Moreover, protein drugs have a successful history at the FDA: Nearly 86 percent of the 77 biotechnology medicines approved by the FDA are recombinant human proteins (others include polyclonal antibodies, purified natural interferon, vaccines, modified natural enzymes and various cell and tissue therapies). (The tables scattered throughout this article list many, although not all, of the FDA-approved recombinant proteins. They include the date of first approval [and indication] as well as subsequent approvals for additional indications.)

Lastly, and perhaps the main factor influencing a company's decision to stick with proteins, is the sales potential. Handsome profits can be made off recombinant protein-based therapeutics. In fact, you'll find a table below that lists the annual sales figures for some of these medicines -- including Amgen's blockbusters Epogen and Neupogen, as well as Genentech's two hot cancer therapies Herceptin and Rituxan. Also included are the sales figures for two insulin products -- Eli Lilly and Co.'s Humulin and Novo Nordisk A/S's Novolin -- which will give you an idea of the ever-increasing market size for a medicine to treat a very common disease, one which affects more individuals each year.

Product	First FDA Approval (Date)	1993 Sales (M)	1994 Sales (M)	1995 Sales (M)	1996 Sales (M)	1997 Sales (M)	1998 Sales (M)	1999 Sales (M)
Actimmune	12/90	-------	-------	-------	-------	-------	$3.9	$4.8
Activase	11/87	$236	$281	$301	$284	$261	$213	$236
Avonex	5/96	-------	-------	------	$77 (partial year)	$240	$395	$621
BeneFIX	2/97	-------	-------	------	------	N/A	$93	$135
Betaseron	7/93	-------	-------	-------	-------	$325	$350	$430
Ceredase/Cerezyme	4/91; 5/94	$125	$172	$215	$265	$333	$411	$479
Enbrel	11/98	-------	------	-------	------	------	$13 (partial year)	$367
Epogen	6/89	$586	$721	$883	$1,071	$1,161	$1,380	$1,760
Herceptin	9/98	------	-------	-------	-------	--------	$31 (partial year)	$188
Humulin	10/82	N/A	N/A	$794	$884	$936	$959	$1,088
Infergen	10/97	-------	-------	-------	-------	$3 (partial year)	$16	$26
Intron-A & Rebetron	6/86 6/98	-------	-------	-------	-------	-------	$705	$1,1006
Kogenate	2/93	-------	-------	-------	-------	-------	$360	$367
Leukine	3/91	$43	$46	$41	$43	$53	$64	$69
Neumega	11/97	------	-------	------	-------	N/A	$53	$45
Neupogen	2/91	$719	$829	$936	$1,017	$1,056	$1,120	$1,260
Novolin	7/91	N/A	N/A	N/A	N/A	N/A	N/A	$1,3001
NovoSeven	3/99	--------	---------	---------	---------	----------	--------	$2401
Procrit	4/93	--------	--------	--------	--------	$1,130	$1,460	$1,800
Proleukin	5/92	$35	$41	$55	$64	$71	$93	$112
Protropin/ Nutropin/Neutropin AQ	10/85; 3/94; 12/95	$217	$225	$219	$218	$224	$214	$2212
Pulmozyme	12/93	-----	$88	$111	$76	$92	$94	$111
Regranex Gel	12/97	--------	---------	-----------	---------	N/A	N/A	$72
Remicade	8/98	------	----------	--------	-------	--------	$28 (partial year)	$44 (6 months)4
ReoPro	12/94	------	------	$23	$149	$254	$365	$4473
Retevase	10/96	----	------	------	N/A	N/A	$65	$45 (6 months)4,5
Roferon-A	6/86	-------	-------	-------	-------	-------	-------	$176
Rituxan	11/97	------	-------	-------	-------	$6 (partial year)	$163	$279
Synagis	6/98	------	-------	------	-----	------	$110 (partial year)	$293

Footnotes to table:

*All sales figures were derived from company earnings reports, analysts' reports or personal communications. In general, these figures represent total sales in all territories.

**N/A: Not available

1) Sales for Novo Nordisk's products Novolin and NovoSeven represent worldwide sales figures. NovoSeven was approved in the U.S. in 3/99, but had already been approved for sale elsewhere.

