R&D
challenges from generic producers, such as
Figure 2: Why investigational candidates are dropped
Ranbaxy. Pfizer is frantically seeking patent
extensions, and developing reformulations,
11%
such as the fixed-dose combination drug
Caduet, using Lipitor and Norvasc
(amlodipine), which itself went off-patent in
28%
2007. Even so, the company will not be able
Adverse events
to fill the huge gap from the expected 80%
drop in Lipitor’s sales once generic
Ef_f_icacy
competition kicks in.
44%
Financial
As a consequence, companies are keen
Miscellaneous to bolster their pipelines by reformulating
Strategic
existing marketed products, generating
much needed revenue to develop novel
therapies. There is almost double the
9% number of reformulated drugs in preclinical
8%
development today (just over 400) than
Source: Pharmaprojects
there were in 1998 (230).
In 1998, the top big pharma companies
announced plans to produce three NCEs
Table 1: Top 10 most popular targets in development
per year to fill the early stages of their
Rank Target Primary disease
pipelines and boost flow throughout all
development stages. This was reflected in
1 HIV-1 gag-pol HIV infection
the mid-1990s when the number of new
2 COX-2 pain
active substances (NASs) reaching the
3 COX-1 pain market averaged around 40-50 products
4 oestrogen receptor 1 hormone replacement therapy
per year. In 2008, however, the figure was
somewhat disappointing, with only 25 NASs
5 calcium channel, voltage- hypertension
successfully launched. This isn’t to say that
dependent, L type,
alpha 1C subunit
NCEs and NASs aren’t being developed; as
of October 2008, Pharmaprojects had 8,982
6 D2 dopamine receptor schizophrenia/Parkinson’s
active drugs in its database, of which 4,433
disease
were NCEs. Pharma companies are clearly
7 µ1 opioid receptor pain
successfully developing NCEs and NASs.
8 glucocorticoid receptor asthma
The question is, are there enough of them,
9 β2 adrenergic receptor asthma
and will they continue to progress
successfully and consistently through the
10 serotonin neurotransmitter depression
12-14 year development time for novel
transporter
drugs, to provide the profits needed to
Source: Pharmaprojects
sustain the industry as its business model
changes?
drugs launched. Why are these drugs not against profits generated by marketed
It is of little surprise that companies are
getting through? As well as poor candidate products. Long-term pipeline potential is
sticking to what they know. Table 1 shows
selection, and the fact that drugs are key to securing investment from the
the top 10 most popular targets in
spending more time in Phase II, attrition financial sector. In the past, pipelines were
development and their associated primary
must be held accountable. According to balanced to produce new drugs in a steady
indication as documented by Pharmaprojects.
Pharmaprojects, between 2000 and 2008, stream to replace profit losses following
Comparing this information with the
1,941 drugs were discontinued. Of the patent expiries on older medicines. This all
launched drugs for these indications (see
projects for which companies have disclosed began to change at the beginning of this
Table 2) it is evident that the most
the reason for discontinuation, a startling decade with the coincidental loss of patent
frequently researched targets, historically,
44% of decisions were strategic, while just protection for a slew of major blockbusters.
are those which already have proven safety
28% of programmes were dropped because In 2001, Lilly’s hugely popular antidepressant
and efficacy, and are therefore more
of lack of efficacy and 11% for poor side- Prozac (fluoxetine) and Bristol-Myers
economically safe for the company to
effect profiles (see Figure 2). Squibb’s anti-diabetes drug Glucophage
develop.
Of course, it is not only in the clinic that (metformin hydrochloride) both came off
This is perhaps not the best news for
drugs are failing due to safety concerns. In patent. The past seven years have witnessed patients for whom there are few or no
2004, Merck & Co’s Vioxx (rofecoxib) was significant loss of blockbuster exclusivity, alternative therapies for their diseases. At
withdrawn due to increased risks of cardiac spelling financial disaster for some the 2007 BIO conference, Michael J Fox
events and now, following a spate of companies, and the trend looks set to appealed for research into novel treatments
lawsuits, the company is being sued by the continue. for diseases, rather than investment in the
state of Florida. Pfizer’s Lipitor (atorvastatin calcium), a more cost-effective, less risky reformulations
Market withdrawals have proven market leader in the cholesterol control that are so popular in the industry today.
calamitous to an industry for which the market and the best-selling drug of all time, Highlighting the need for novel therapies,
costs of developing a drug, possible lawsuits, faces patent loss from 2010, and the Mr Fox pointed out that the “gold standard”
and product attrition must be balanced company is already fending off patent in the Parkinson’s disease field, and the drug
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