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ROCHE PHOTO |
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Not long ago, biotechnology was the ultimate bugbear topic in
the labs of top 10 pharmaceutical companies. It challenged drug
researchers' traditional grounding in the development of small-molecule
medicines. It sparked friction between medicinal chemists, the
workhorses of the 20th-century drug bonanza, and biologists, the
presumed heroes of a 21st-century genomics revolution. Worst of
all, perhaps, biotech challenged drug companies to make fundamental
changes to their routine.
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BIG PHARMA/
BIOPHARMA |
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Despite years of work on pharmaceutical proteins at some large
drug companies, there persists a polarity of perception regarding
large- and small-molecule therapeutics. Big drug companies are
typically viewed as committed to small-molecule drugs--even if
they employ biotechnology steps in discovery and early development.
Advances in biopharmaceuticals, on the other hand, are credited
to the labs of relatively small, purely biotech companies.
History, however, defies these views, according to research
heads at large drug firms. They claim their companies are already
key players in biopharmaceuticals and that their chemists and
biologists work effectively on teams that follow science in the
direction of large or small molecules without prejudice. Some
say the current state is precisely the result of a surprisingly
rapid transformation in business and research over the past three
to five years.
These large firms, however, have put a distinctly "big company"
stamp on biopharmaceuticals, beginning with buying into the business.
Most biopharma products in the top drug companies' portfolios
were acquired along with the biotech firms that developed them.
Others were accessed through partnerships. Through acquisition,
major companies have also taken over well-established biopharma
R&D and manufacturing operations.
In most cases, the big drugmakers avoided the risks taken by
biopharma pioneers. Research directors say their companies purposely
held off on major commitments until technologies matured. Once
in the game, however, these executives claim that they wield the
advantage of scale, working biotechnology into a broad range of
therapeutic research categories.
LARGE ACQUISITIONS include Pfizer's
buy of Pharmacia, which gave it a biopharma product portfolio
and a state-of-the-art research facility in St. Louis. Similarly,
Wyeth's purchase of Genetics
Institute set the drug firm up with manufacturing in Andover,
Mass., and Abbott Laboratories'
acquisition of BASF's Knoll Pharmaceuticals did the same for Abbott
in Worcester, Mass., and Ludwigshafen, Germany.
All of the major drug players had begun biopharma programs
prior to their big acquisitions, however. "People associate Wyeth
and biotechnology with the acquisition of Genetics Institute,"
says Robert Ruffolo Jr., president of R&D at Wyeth. "But it
predates that. It goes back to the days of our investment in Immunex.
We've been a biotech company for over a decade."
Wyeth acquired its stake in Immunex in 1994, bringing in its
first major protein therapeutic, Enbrel (etanercept) for rheumatoid
arthritis. And two years later, the firm bought a majority interest
in Genetics Institute, which had an important bone drug in development
as well as recombinant proteins for hemophilia.
These candidates emerged as InFuse (dibotermin alfa), a recombinant
human bone protein; Benefix (coagulant factor IX), a drug for
factor B hemophilia; and Refacto (moroctocog alfa), a factor A
hemophilia drug. But the big target in buying Genetics Institute,
according to Ruffolo, was proteomics and genomics discovery and
the manufacturing operations in Andover.
Ruffolo describes Wyeth's biopharma efforts as vibrant. Much
centers on developing new indications for the seven products the
company has on the market. New applications for Enbrel, for example,
are under investigation in asthma and heart disease, and the U.S.
Food & Drug Administration approved Enbrel for psoriasis
last week. The company is also working on a range of oncology
indications using a cell-targeting mechanism employed by its leukemia
drug Mylotarg (gemtuzumab ozogamicin).
Mylotarg, in fact, represents a breakthrough biopharmaceutical
technology, according to Ruffolo: an antibody-targeted cytotoxic
agent. "That's the Holy Grail, where you take a powerful poison,
in this case calicheamicin, and link it to an antibody that identifies
only the cancer cell." Mylotarg targets an antigen called CD33
in patients with leukemia.
