‘Peel Chair’. Photo courtesy of thisisfurniture.com, 27 Hampstead Road, London NW1 3JA, UK. Tel: 020 7388 8871
The selection of the right targets for drug executives to believe that there will soon be a
been the case in the past, and it will probably
discovery is one of the key decisions in pharma-
revolutionary improvement in the industry’s
continue in the foreseeable future. Prices of
ceutical and biotechnology research and devel-
ability to identify and pursue novel targets. As
opment (R&D). A fundamental choice that
creasing pressure in all markets, such that all
companies have to make is the balance between
migrated much of their R&D investment
going after ‘tried-and-true’ drug targets, or
towards novel targets, beginning in the early
provements to existing drugs in terms of effi-
going after novel targets. Interestingly, the num-
1990s. According to recent research, most
cacy, reductions in side effects and convenience/
ber of tried-and-true drug targets is actually
pharmaceutical companies devote ~60–70%
effectiveness of dosing. However, clinically
quite small, at around 5001. G-protein-coupled
of their drug discovery portfolios towards
receptors (GPCRs) form one important class of
novel targets2. Today, given that pharmaceuti-
mance can come from new molecules against
drug targets that represents 20% of the top 50
known targets, and these do not necessarily
best-selling drugs (FIG. 1), including such well-
novel targets for nearly a decade, the time is
known brands as Claritin, Zyprexa, Zantac and
right to ask: how much value do novel drugs
sequently, the second message is that pharma-
Cozaar. The success of GPCRs as drug targets
ceutical R&D organizations should reconsider
over the past 20 years has spawned significant
the overall distribution of targets in their
imitation in certain categories, such as beta-
No higher returns for novelty
R&D portfolios. Individual companies will
blockers against hypertension. Hence, by some
In a recent set of analyses on product launches
estimates, GPCRs account for 50% of all drugs
from 1991–2000 for the top 15 pharmaceutical
on the market. The review by Chalmers and
companies, drugs were divided into two cate-
precedented targets, but they must be quite
Behan on constitutively active GPCRs in this
gories: unprecedented/novel and precedented.
rigorous in assessing the true risks of under-
issue provides valuable input to discussions on
Analyses showed that novel approaches had
taking a portfolio that is heavily weighted
target selection within the GPCR class, which
higher risk, as seen by the lower survival rate of
towards new targets. There is no single cor-
contains many novel as well as known targets.
rect answer in balancing a portfolio. Overall,
How aggressively should pharmaceutical com-
approaches. Moreover, the higher risk that is
panies be going after novel targets? This issue
associated with novel approaches did not gen-
represents one of the greatest challenges in port-
erate higher returns, as seen by the lower aver-
folio management today, and getting the balance
age present value of sales of US $2.8 billion
right could create significant value in the future.
compared with US $3.6 billion for precedented
before they consider new compounds against
approaches. If the precedented drugs are sorted
Focusing on novel targets
into ‘fast followers’, ‘differentiators’ and ‘late
comers’ on the basis of whether they hit the
increasing focus among many pharmaceutical
market from 2–15 years after the launch of the
improvements in the process by which they go
companies to discover ‘first-in-class’ novel
first-in-class drug, fast followers generated the
after novel targets. Analyses indicate that if
drugs. Drivers for this strategy include the past
most value, but differentiators and even late
current ‘high-throughput, high-novelty’ app-
success of drugs such as Prozac (for depression),
comers could be strong value creators. In fact,
roaches do not fundamentally improve, there
high expectations from financial markets for
of the 31 blockbusters (drugs with annual sales
will be significantly higher costs to generate a
new blockbuster drugs and an increasing con-
greater than US $1 billion) that were launched
new chemical entity (NCE). In particular,
cern that managed care would limit opportu-
by the industry throughout the 1990s, 74%
significant improvements will be needed in
nities for ‘me-too’ molecules. As demand for
(23) have come from precedented approaches.
R&D stages of biological validation and early
clinical development leading up to Phase II
advances in technology, especially ‘high-
Implications for drug discovery
‘proof-of-concept’ studies. Improvements can
throughput’ technologies, such as genomics,
The first key message is that there is value to
come from changes in processes, including
have led many scientists and top pharmaceutical
be created from precedented targets. This has
decision processes on whether compoundsshould or should not advance, as well as frominvestments in the right technologies — for
All drugs Top 50 drugs worldwide
example, predictive toxicology tools, structuralproteomics and clinical genomics/pharmaco-
genomics tools. However, investments in new
technologies will require parallel investmentsin top-rate bench science from biologists,chemists and pharmacologists to truly deliver
Figure 1 | Share of GPCR-based targets for drugs on the market. GPCR, G-protein-coupled receptor.