2) Genentech always reports combined sales figures for all three growth hormone products.

3) Sales for ReoPro are end-sales to customers as reported by Centocor Inc.'s marketing partner, Eli Lilly and Co.

4) The latest sales figures for Centocor's products Remicade and Retevase are 2Q:99, and represent 6-month figures. Centocor was acquired by Johnson & Johnson in 10/99; the latter does not break out sales figures for individual products.

5) Centocor acquired U.S. and Canadian marketing rights to Retevase from Boehringer Mannheim in March 1998. The 1998 yearly sales figure above represents total sales ($65.2M), including sales by Boehringer Mannheim prior to Centocor's acquisition of the product. Centocor's sales of Retevase in 1998 were $55.4M.

6) Sales figures for Intron A include those for the combination therapy Rebetron (which consists of Intron A plus Rebetol [ribavirin]).


Of the many companies that are developing recombinant medicines, however, we'll focus on only three in this article: Genetics Institute Inc., Centocor Inc. and ZymoGenetics Inc. These three share some common traits: They were all stand-alone biotech companies in the 1980s; they've all been acquired by big pharma; and all three have been responsible for the development of products that are on the market today. But there the similarity ends.


If there was ever a dark horse in the biotech product development race, it's ZymoGenetics. Those of you who've been following the biotech industry for the last 25 years may remember the small Seattle-based company, but newcomers have probably never heard of it. That's about to change.

ZymoGenetics, which was founded in 1981 by three university professors, established its reputation by developing yeast-based expression and production systems (thus the company's name) for recombinant proteins. It was especially well-known for platelet-derived growth factor (PDGF), a tricky molecule that several biotech firms were working on at the time. ZymoGenetics licensed its PDGF technology to Chiron Corp. and Chiron's partner the R.W. Johnson Pharmaceutical Research Institute (a unit of Johnson & Johnson). Today, Ortho McNeil Pharmaceuticals Inc. (also a Johnson & Johnson company) sells that product as Regranex Gel, which the FDA approved in December 1997 for treating diabetic foot ulcers.

But ZymoGenetics wasn't slated to remain independent for very long. In 1988, following a collaboration with Danish pharmaceutical giant Novo Nordisk on recombinant insulin (now sold as Novolin), the latter bought the Seattle firm for about $30 million in cash. The companies had also partnered to develop a yeast-based production system for recombinant Factor VIIa (now marketed as NovoSeven for treating hemophilia).

For the next 12 years or so -- until May 2000 -- ZymoGenetics disappeared off almost everyone's radar screens. But just because its parent company wasn't talking about R&D projects doesn't mean that ZymoGenetics was idling. Far from it: The firm's technology underlies five marketed products -- not only Regranex Gel , Novolin and NovoSeven, but also Glucagen (for treating severe hypoglycemia; also sold by Novo Nordisk) and a recombinant tissue plasminogen activator sold in Japan by a Japanese partner. Together, these represent about $1.5 billion in annual worldwide sales, according to Bruce Carter, ZymoGenetics' president. (See the table of product sales for details.) Also, Amgen Inc. and Kirin Brewery Co. Ltd. have licensed ZymoGenetics' thrombopoietin (TPO), which is in development.


The main reason that we now know what ZymoGenetics has been up to all these years is because its parent company, Novo Nordisk, is spinning it off. The spin-off strategy is certainly not unusual in the biotech world (see the Signals article "Biotech Spin-Offs Seek New Orbits," for examples), but spinning off an acquisition is fairly unique. The move, which is scheduled to be completed by the end of this year, is expected to be accomplished through a huge private financing -- reportedly as much as $200 million, garnered from a group of private investors with very deep pockets.

Some of that cash will no doubt go to rebuilding ZymoGenetics' product development capabilities, which it forsook about five years ago in favor of a research-intensive staff. One project on the near horizon is to ramp up activities at the company's fermentation/manufacturing facilities.