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CHANGING COURSE A breakdown of clinical development
candidates among the top pharmaceutical companies shows that
major drug firms are paying increasing attention to large-molecule,
primarily protein, therapeutics. Biopharma leader Amgen's clinical
pipeline breakdown is included for comparison. |
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The company is developing another drug, CMC-544, that delivers
calicheamicin to an antigen associated with non-Hodgkins lymphoma.
Ruffolo says the firm's most exciting work in this area is on
a candidate called CMD-193, which uses the same targeting technique
against the Lewis Y antigen, which is associated with "the big
four": breast, colon, prostate, and lung cancers.
"And we are back in business, now, in Alzheimer's," he says,
following a failed vaccine program. AAB-001, a synthetic version
of the protein that the vaccine was meant to trigger, is going
into clinical trials. In all, Wyeth has 10 proteins in development,
Ruffolo says.
He maintains that Wyeth's pursuit of biopharmaceuticals has
always been directed by an open approach to drug discovery that
does not favor large- or small-molecule drugs.
This approach is part of a new way of thinking at companies
where medicinal chemistry has generally held sway, Ruffolo says.
"We've gotten mature enough and good enough at this so that we
no longer think small molecule whenever possible. Now we ask,
'What's the best approach?'"
At the same time, Wyeth has backed its internal efforts with
more than 100 collaborative agreements with small biotech companies
and other partners. "Partnerships are virtually dictated by patent
complications," Ruffolo says. They are also the most direct means
to access new technologies.
Wyeth recently entered a partnership with the Belgian firm
Galapagos Genomics
that provides access to Galapagos' RNA interference (RNAi) technology
for osteoporosis. Frank Walsh, senior vice president of discovery
research, says Wyeth had an "embryonic" RNAi program and chose
partnership to ramp up fast once it ascertained the importance
of the technology. Other recent partnerships include deals with
Caprion Pharmaceuticals
to identify biomarkers and with Neurome to use quantitative neuropathology
in the area of central nervous system disorders.
Wyeth also looks to partners for production of many of its
products: Refacto is manufactured by Biovitrum in Stockholm and
GlaxoSmithKline (GSK) is an outside
supplier of Benefix, according to Michael E. Kamarck, senior vice
president for biopharmaceuticals. Wyeth makes Benefix, InFuse,
and other biopharmaceuticals in its Andover facility, which was
recently expanded at a cost of $350 million. The company will
add significantly to its manufacturing base with a $1.5 billion
facility in Grange Castle, Ireland, where it will produce a wide
range of products.
Among the top 10 drug companies, Roche
has the longest involvement in biopharmaceuticals, according to
Jonathan Knowles, president of global research, beginning with
its production of vitamin C from paprika in the 1930s. In the
1980s, the company was among the first firms to produce interferon- ,
at its Nutley, N.J., laboratories. Roche was the first to put
a recombinant interferon-a protein into the clinic, and its Roferon-A
was approved for melanoma in 1986.
This was followed by Pegasus, a PEGylated interferon-a. Then,
in 1990, Roche made a key move, purchasing a majority interest
in biopharmaceutical pioneer Genentech. Roche upped its manufacturing
capabilities with the acquisition of Boehringer Mannheim in 1998
and further extended its reach two years ago by acquiring a majority
stake in Chugai.
With 40% of its sales coming from biopharmaceuticals--top products
include Rituxan (rituximab) for non-Hodgkins lymphoma and erythropoietin
for treating anemia--Roche is the second largest biopharma firm
in the world by sales, Knowles claims. Of Roche's 61 new molecular
entities, 15 are proteins, Knowles says, and more than 80 of its
approximately 250 discovery candidates are proteins. Half of these
are credited to Genentech and a quarter to Chugai.
Like Wyeth, Roche is applying its R&D firepower to moving
approved protein therapeutics into new disease areas. For example,
Rituxan, a product that Genentech initially licensed from Idec
Pharmaceuticals, is showing promise in rheumatoid arthritis
and other autoimmune diseases, Knowles says.
