A Revolution in R&D

PHARMACOGENETICS—FOUR APPLICATIONS
To evaluate pharmacogenetics properly, companies
need to take an especially close look at the market
dynamics. These dynamics vary according to how
pharmacogenetics is used. We have identified four
such applications (each associated with a different
category of patient responding to a given drug). The
first three are used to exclude patients from trials;
the fourth is used to expand the potential market for
the drug.
First, efficacy prediction identifies patients who will
show no real or significant response to the drug—
perhaps because they metabolize the drug in an
unusual way, or have an unusual form or combination
of susceptibility genes. A typical drug produces
this negligible response in about a third of patients,
but sometimes the proportion is far higher. For
example, Cognex (tacrine), the first drug for
Alzheimer’s, is inefficacious in more than 50 percent
of patients. The varying response is associated with
differing versions of the ApoE gene, and is therefore
readily predictable by a pharmacogenetic test.
Second, common-side-effect prediction identifies
patients likely to experience familiar side effects, as
a result of metabolic difficulties caused by wellknown
enzymes. A test can screen out negative
responders—“slow acetylators,” for instance. The
acetylation polymorphism in the NAT2 gene is one of
the commonest genetic variations in drug metabolism;
it has the effect of reducing the enzyme’s lifespan
and thus reducing the effective amount of the
enzyme in cells at any one time. This polymorphism
is present in more than 50 percent of Caucasians,
who are thus at greater risk of drug toxicity.
Knowledge of this polymorphism could save a drug
in clinical trials that would otherwise be abandoned.
Third, very-rare-side-effect prediction identifies patients
at risk for unconventional side effects, but
comes into play only after the drug is on the market.
Unlike most of the common side effects, which are
associated with metabolic pathways and usually
emerge in preclinical studies, these rare side effects
tend to be provoked by nonmetabolic genes, and to
be overlooked at first. They cannot easily be predicted,
since there are too many possible sources
(modifications of the target or of the disease pathway,
or unrelated pathways), and they may occur too
rarely to show up in clinical trials.
A case in point is Lotronex, a drug for irritable bowel
syndrome, now withdrawn from the market. Only
after its market launch, and 450,000 prescriptions,
did its severe side effect (bowel impaction) become
apparent. About one in 6,500 patients was
affected—a frequency far too rare for a standard
clinical trial to detect beforehand. (A typical trial
involves about 5,000 patients: for this side effect to
have been manifest in a statistically significant way,
a trial of nearly 100,000 patients would have been
needed.) Pharmacogenetics could in certain cases
come to the rescue of such compromised drugs, by
belatedly devising a screening test.
Finally, market expansion identifies patients who are
currently unsuited to the drug but potentially responsive
to it. Since fine-tuning of dosages or formulation
can often reduce side effects and occasionally
improve efficacy, pharmacogenetics could reassess
and upgrade many of the supposedly ineligible
patients. The market for the drug might expand considerably
as a result.
Take the case of cyclophosphamide, a chemotherapy
drug, which works only when metabolized by the
enzymes CYP3A4 and CYP3A5. Some patients
appear underresponsive to it: a genetic variation
suppresses the activity of the enzymes, thereby
decreasing the amount of active drug in the bloodstream.
The best course is not to discontinue the
drug, but to compensate by taking a higher dosage.
A pharmacogenetic test could identify the appropriate
patients prior to treatment, and their consumption
of the drug, instead of declining to zero, would
actually increase.
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