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Scientists are likely to find
most human genes within the next ten years. This will have
huge implications for human health, since most common diseases
have some genetic component.
Identifying regions of the genome
associated with susceptibility to certain diseases such
as cancer, osteoporosis, arthritis, diabetes and cardiovascular
disease, will enable physicians to identify individuals
most at risk, allowing them to take preventative measures.
Investigation of the role that genes play in triggering
disease will also enable the development of therapeutics
based on those genes. These drugs will be targeted to specific
diseases and disease sites in the body, and therefore have
fewer side effects than many of today's medicines.
The greatest implication of this
revolution for the pharmaceutical industry is that gene-based
treatments will be tailor-made for each person's genetic
makeup - in other words, they will be personalised medicines.
Such a revolution in the way patients are treated may initially
threaten the established pharmaceutical industry, but is
ultimately likely to present it with far greater opportunities.
More effective, less toxic
drugs
Today, some 20-40% of patients
are prescribed a drug that has no effect on their condition,
according to Millennium’s Mark Levin, speaking at the
IBC Drug Discovery Technology Conference in August 2001.
In addition, tens of thousands of people die each year from
adverse drug reactions, and millions more tolerate uncomfortable
and sometimes dangerous side effects.
Many
of these treatment failures and adverse events could be
eliminated if the genetic basis of drug
response and drug reactions could be understood. Genetic
testing could ensure that the physician is aware of any
risks and so can treat patients more safely and effectively.
The benefits of such tests to patients are numerous:
Advance knowledge of a patient's
susceptibility to disease will allow them to make appropriate
lifestyle changes to avoid or minimise the effects of a
genetic disease. Likewise, the patient can be closely monitored
and given treatment at an early stage of the disease.
Instead of the usual trial-and-error
method of matching patients with the right drugs, physicians
will be able to use genetic profiles to prescribe the most
appropriate drug therapy. As well as being more effective,
this will also reduce the likelihood of adverse effects.
A patient's genetic profile will
include details of their metabolism and ability to process
medicines. This will maximise the effectiveness of the administered
drug and decrease the chances of an overdose.
Drugs based on the proteins,
enzymes, and RNA molecules associated with genes and diseases
will be more targeted to specific diseases. This specificity
will maximise therapeutic effects and decrease damage to
healthy cells.
Benefits to industry too
As well as benefits for patients,
the era of personalised medicines will also offer opportunities
for the pharmaceutical industry, including:
- Reviving failed drug candidates
Previously failed drug candidates
may be revisited, and tested and submitted for approval
for the treatment of an appropriate genetically-defined
sub-population. Many drugs withdrawn from the market, or
abandoned during development because of either lack of efficacy
or adverse effects, could be found to be very effective
and safe for a section of the population with the appropriate
genetic profile. For example, Roche/Genentech's breast cancer
drug, Herceptin (trastuzumab), "would never have
made it to the market", according to the Head of Roche Diagnostics,
Heino von Prondzynski, if it wasn't for the discovery of
the HER-2 receptor. In the general patient population, the
response rate of Herceptin is 6%, while in the 15-20% of
the population that strongly expresses HER-2, the response
rate is close to 100%.
The systematic discovery and
analysis of genetic variations in drug response should lead
to more cost-effective drug development. The industry currently
spends around $500 million on R&D for every approved
drug. With trials targeted at specific genetic populations,
regulatory hurdles should become easier and cheaper to overcome.
The risk and expense of clinical trials will be reduced
by targeting only those patients likely to respond.
As knowledge of the relationship
between genes and various diseases increases, so new markets
for treatments will be created in currently underserved
or unrecognised areas. The processes of ageing, for example,
will be better understood and, perhaps, vulnerable to medical
intervention.