Overall, Knowles notes an evolution away from a prejudice favoring
small molecules. "People hang on to what they believe works,"
he says. "There was a great deal of small-molecule prejudice,
because that's where a great many of the medicines of the '70s
came from. All of the neurotransmitter-based pharmacology that
led to the drugs of the '70s, '80s, and '90s is based on bringing
organic chemistry together with pharmacology. There is probably
still a major prejudice saying that some diseases' internal mechanisms
cannot be approached by biotherapeutics. I can imagine at some
companies that can lead to tension."
MINDS HAVE CHANGED
since the late 1990s, however, as protein drugs gained
a track record, Knowles says. "Some years ago, nobody understood
why antibodies might be important," he says. "We could understand
how Epogen might work, because it's a natural hormone, but antibodies
are artificial mechanisms. Only in the past five years has it
been understood that antibodies can be extraordinarily potent
therapeutic agents, that they can do things that small molecules
can't."
Abbott has followed a similar track in building a biopharma
presence, purchasing Knoll Pharmaceutical in 2001. With the acquisition,
Abbott established a centralized biologics group that operates
as a resource for discovery and research in all therapeutic areas.
It took over Knoll's R&D base in Ludwigshafen.
The deal also landed Abbott its cornerstone biopharmaceutical,
Humira (adalimumab), for rheumatoid arthritis. The company currently
has clinical trials for Humira in six other indications, according
to Alejandro A. Aruffo, president of the Abbott Bioresearch Center.
Abbott has been using
its new biotech research strength to stoke the pipeline. ABT874,
an IL12 antibody, recently completed Phase II trials for Crohn's
disease, and the company is currently enrolling patients in early
clinical trials for multiple sclerosis. "As with Humira, we believe
the anti-IL12 drug will be effective in the treatment of multiple
autoimmune diseases," Aruffo says.
Abbott's new infrastructure for biotech research has opened
up choices in discovery, Aruffo says, and protein options now
have equal standing with small molecules. "Our philosophy is to
look at the molecular targets that drive a disease and at the
standard of care for the disease. Then we ask, 'What's the best
approach?' "
In fact, he says, small molecules have hit brick walls in some
areas. "There are a lot of companies saying they are going to
replace insulin with a small molecule," Aruffo says. "Well, we've
been waiting a long time, and it ain't happened yet. We let science
dictate the choice rather than try to artificially force a choice."
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Ruffolo
WYETH PHOTO |
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Industry sources agree that the two largest drug companies,
Pfizer and GSK, are playing a fast game of catch-up in biopharma.
GSK, which organized its R&D into six "centers of excellence
for drug discovery," or CEDDs, two years ago, added a seventh
CEDD this year for biopharmaceuticals. The company currently has
no commercial biopharma drug, but it parallels Roche in the number
of large-molecule drug candidates in the clinic. GSK's pipeline
includes interleukin-18, a treatment for immunologically sensitive
cancers, such as melanoma and renal cell cancer, currently in
clinical trials. Early-stage candidates include monoclonal antibodies
for severe neurological disorders and DNA vaccines for cancer
and viral infections.
Pfizer, on the other hand, came out of nowhere in biopharma
when it bought Pharmacia last year. It now has a research and
pilot facility for both mammalian cell culture and fermentation
in St. Louis, as well as a product portfolio. This includes Genotropin
(somatropin), a growth hormone; Fragmin (dalteparin sodium), for
hip replacement treatment; and Exubera, an inhaled insulin.
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Knowles
ROCHE PHOTO |
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"The fact that we had biopharma products for the first time
gave the company a real boost," says Martin Mackay, senior vice
president for R&D. Mackay notes that Pfizer has collaborated
with Abgenics, Cambridge Antibody Technology, and MorphoSys since
the early 1990s, accessing tools such as transgenic mice and phage-display
technologies. This preliminary work indicated that antibodies
showed promise.
"There were a lot of diseases that seemed to be amenable to
antibody therapy once the antibody world had matured sufficiently
to be able to make them viable," Mackay says. Pfizer's interest
in biopharmaceuticals factored into the decision to acquire Pharmacia
and the integration of the biotech assets following the deal.