VOLUME 1 | AUGUST 2002 | 5 7 1
Box 1 | Attrition rates and cost for different R&D models
GPCR-based drugs (TABLE 1). Many pharma-ceutical companies have shifted their R&D
In the early 1990s, pharmaceutical companies began to invest substantially in developing a new
portfolios towards novel targets in the hope of
high-throughput, high-novelty approach to drug discovery. Research indicates that even with recent
developing more first-in-class drugs. Drugs
improvements in the ability of pharmaceutical companies to generate and work with novel targets, there are still significant challenges with the high-throughput, high-novelty approach. A comparison
that are based on novel targets have created less
of a low-throughput, low-novelty approach, which was used in the industry pre-1990s, with a high-
value on average than drugs that are based on
throughput, high-novelty approach, is shown in the figure below. The numbers shown are for the
precedented targets, and have had a higher risk
success rate at each stage of development, and the risk-adjusted cost per New Chemical Entity
of failure (FIG. 1). Many pharmaceutical compa-
(NCE). Biological validation and Phase II testing will probably be the key drivers for the relative
nies have focused on novel targets over the past
success of the high-throughput, high-novelty approach. Without substantial improvements, the total
decade, but what is the productivity impact of
risk-adjusted costs of research and development (R&D) for the high-throughput, high-novelty approach could be ~40% higher than the low-throughput, low-novelty approach per NCE generated. The high-throughput, high-novelty approach should not be abandoned, but these data reflect the Philip Ma* and Rodney Zemmel‡ are partners in the fact that the industry is in transition, and substantial improvements in processes and technology are Pharmaceuticals and Medical Products Practice, required to generate higher returns on R&D investments. B, billion. McKinsey & Company, *3075A Hansen Way, Palo Alto, California 94304, USA; and ‡55 East 52nd Low throughput, low novelty High throughput, high novelty Street 21st Floor, New York, New York 10022, USA. e-mails: Philip_Ma@McKinsey.com; Rodney_Zemmel@McKinsey.com Success rate Success rate
Drews, J. Drug discovery: a historical perspective. Science287, 1960–1964 (2000). Fruits of Genomics (Lehman Brothers, New York, 2001). Online links DATABASES The following terms in this article are linked online to: LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/ Drug output Drug output
adrenoceptors | angiotensin receptors | dopamine receptors |gonadotrophin-releasing-hormone receptors | histamine receptors |
Risk-adjusted cost/NCE ~US $0.7 B ~US $1.0 B
5-HT receptors | muscarinic acetylcholine receptors | PGE1 receptors Medscape DrugInfo: http://promini.medscape.com/drugdb/search.asp
Table 1 | Examples of GPCR-based drugs in the top 200 best-selling prescriptions
Allegra | Atrovent | BuSpar | Claritin | Coreg | Cozaar | Cytotec |Imitrex | Pepcid | Plavix | Prozac | Requip | Risperdal | Serevent |
GPCR target 2000 sales
Singulair | Toprol-XL | Zantac | Zoladex | Zyprexa
Access to this interactive links box is free online. Average present values of sales (US $ billions) Overall development survival rate (%)
Figure 2 | Value and survival rate of precedented compared with novel approaches.
Drugs that target precedented approaches create
more value on average. Precedented approachesalso have higher rates of development success.
This data refers to drugs that were launched
Source: McKinsey Analysis. COPD, chronic obstructive pulmonary disease; GPCR, G-protein-coupled receptor;
between 1991–2000. Source: McKinsey Analysis.
5-HT, 5-hydroxytryptamine (serotonin). 5 7 2 | AUGUST 2002 | VOLUME 1
Yesterday we talked about the loop product and the associated Gerstenhaber andBV structures on the loops space of the manifold. I’m going to put the equivariantpart of the story on hold for a little bit and come back to it. Since the first papers of Chas-Sullivan, others have taken these ideas and madethem more rigorous. To my knowledge, Cohen-Jones was the first one. This usesthe language of
Microbiological Hazards in the Vegetable Industry - a review Robert Premier and Julia Behrsing Microbiological Hazards in the Vegetable IndustryThe purpose of this review was to identify the human microbial pathogens that havebeen associated with fresh vegetables and which are known to pose a risk or aresuspected of doing so. Three classes of organisms were examined, bacteria,
‘Peel Chair’. Photo courtesy of thisisfurniture.com, 27 Hampstead Road, London NW1 3JA, UK. Tel: 020 7388 8871
The selection of the right targets for drug executives to believe that there will soon be a
been the case in the past, and it will probably
discovery is one of the key decisions in pharma-
revolutionary improvement in the industry’s
continue in the foreseeable future. Prices of
ceutical and biotechnology research and devel-
ability to identify and pursue novel targets. As
opment (R&D). A fundamental choice that
creasing pressure in all markets, such that all
companies have to make is the balance between
migrated much of their R&D investment
going after ‘tried-and-true’ drug targets, or
towards novel targets, beginning in the early
provements to existing drugs in terms of effi-
going after novel targets. Interestingly, the num-
1990s. According to recent research, most
cacy, reductions in side effects and convenience/
ber of tried-and-true drug targets is actually
pharmaceutical companies devote ~60–70%
effectiveness of dosing. However, clinically
quite small, at around 5001. G-protein-coupled
of their drug discovery portfolios towards
receptors (GPCRs) form one important class of
novel targets2. Today, given that pharmaceuti-
mance can come from new molecules against
drug targets that represents 20% of the top 50
known targets, and these do not necessarily
best-selling drugs (FIG. 1), including such well-
novel targets for nearly a decade, the time is
known brands as Claritin, Zyprexa, Zantac and
right to ask: how much value do novel drugs
sequently, the second message is that pharma-
Cozaar. The success of GPCRs as drug targets
ceutical R&D organizations should reconsider
over the past 20 years has spawned significant
the overall distribution of targets in their
imitation in certain categories, such as beta-
No higher returns for novelty