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Old Drugs In, New Ones Out
New York Times
By ANDREW POLLACK
Saturday, June 30, 2007
CAMBRIDGE, Mass. — Can an antipsychotic drug from the 1950s be
paired with a 1980s antibiotic to shrink 21st-century tumors? Might
an anticlotting drug help a steroid relieve arthritis? How about
a cholesterol treatment and a pain reliever teaming up to tame diabetes?
Alexis Borisy, the pharmaceutical industry's master matchmaker,
is betting they can. And if he is right, he may have found a cheap
and quick way to develop a new cornucopia of medicines.
Mr. Borisy is the 35-year-old co-founder and chief executive of
CombinatoRx, a biotechnology company dedicated to the proposition
that two old generic drugs can together make a powerful new medicine,
often for an entirely different disease.
It is too early to tell if Mr. Borisy will succeed and, indeed,
one of his company's drugs failed in a clinical trial this week.
But with drug makers big and small struggling to fill their product
pipelines, other biotechnology companies are also betting that pairing
old drugs can be a better business than inventing new ones from
scratch — which can take years and cost hundreds of millions of
dollars, with no guarantee of success.
For example, Pozen, based in Chapel Hill, N.C., is developing combination
drugs in partnerships with the pharmaceutical giants GlaxoSmithKline
and AstraZeneca.
Orexigen Therapeutics of San Diego, recently went public based
on the prospects for two combination drugs it is developing to treat
obesity. And privately held Celator Pharmaceuticals of Princeton,
N.J., has raised more than $40 million from venture capitalists
to combine old cancer drugs in a new way.
"We think if we prove this concept clinically we have an almost
unlimited pipeline," said Andrew S. Janoff, the chief executive
of Celator.
Helping propel the trend is the growing supply of drugs that have
lost patent protection, providing a lode of material to test for
newfound potential.
Information technology also plays a key role for CombinatoRx (which
is pronounced com-bin-a-TOR-ics, as in the mathematics field that
deals with combinations). The company relies on the latest robotic
drug-screening technology and software to test several thousand
pairs of medicines a day.
At its laboratory here, researchers and robots systematically pair
about 2,000 generic drugs with one another, with 2 million different
combinations possible. Each is tested on human cells. If a drug
pair inhibits the cells' production of inflammatory proteins, for
example, that might be reason to explore whether the combination
might work against arthritis.
Mr. Borisy describes it as a "dumb, brute-force, empirical approach"
that assumes current knowledge of disease is too limited to predict
in advance what combinations might work. The company does, though,
give priority to testing pairs it believes have the best chance
of working.
Eight of the company's randomly arranged marriages, including drugs
for cancer, arthritis and diabetes, have moved into clinical trials
— an unusually high number for a company that is only seven years
old. Other companies are taking more calculated approaches. Orexigen,
in creating its obesity drug Contrave, took a treatment used for
drug and alcohol addiction and combined it with an antidepressant
sometimes used to help people quit smoking.
Meanwhile, Celator is focusing on drugs that are already used together
to treat cancer. But while doctors now generally use the maximum
tolerable dose of each drug, Celator says the ratio of the drugs
is what matters more. So the company is developing combination products
meant to deliver optimal ratios of the drugs to tumors.
Besides being quicker or cheaper to develop than single new drugs,
combinations might also be more effective. Scientists have long
known that the biochemical pathways involved in disease are complex,
with numerous alternate routes. Trying to interfere with disease
by blocking a single point can be like trying to keep traffic from
reaching downtown Manhattan by closing a single intersection.
That is why doctors routinely use two or more drugs to treat people
with cancer, heart disease, H.I.V. infection and other diseases.
But only more recently have pharmaceutical companies decided to
do the combination themselves as a way to increase their profit.
Successful combination drugs already on the market include Advair
from GlaxoSmithKline, which pairs two asthma drugs, and Vytorin,
which combines cholesterol-lowering drugs from Merck and Schering-Plough
that work in different ways.