Novo Nordisk will retain a small stake in ZymoGenetics (which has yet to be determined), but it will no longer have control. The parent company will, however, retain the option to license ZymoGenetics' protein therapeutics outside North America and plans on taking two board seats. (Also joining ZymoGenetics' board will be two of biotech's founding fathers -- George Rathmann and Edward Penhoet.)


Now that ZymoGenetics is re-emerging as a biotech player, it's also upfront about where it stands. Carter's presentation at the Allicense 2000 meeting in Basel in May was the first time that the firm's strategy and strengths were outlined in a public forum. The strength and the strategy are the same -- protein-based therapeutics.

Bruce Carter

In fact, ZymoGenetics has amassed a stack of patents on recombinant proteins. According to Carter, that amounts to 173 issued U.S. patents, and hundreds more pending. All together, ZymoGenetics has filed patents on about 500 proteins. And, more often than not, it's been the first company to do so, Carter said. For instance, between 1993 and August 1998, ZymoGenetics was first to file on more patent applications for possible protein therapeutics than any other company save Human Genome Sciences Inc. (Genentech Inc. was third; Genetics Institute Inc. was fourth.) Moreover, since 1996, he added, ZymoGenetics has filed first the most often, followed by Genentech and Human Genome Sciences.

Why proteins? Because, protein therapeutics provide exclusivity, and "Exclusivity is the holy grail of the pharmaceutical industry," Carter said. Small molecule drugs afford only limited patent protection, and it's relatively easy to synthesize variants, or "me toos" (thus quickly eroding market share). "In the last 10 years, these drugs [new chemical entities, or NCEs] have been very rapidly copied. For instance, there must be 20 ACE inhibitors on the market today," he said. "When a small molecule comes off patent, it can lose up to 80 percent of its sales within one year."

Proteins, on the other hand, have unique modes of action and they can be protected by composition-of-matter, use and/or production patents. "There's only one erythropoietin," Carter said. "This exclusivity has allowed Amgen to build a company with a huge market cap." Still, even in the realm of biological molecules it's possible to find competitors in the marketplace today (there are several recombinant tissue plasminogen activators on the market, for instance, and the number of alpha interferons is even higher). But, according to Carter, that's all in the past. "We won't see this situation in the future." That's because a patent can be written such that it covers not only the protein per se, but also proteins that are "substantially homologous" in composition, he continued.

Product Name	Company (s) [Developer; Marketer])	Product Category	First Indication Approved By FDA	Date Of First FDA Approval	Additional FDA-Approved Indication(s)	Date(s) Of Additional FDA Approval(s)
Epogen	Amgen	Recombinant human erythropoietin	Anemia associated with chronic renal failure including dialysis & non-dialysis patients; also anemia in Retrovir-treated HIV patients	6/89	Anemia caused by chemotherapy in patients with non-myeloid malignancies Prevention of anemia associated with surgical blood loss Anemia in children with chronic renal failure undergoing dialysis	4/93 12/96 11/99
GlucaGen	Zymo-Genetics; Novo Nordisk	Glucagon; recombinant DNA	Treatment of hypoglycemia; also for use as diagnostic aid	6/98	-------	---------
Herceptin	Genentech (Roche)	Humanized monoclonal antibody to HER2 growth factor receptor	Treatment of HER-2 overexpressing metastatic breast cancer	9/98	-------------	-----------------
Humulin	Eli Lilly (licensed from Genentech)	Recombinant human insulin	Diabetes	10/82	------------	--------------
Infergen	Amgen; Yamanouchi Pharmaceutical Co.	Consensus interferon; non-natural recombinant type 1 alpha interferon	HCV infection (chronic)	10/97	--------------	---------------
Intron A	Schering-Plough (licensed from Biogen)	Recombinant human interferon alfa-2b	Hairy cell leukemia	6/86	Genital warts AIDS-related Kaposi's sarcoma HCV infection HBV infection Malignant melanoma Follicular lymphoma in conjunction with chemotherapy HBV infection in pediatric patients	6/88 11/88 2/91 7/92 12/95 11/97 8/98
Kogenate	Bayer (licensed from Genentech)	Recombinant antihemophilic factor (Factor VIII)	Hemophilia A	2/93	-------------	--------------
Leukine	Immunex	Recombinant granulocyte macrophage-colony stimulating factor (GM-CSF)	Autologous bone marrow transplant (BMT)	3/91	Neutropenia resulting from chemotherapy in acute myelogenous leukemia Allogeneic BMT Peripheral blood progenitor cell mobilization & transplantation	9/95 11/95 12/95