In short, the timing was right, according to MacKay. "The decision
to pursue antibodies had mostly to do with technology's maturation,"
he says. "We really watched antibodies though the 1990s, and through
the mid-'90s we didn't feel the field was mature enough to sustain
an internal drive."
That drive is now under way. Mackay says Pfizer has 14 drug
targets in development across six therapeutic areas with 20 protein
therapy programs in discovery.
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Aruffo
ABBOTT PHOTO |
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"Our aim is to identify targets amenable to antibody therapy,"
Mackay says. "When we first started this drive in 2000, we really
had no idea how many would come forward. But the scientists keep
on coming up with new targets amenable to this type of therapy."
The company has identified 10 new targets in the past two years.
"Five targets per year isn't near the size of our low-molecular-weight
pipeline," Mackay says, "but it is a significant piece of the
portfolio."
Pfizer's heightened commitment to biotech is one of the sources
of culture change that the company has had to contend with in
the wake of two major acquisitions. "We have been a low-molecular-weight
company that hadn't played in this area," Mackay notes. "You have
to believe there was some bias to low-molecular-weight drugs.
But there are no internal barriers now, due to internal results
and data."
Biologists, chemists, and drug metabolism experts now work
on project teams, he says. "Chemists and biologists sit across
the hall from each other. At many times in our history, we had
chemists and biologists in different buildings. Even at different
sites."
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Mackay
PFIZER PHOTO |
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Mackay insists that Pfizer is at no real disadvantage to Roche,
Wyeth, and other big drug companies with longer standing biopharmaceutical
efforts. "If you really get behind a strategy, you can do an amazing
amount quickly," he says. "We aren't world leaders, but we are
right up there now from a position of being complete novices."
Pfizer has found that being able to push proteins into multiple
therapeutic areas is a key to success. "If you are only active
in the world of oncology, you only come up with oncology antibodies,"
Mackay says. "We found that by testing these antibodies for other
indications, such as inflammation or infectious diseases, you
can get some very neat surprises. It's the wonder of biology--how
it's all tied up in the body one way or another. It still never
fails to amaze me as a scientist."
Pfizer is currently contracting out its commercial protein
production, but that may change. "As we develop products, it will
be interesting to see just how much of it we do internally and
how much externally," Mackay says. "We have some decisions to
make about how we handle the production of marketed products."
The ability of large drug companies to enter new businesses
via acquisition is part of a great leap forward in biotech, Mackay
says. "If we had to build the St. Louis facility from scratch,
it would be quite a hurdle to get over."
In fact, he says one lesson from Pfizer's experience with biopharmaceuticals
is that even the largest company can make fundamental changes
rapidly. "It is not overstatement to call it a radical transformation
in a three-year time period," Mackay states. "From a standing
start to sprinting is a good feeling. For an industry criticized
for being big and clumsy, we couldn't have been more nimble in
this area."
Approaches to the market are similar among top 10 companies,
but views on the future of biopharmaceuticals vary. Companies
involved longest take a more conservative view.
"There probably is some finite number of targets for protein
therapeutics," Knowles says. "I don't know what it is. In another
10 years, there will be few proteins and we will focus more on
small molecules. If you look at the number of biotherapeutics
in the portfolios of large drug companies, you will definitely
see a dramatic increase over the past few years. But I'm not sure
how far that will go. It can't go all the way, because these are
injectables."
Wyeth's Walsh agrees, noting that long-term development programs
often end in a small molecule. For example, in a bone therapy
project in which Wyeth is bringing an antibody into Phase I trials,
a small-molecule follow-up is already in the works.
Aruffo, on the other hand, has a less clear view of an end
of the road. "There doesn't seem to be a near-term barrier to
the number of targets for proteins," he says. The key to growth,
however, is to develop equal strength in large- and small-molecule
therapeutics. This view, he says, is supported by recent moves
at biopharmaceutical companies to advance small-molecule programs.
Just as Abbott purchased Knoll, Amgen recently acquired Tularik,
he says. "Those companies that can bring forth the best benefits,
unconstrained by requirements to pursue large molecules or small
molecules, will be doing better down the road."
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