synthesised or produced by fermentation on an industrial scale
economically?)
E. intellectual property (e.g. can the drug and its derivatives be adequately
protected by patents?)
G C Rausser & A A Small (2000) J Political Economy, 108, 173-206
They ignore that fact that making a Natural Product in commercial quantities
is often very hard indeed and often too expensive to lead to a viable product
unless it is a very important treatment.
Progesterone
Vinblastine
Streptomycin
Taxol
Liquorice or licorice is the root of
Glycyrrhiza glabra, from which a sweet
flavour can be extracted.
Liquorice extract is produced by boiling
liquorice root and subsequently
evaporating most of the water. Its active
principle is Glycyrrhizin, more than 50
times as sweet as sugar.
Bioprospecting – leads to conservation?
 TAXOL – a highly successful anti cancer drug
 Extracted from the bark of the Pacific Yew Taxus brevifolia
 3000 trees to get 1 kg – the trees die when the bark is taken
 75,000 trees pa needed to treat ovarian cancer in the USA
 No economic synthesis available
Bioprospecting – evidence of enthusiasm?
 Merck’s $1million invested in INBio – impressed?
 Merck’s 2003 sales were $20,130
 Merck’s R&D 2003 R&D budget $3,957 million
 Was the investment in INBio from the R&D budget
or their PR budget?
So where will future generations of drugs come from?
Preserving biodiversity
Combinatorial chemistry
Rational drug design
High throughput screening
OR
Finding new NPs
Exploiting ethnobotanical knowledge
Exploiting ecological knowledge
Maybe neither
• NPs can have specific, potent biomolecular activity
• They are very often very difficult to make synthetically
• The majority of organisms making NPs may not even be
accessible - < 10% of microbes can be cultured
So where will future generations of drugs come from?
Genetically manipulated microbes?
• Choose a microbe that makes a good range of
chemical diversity and can be cultured on a large
scale
• Add a gene coding a NP producing enzyme from
another organism
• Look for new chemical diversity
• Repeat and repeat and repeat with different genes
… from plants, from unculturable microbes, etc..
Combinatorial biochemistry.
Summary
• NPs are very important in the huge pharmaceutical industry
• NPs could become more important again
• Bioprospecting has been oversold by environmentalists. We
should not rely on income streams from bioprospecting for
conservation.
• The Screening Hypothesis could be a more productive guide to
the pharmaceutical industry than previous models