There's another advantage to proteins over small molecules, Carter said. Proteins positively affect biological processes that occur in the body; small molecules usually act in a negative manner -- by inhibiting biological activity. "The drug industry was founded on chemistry, and chemistry is good at stopping processes (through the action of inhibitors, blockers or antagonists). Proteins, on the other hand, act positively, as effectors." Thus, it can be easier to study proteins in the clinic. "With a biologic, you can find out sooner whether the product is going to work," Carter said. And, the sooner a company can decide whether to forge ahead with large-scale trials or to terminate clinical development, the more cost-effective it is.

ZymoGenetics uses a genomics-based approach to identify its potential product candidates. It's been a subscriber to Incyte Genomics Inc.'s EST sequence database since August 1995 and it's also developed an extensive in-house sequence database. "We use bioinformatics to look for DNA sequences that are similar to proven ones," Carter said. "We search for sequence homology and structural motifs." Since only about one to two percent of the genes in the human genome code for "plausible protein therapeutics," it's not such a huge search. At ZymoGenetics, that search includes about "30 different families [of genes]," he said. "The challenge is to clone and patent only those that look interesting." As well, starting with the gene and then determining its function -- rather than the other way around -- allows a company to take a more opportunistic approach to product development, defining therapeutic areas as it goes. Now, armed with a hefty patent portfolio, ZymoGenetics is ready to make good on its heritage.


While ZymoGenetics may be the dark horse in the protein patent and product race, there are lots of other contenders that have captured the crown time after time. Take Genetics Institute: The company has also been extremely active in its efforts to protect its intellectual property, ranking right up there with ZymoGenetics, Human Genome Sciences and Genentech in the number of protein patents filed between 1993 and 1998. As well, in its current guise, the company's been responsible, either directly or indirectly, for the market introduction of seven recombinant protein therapeutics, explained L. Patrick Gage, president of Wyeth-Ayerst Research. "We're marketing more recombinant protein products than any other company except Genentech," he said. Plus, Wyeth-Ayerst sells a number of recombinant protein-based vaccines and it's in the final stages of filing for regulatory approvals in both the U.S. and Europe on BMP-2 (recombinant human bone morphogenic protein; for repairing long-bone fractures and dental/craniofacial surgery), he added.

Product Name	Company (s) [Developer; Marketer])	Product Category	First Indication Approved By FDA	Date Of First FDA Approval	Additional FDA-Approved Indication(s)	Date(s) Of Additional FDA Approval(s)
Mylotarg	Wyeth-Ayerst (AHP); Celltech Group	Humanized anti-CD33 monoclonal antibody, conjugated with calicheamicin (chemotherapy)	Relapsed acute myeloid leukemia in CD33+ patients who are 60+ years old and are not candidates for cytotoxic chemotherapy	5/00	-------------	--------------
Neumega	Genetics Institute; Wyeth-Ayerst (AHP)	Recombinant human interleukin-11 (platelet growth factor)	Chemotherapy-induced thrombocytopenia (platelet depletion)	11/97	-----------------	---------------
Neupogen	Amgen; Kirin Brewery Co.	Recombinant granulocyte colony stimulating factor (G-CSF)	Chemotherapy-induced neutropenia	2/91	Autologous or allogeneic bone marrow transplantation (BMT) Chronic severe neutropenia To support peripheral blood progenitor cell transplantation Acute myelogenous leukemia	6/94 12/94 12/95 4/98
Novolin	Zymo-Genetics; Novo Nordisk	Recombinant human insulin	Insulin-dependent diabetes	7/91	--------------	-------------
NovoSeven	Zymo-Genetics; Novo Nordisk	Recombinant factor VIIa	Treatment of bleeding episodes in hemophilia A or B patients with inhibitors (antibodies) to factor VIII or factor IX	3/99	-------------	---------------
Nutropin	Genentech (Roche)	Recombinant human growth hormone (hGH)	Growth failure in children due to chronic renal insufficiency; growth hormone inadequacy in children	3/94	Turner's syndrome Growth hormone inadequacy in adults	12/96 12/97
Nutropin AQ	Genentech (Roche)	Recombinant hGH (liquid)	Growth failure in children due to chronic renal insufficiency; growth hormone inadequacy in children	12/95	Turner's syndrome Growth hormone inadequacy in adults	12/96 12/97
Nutropin Depot	Alkermes; Genentech (Roche)	Recombinant hGH (sustained-release)	Growth hormone deficiency in children	12/99	-------------	-------------

