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'Big pharma' is weaving biotech into its research regime, developing multiple therapeutic indications for protein drugs

by Rick Mullin
May 10, 2004 | A version of this story appeared in Volume 82, Issue 19




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.

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.

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."


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.


"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.


"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."


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."



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.

Ruffolo <br > WYETH PHOTO

Knowles <br > ROCHE PHOTO

Aruffo<br > ABBOTT PHOTO

Mackay <br > PFIZER PHOTO



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