Pharma companies' gene-based
R&D
A search on the word "gene" on
the R&Dfocus
database, which covers
over 7,000 active R&D programmes, produces more than
1,600 hits, suggesting that at least 20% of current pharmaceutical
research activity is on gene-related programmes. Around
two-thirds of these are still in the preclinical stage,
suggesting that most gene-based treatments will not be commercially
available for several years, but over 100 are in late stage
(Phase II and above) human trials. The majority of gene-based
therapies are under investigation for the treatment of cancer,
with infectious disease being the second most common indication.
Breakdown of
"gene-based" drug R&D programmes by therapy area
L = Cancer; J = Anti-infective;
C = Cardiovascular; M = Musculoskeletal; N = CNS; B = Blood
products
Source: R&Dfocus
The success of gene-based programmes
varies between therapy areas. R&Dfocus attaches
the designation "Active" to ongoing research programmes,
as opposed to those that have been suspended or discontinued.
An analysis of the R&Dfocus database reveals
that, of the major therapeutic areas being targeted for
gene-based therapy, CNS may be the most fruitful, with over
75% of CNS programmes in active development. In contrast,
gene-based infectious disease and blood product programmes
are perhaps less likely to succeed, with only around half
of these projects still under active development.
In the case of blood product
programmes, this high failure rate appears to be due to
the high number of suspended Factor VIII and IX gene therapy
programs for haemophilia, only one of which (Avigen/Children's
Hospital of Philadelphia's hepatically delivered gene therapy
for haemophilia B, COAGULIN-B) has reached Phase
II trials. The high infectious disease failure rate is mainly
a reflection of the high number of suspended or discontinued
gene vaccines.
"Gene-based"
drug R&D programmes in active development
L = Cancer; J = Anti-infective;
C = Cardiovascular; M = Musculoskeletal; N = CNS; B = Blood
products
Source: R&Dfocus
The threat posed by personalised
medicine
Despite the promise of personalised
medicine for the pharmaceutical industry as well as patients,
many companies are understandably wary of the impending
changes in the way medicines will be discovered, developed
and prescribed. These changes could be severely disruptive
to the business of the big drug companies, which rely on
blockbuster products to drive their sales and earnings growths.
Think of the damage to sales if a $1 billion product is
found to work in only the 20% of patients with the appropriate
genetic
profile, for instance.
US companies grasping the
nettle
On the other hand, companies
which grasp the personalised medicine nettle could find
that they maximise sales and profits by discovering and
commercialising drugs that work in close to 100% of an appropriately
defined patient population. This would mean fewer treatment
failures, almost guaranteed success in treatment, and a
consequent premium pricing advantage.
According to R&Dfocus,
it seems this advantage will be enjoyed first by US firms;
over 75% of all gene-based drug R&D is currently carried
out in the USA. The graphic below, which covers both preclinical
and clinical programmes, shows how the USA is the country
of choice for carrying out trials on gene-based medicines.
Less than 10% of all gene-based drug R&D is performed
in the UK, the second country on the list. Germany, despite
boasting a booming biotech sector, is bottom of the list:
its biotech companies are focused more on bioinformatics
and other supporting technologies, rather than actual drug
development.
Breakdown
of "gene-based" drug R&D trials by country
Source: R&Dfocus
A new paradigm
In the future, understanding
an individual's genetic makeup will be the key to preserving
and improving their health, first by recommending changes
in lifestyle, diet and environment, but also by creating
personalised drugs with greater efficacy and safety. In
the next 15-20 years, doctors will be able to choose the
treatment with the greatest potential benefit on an individual
level. In general, decreases in the length of time a patient
is on medication, the number of medications a patient must
take to find an effective therapy and the number of adverse
drug reactions will promote a decrease in the cost of health
care.
In addition, decreases in the
number of failed drug trials and the time it takes to get
a drug approved will improve the efficiency of the drug
discovery and development process. It is quite possible
that, following in the footsteps of the Industrial Revolution
and the Information Revolution, we are on the verge of a
Healthcare Revolution, where huge increases in the "productivity"
of healthcare over a range of measures, from the cost of
drug discovery through to patient recovery, create a new
paradigm for the preservation of human health.
Copyright IMS HEALTH, 18 December 2001
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