What one has to take into account, however, is Genetics Institute's history -- plus that of its sister company Immunex Corp. and their parent organization, American Home Products Corp. (AHP). Genetics Institute was acquired by AHP in December 1996 for about $1.25 billion, but the big pharma already owned 60 percent of the biotech, which it bought in 1991. (At that time, this "60 percent solution" was a popular means for big pharmas to take significant stakes in leading biotech firms without acquiring them lock, stock and barrel. Roche did it with Genentech; Sandoz did it with SyStemix). Also, in 1994 AHP acquired a stake in Immunex through its acquisition of American Cyanamid (which had merged its Lederle oncology business with Immunex the previous year). By the spring of 1998, Genetics Institute had been integrated into AHP's Wyeth-Ayerst Research division, with Gage at the helm. Gage had been at Genetics Institute since 1989, and was its COO and president at the time of the acquisition.

Thus, the products developed by these entities -- which all fall under AHP's marketing umbrella -- include EPO (recombinant human erythropoietin, Genetics Institute's product that is blocked from the U.S. market by Amgen but was approved in Japan and Europe in 1990, where it is sold as Epogin and Recormon, respectively); Recombinate; Neumega; BeneFIX; Refacto; Enbrel; and Mylotarg. (Please refer to the tables scattered throughout this article for the details on these products).


Why has Genetics Institute -- in both former and current incarnations -- chosen to work with protein therapeutics? Simply put, "Proteins make great drugs," Gage said. He cited a number of reasons why this is true. First, and especially because of the genome sequencing efforts, there's now a massive amount of data on new genes. And, since genes code for proteins, there's an immediacy to turning these new discoveries directly into marketed products.

"We can go very quickly from the gene to a protein product, without the steps of target identification, screening, picking lead compounds, optimization and testing. We can go from a new gene to a drug in three to four years," he claimed. "It's the fast way to take advantage of the explosion of new genetic information."

L. Patrick Gage

"Until small molecule mimetics are developed, it's the only way to address some of the opportunities presented by genes," he explained. "We can't do this [yet] through small molecules. For instance, researchers are still struggling to develop an oral formulation of EPO, but in the meantime [the recombinant protein] is a great drug." (AHP, of course, also develops and sells small molecule drugs and vaccines.)

As well, using proteins per se "allows us to get into areas that traditional pharmaceuticals have never been in -- such as regenerative medicine, including tissue and organ repair -- using growth promoters and differentiation factors," Gage continued. "No-one thought to do this with small molecules." In this area, Wyeth-Ayerst's leading candidate is BMP-2, for which it is now filing marketing applications in the U.S. and Europe. But, since BMP-2 is a member of a much larger family of genes, "we've just scratched the surface in terms of pharmacological intervention to repair the body." BMP is a member of the TGF-beta (transforming growth factor) superfamily, which is now though to consist of about 40 separate genes. Of those, "there are 30 or so that are structurally similar to BMP. Many are involved in the development of the major organs and tissues of the body," Gage explained.