When they work, combination drugs mean fewer pills to swallow,
making it easier for patients to complete a course of treatment
— and, as a result, for companies to hit sales targets.
Combination drugs can also let a weaker-selling medication ride
the coattails of a stronger drug, or partly shield a product that
has lost patent protection from generic competition. One of the
ingredients in Vytorin, for instance, is Merck's Zocor, which has
gone off patent.
But for companies like CombinatoRx, which do not have any drugs
of their own, finding value in off-patent products is the whole
point.
Mr. Borisy, who dropped out of a Harvard chemistry doctoral program
to become a drug industry consultant, started CombinatoRx in 2000
with three researchers from his former Harvard laboratory.
The company's approach to drug research has attracted considerable
attention, including Mr. Borisy being named 2003 "innovator of the
year" among people under 35 by the Massachusetts Institute of Technology's
magazine Technology Review. The company has raised nearly $200 million
from investors, including $44 million from its initial public offering
in November 2005.
Several disease foundations have paid CombinatoRx to try to find
combinations for treating their specialties. And Angiotech Pharmaceuticals,
the company that supplies the drug used in Boston Scientific's drug-coated
stent for coronary arteries, has found combinations it hopes to
use in future stents.
"They were far ahead of anyone else, and the way they were doing
it we thought was just elegant," said Dr. Rui Avelar, the chief
medical officer for Angiotech.
For all the company's promise and attention, though, it is far
from clear that any of CombinatoRx's drugs will reach the market.
Three of the eight drugs that made it to clinical trials have since
been dropped — including one on Thursday — because they did not
work well enough in people, despite their effectiveness in the cell-based
laboratory tests.
Those cold clinical realities have helped pull the company's shares
to the $6 range, below the initial public offering price of $7 and
well under a high of almost $14 in early 2006.
Currently, the company's lead drug is a treatment for rheumatoid
arthritis and osteoarthritis that combines prednisolone, a steroid,
and dipyridamole, a blood anticoagulant.
Steroids are used to treat arthritis, but they have undesirable
side effects. Adding an anticoagulant seems somehow to amplify the
steroid's desirable effects, allowing use of a very low dose with
greatly reduced side effects, Mr. Borisy said. The drug has shown
promise in early clinical trials.
Combinations of existing drugs can enter clinical trials more quickly
than totally new medicines because much is already known about their
toxicity and how they behave in the body.
But some industry executives say the combinations risk encountering
regulatory problems downstream. They say the Food and Drug Administration
must be persuaded that a combination offers a real benefit to patients
and is not just a commercial gimmick, because each additional drug
a patient uses can raise the risk of safety problems, in part from
interactions between the drugs.
Another risk for companies as they mine drugs no longer protected
by patents is that other companies might try to sell similar combinations.
While the combinations themselves can be patented, legal challenges
could arise if the combination is deemed too obvious. Mr. Borisy
says he is not worried because "our patents are so obviously non-obvious."
Another business risk is that even if a combination pill is protected
by patents, doctors might prescribe the two ingredients separately,
especially if that would save the patient money.
Pozen, for instance, is developing a combination of the generic
pain reliever naproxen with AstraZeneca's popular heartburn remedy
Nexium. The idea is that Nexium will protect the stomach from naproxen's
potentially ulcer-causing side effects. But many physicians are
already prescribing an antacid pill along with a pain killer — and
using generic stomach drugs rather than Nexium.
William L. Hodges, chief financial officer of Pozen, contends that
his company's combination pill will be more effective than two drugs
taken separately. In the Pozen pill, he says, the naproxen is not
released until Nexium has already lowered the stomach's acidity.
Assuming companies like Pozen and CombinatoRx can surmount the
challenges of two-drug combinations, the next question is whether
three drugs might be even better. The answer appears to be yes,
but developing trio drugs would be even more difficult.
For a triple combination, the F.D.A. might want evidence that the
trio is better than not only the individual parts but also better
than any of the possible pairs. Showing that would require huge
and costly clinical trials.
But Mr. Borisy says his researchers and robots will be up to the
task. "We're going to get to that," he said, "each step in time."

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