Product Name	Company (s) [Developer; Marketer])	Product Category	First Indication Approved By FDA	Date Of First FDA Approval	Additional FDA-Approved Indication(s)	Date(s) Of Additional FDA Approval(s)
Orthoclone OKT3	Ortho Biotech (J&J)	Murine monoclonal antibody to CD3 receptor	Reversal of acute kidney transplant rejection	6/86	Reversal of heart and liver transplant rejection	6/93
Proleukin	Chiron; Ligand (Canada)	Recombinant human interleukin-2	Renal cell carcinoma	5/92	Metastatic melanoma	1/98
Protropin	Genentech (Roche)	Recombinant hGH	hGH deficiency in children	10/85	------	--------
Pulmozyme	Genentech (Roche)	Recombinant human DNase	Reduction of incidence of respiratory tract infections in patients with cystic fibrosis (CF)	12/93	Treatment of CF in severely ill patients (less than 40% lung function) Treatment of CF in infants and young children	12/96 3/98
Recombinate	Genetics Institute (AHP); Baxter Healthcare	Recombinant antihemophilic factor (rAHF); recombinant Factor VIII	Prevention & control of bleeding in Hemophilia A	12/92	------------	--------------
Recombivax HB	Merck & Co. (licensed from Chiron)	Recombinant HBV vaccine	Prevention of HBV infection	7/86	-----------------	-----------------
Refacto	Genetics Institute; Wyeth-Ayerst (AHP) (purchased rights from Pharmacia & Upjohn in 8/97)	Recombinant factor VIII SQ; albumin-free	Hemophilia A; also, short-term prophylaxis to reduce frequency of spontaneous bleeding episodes	3/00	-----------------	-------------
Regranex Gel	Chiron; Ortho-McNeil Pharmaceuticals (J&J) (licensed from ZymoGenetics)	Recombinant human platelet-derived growth factor-beta	Lower extremity diabetic neuropathic ulcers	12/97	------------	--------------

But, there are some negative aspects of developing protein-based medicines. For one thing, patents can be a double-edged sword: While patent protection is critical, it's often the case that more than one company will stake a claim -- and defend it. Cross-licensing agreements can solve this dilemma -- but conflicts often end up in the courts first. The patent situation is "very different with small molecules, which are unique. There, the patent position is clear," Gage said. "On the other hand, because proteins are so hard to duplicate, their [product] life cycles are much longer. There's not as much competition as there is with 'me-too,' small molecule drugs."

Another issue surrounding proteins is their method of manufacture. "For protein therapeutics, the manufacturing element becomes critical," Gage explained. "It's easy to find contract manufacturers for small molecules [chemicals], which can be made anywhere," but biologics face a unique set of regulatory demands and restrictions. "The FDA cares a lot about the manufacturing facility, compliance issues, QC/QA, and so forth. There's only a few contract manufacturers [for biologics], and they're fully booked," he said. That's because recombinant protein products have become "more successful than people expected."

Not surprisingly, AHP has just relegated about $1.5 billion to expand its manufacturing capacity -- including a new facility in Ireland. It's always risky to make huge investments in a manufacturing plant before the company knows if its lead product will be successful; AHP mitigates the risk by having a large product pipeline. "This is a critical success factor for our company," Gage added.


Recombinant protein-based medicines have certainly taken their place in the physician's arsenal. Direct replacement products -- such as EPO, human growth hormone or insulin -- have established very successful franchises. But monoclonal antibodies have taken a little longer to gain their rightful place. (Antibody-based diagnostics, both in vivo and in vitro, are not included in this discussion.)

The first antibody-based therapeutic to gain FDA approval, in June 1986, was Ortho Biotech's Orthoclone OKT3, a murine monoclonal for reversing kidney transplant rejections. The latest, which received FDA's imprimatur in May 2000, was Wyeth-Ayerst's Mylotarg, a humanized antibody, conjugated with a chemotherapeutic agent, for treating acute myeloid leukemia. (See the tables of FDA-approved products in this article for more antibody-based drugs.) In between, the annals of clinical development have recorded both dazzling successes and spectacular failures.

Product Name	Company (s) [Developer; Marketer])	Product Category	First Indication Approved By FDA	Date Of First FDA Approval	Additional FDA-Approved Indication(s)	Date(s) Of Additional FDA Approval(s)
Remicade	Centocor (J&J); Schering-Plough	Chimeric monoclonal antibody to tumor necrosis factor-alpha	Moderate-to-severe Crohn's disease (including fistulizing Crohn's disease)	8/98	Rheumatoid arthritis in patients who have had inadequate response to methotrexate	11/99
ReoPro	Centocor (J&J); Lilly	Chimeric monoclonal antibody fragment to GPIIb/IIIa platelet receptor	Anti-platelet; prevention of blood clots in the setting of high-risk percutaneous transluminal coronary angioplasty (PCTA)	12/94	Refractory unstable angina when PCTA intervention is planned	11/97
Retavase	Centocor (J&J) (acquired rights from Boehringer Mannheim & DuPont Merck Pharmaceuticals)	Recombinant tissue plasminogen activator	Treatment of acute myocardial infarction	10/96	-------------	--------------
Rituxan	Idec Pharmaceuticals; Genentech; Hoffmann-La Roche	Chimeric pan-B monoclonal antibody that targets CD20 antigen on B cell surface	Treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin's lymphoma	11/97	--------------	--------------
Roferon-A	Hoffmann-La Roche (licensed from Genentech); Gilead Sciences (for HCV)	Recombinant interferon alfa-2a	Hairy cell leukemia	6/86	AIDS-related Kaposi's sarcoma Chronic myelogenous leukemia HCV infection	11/88 11/95 11/96
Synagis	MedImmune; Abbott Laboratories	Humanized monoclonal antibody that binds to the F (fusion) protein on surface of respiratory syncytial virus (RSV)	Prevention of serious lower respiratory tract disease caused by RSV in high-risk pediatric patients	6/98	-------------	-------------
TNKase	Genentech (Roche); Boehringer Ingelheim Pharma KG	Tenecteplase; Recombinant tissue plasminogen activator (2nd-generation); single-bolus; can be admin over 5 seconds in 1 dose	Acute myocardial infarction in adults	6/00	--------------	-------------
Zenapax	Protein Design Labs; Hoffmann-La Roche	Humanized monoclonal antibody (SMART Anti-TAC) that binds to the interleukin-2 receptor on activated T cells	Prevention of acute kidney transplant rejection	12/97	-------------	-------------

Centocor's products ended up in both categories. Its anti-platelet antibody product ReoPro, which the FDA first approved in December 1994 for treating high-risk angioplasty patients, is generally regarded as best of its kind. Initially overlooked by Wall Street, opinions quickly changed after the drug had been on the market a while. By early 1996, it was being hailed as biotech's next blockbuster product. In fact, though ReoPro has yet to match the annual sales figures for Epogen or Neupogen, its cumulative sales passed the $1 billion mark one year ago.

But before ReoPro, there was Centoxin -- and that drug's stunning clinical blow-up almost caused Centocor's demise. Centoxin wasn't the only biotech drug in the clinic that failed to treat sepsis and septic shock, however: Synergen Inc., Xoma Ltd. and other companies also ran up against this still-unbreachable wall.

In the septic shock debacle, Centocor stood on the edge of ruin: Its lead product had failed, it was dangerously short on cash and the business plan didn't look too promising. Yet, the company came back from that brink. It went on to develop ReoPro, added to its product portfolio by acquiring the already-approved clot-buster Retevase and brought to market the Crohn's disease drug Remicade. Flush with success, the 20-year-old company attracted a serious suitor: In July 1999, pharma giant Johnson & Johnson bid an eye-popping $4.9 billion to acquire Centocor; by October, the deal was completed, and Centocor is now a wholly owned subsidiary.


But how did the biotech firm regain its balance and rise to the top? Most analysts attribute that remarkable turn-around to David Holveck, who was president and CEO at the time. (He's now the company group chairman.)

David Holveck

With its lead product -- and its business -- in near ruins after Centoxin, Centocor had the perfect opportunity to switch directions. It could have headed straight for the small-molecule arena, abandoning all programs devoted to monoclonal antibody-based therapeutics. Or, it could have refocused on developing small peptide molecules; it had already established a research program in this area, spun off to public investors as Tocor II in 1992 and reacquired in early 1994, that could have given it new direction. Yet, it stuck to monoclonals. In retrospect, it was obviously the right decision, but what were the reasons?