New Battleground For Biotech Drugs:
Autoimmune Ills Amgen's Enbrel and Others
Are Hard to Make, Costly And Prey to Competition
By DAVID P. HAMILTON
Staff Reporter of THE WALL STREET JOURNAL
Enbrel, a drug for rheumatoid arthritis, costs more than $14,000 a year. To make it, workers at Amgen Inc. must culture hamster-ovary cells for three weeks and then wait another three weeks while the cells produce a billion trillion copies of a single protein. Simple errors can contaminate a batch valued at several million dollars.
Expensive, hard-to-make drugs such as this are now at the center of one of the drug industry's hottest new markets: treatments for autoimmune disease, in which the body's defenses target its own tissues. In the past year, Abbott Laboratories, Biogen Inc. and Genentech Inc. have launched bioengineered drugs targeting autoimmune disease, joining Amgen and its longtime rival Johnson & Johnson. More than a dozen other companies are pursuing a market that Abbott estimates could reach $14 billion by 2010.
Enbrel's original manufacturer, Immunex Corp., couldn't make enough Enbrel to meet demand when it launched the drug in 1998. Amgen bought the company for $11 billion and spent more than $1.5 billion upgrading Immunex's Rhode Island plants.
Today Enbrel is on track to record sales of at least $1.2 billion this year, up about 50% from last year, although it remains No. 2 amid increasingly tough competition. Amgen also is aggressively expanding the drug's approved uses to other immune-related diseases, especially the skin condition psoriasis.
Despite recent advances, scientists don't fully understand the immune system. For years doctors treated autoimmune disorders with drugs such as cortisone that suppress the entire immune system. The result was often severe side effects, including infections, osteoporosis or damage to internal organs.
New drugs such as Enbrel target individual immune-related proteins, rather than bludgeoning the entire immune system. They rely on scientific work that dates from the late 1980s, when researchers began to dissect some of the biochemical "messages" the immune system uses to coordinate its attacks on infectious disease.
The field is still full of mystery. Immunologists debate exactly why Enbrel works against rheumatoid arthritis, a degenerative bone-and-joint condition, and psoriasis. Drugs designed to fight autoimmune diseases are hard to make and many fail to work in human tests.
Amgen itself had limited success with its own earlier arthritis drug. Just this year, anticipated biotech drugs from Biogen for Crohn's disease, an inflammatory bowel condition, and Regeneron Pharmaceuticals Inc. for rheumatoid arthritis both failed in human tests. Several other best-selling bioengineered drugs for multiple sclerosis, another autoimmune condition, so far only slow the disease's progress without producing the dramatic remissions associated with Enbrel and its ilk.
Finding Relief
But for some patients, the new drugs can be potent. Thirteen years ago, rheumatoid arthritis began slowly eating away at Barbara Greenberg's joint tissue and twisting her bones. The 78-year-old San Francisco artist eventually had difficulty walking and was forced to give up painting. Roughly 2.1 million Americans, many of them older women, suffer from the disease.
Ms. Greenberg controlled the pain for nearly eight years with shots of cortisone, but the drug led to frequent infections and osteoporosis that caused her to shrink two inches in height. Then in 1998, Ms. Greenberg's physician recommended twice-weekly injections of Enbrel. She felt better almost immediately and soon resumed painting and taking strolls.
The new drugs don't work for everyone, and they don't come cheaply. Johnson & Johnson's Enbrel rival, called Remicade, carries a wholesale cost of as much as $16,000 for a year's treatment. It is covered by Medicare because it is administered intravenously in a doctor's office. Biogen's psoriasis drug, Amevive, can cost $7,000 to $10,000 for a 12-week treatment, which on average produces a seven-month remission.
Development of Enbrel began in the early 1990s. Scientists at Immunex, then an unprofitable Seattle biotech company, originally figured it would be useful against sepsis, a life-threatening inflammatory response related to overproduction of a protein called tumor-necrosis factor, or TNF. But the drug failed to save lives in a 1993 test of 141 patients, and high doses appeared to harm some participants.
Other experiments suggested that Enbrel might be effective against autoimmune disorders such as rheumatoid arthritis and Crohn's disease, so the company began testing the drug in small groups of patients with these conditions. Initial results in the arthritis group looked promising, and by 1995 a larger test of 180 patients produced surprisingly strong responses.
Enbrel was approved for rheumatoid arthritis in 1998, the first bioengineered drug to target an autoimmune disorder so precisely. It posted sales of $500 million in just 18 months, more than a year ahead of Immunex's projections.
But neither the company nor its partner, German drug maker Boehringer Ingelheim GmbH, could meet demand. In 1999, Immunex arranged to renovate an old drug factory in Rhode Island for more Enbrel production, but the new facility wouldn't begin production until mid-2002 at the earliest.
With supplies limited, in January 2001 Immunex started enrolling would-be patients on a waiting list, which swelled to more than 40,000 names by last year. The shortfall created opportunities for Johnson & Johnson's Remicade, a rival therapy originally aimed at Crohn's disease but approved for rheumatoid arthritis in 1999.
By late 2001, Immunex officials began to consider selling the company to a larger outfit with more manufacturing experience. Amgen was a natural suitor, having manufactured genetically engineered proteins for almost two decades. Not long after Amgen announced plans to acquire Immunex in December 2001, about 100 Amgen employees arrived in West Greenwich, R.I., to serve as consultants on the Immunex plant's renovations until the merger closed.
What they found there was a mess. Subcontractors had worked independently, creating a hodgepodge of inconsistent designs and mismatched parts. Leaks from more than 250 miles of pipes had let water seep invisibly into the walls, contaminating areas that were supposed to be sterile. Immunex's former chief executive, Edward Fritzky, said the company had trouble hiring enough manufacturing experts to push the work forward as fast at it would have liked.
Amgen standardized as much of the plant as it could and ended up spending more than $1.5 billion on the project. The FDA approved the first of two factories at the site last December. Late last year, Amgen removed the last patient names from the Enbrel waiting list, although the drug still lags behind Remicade in sales, according to market-research firm IMS Health. In its competition with Remicade and Humira, Enbrel held a 41% market share in August, compared with 51% for Remicade and about 8% for Humira, according to IMS Health.
With the added capacity, Amgen is joining a three-way battle over the new rheumatoid-arthritis market. Johnson & Johnson officials claim that Remicade is still growing fastest, with 40% of new patients choosing the drug. Abbott touts the greater convenience of Humira, which patients can inject themselves once every two weeks instead of receiving it intravenously at a doctor's office, as Remicade requires. Amgen emphasizes Enbrel's long safety history and says the drug is almost as convenient as Humira, since it is also self-injected and just received FDA approval for weekly dosing.
Coming Fight
The next fight will be over psoriasis. An unsightly and sometimes emotionally scarring disease, psoriasis afflicts between four million and seven million Americans with itching and burning skin lesions.
More than a decade ago, Biogen and Genentech began investing hundreds of millions of dollars in new psoriasis treatments designed to interfere with certain "T cells," immune-system warriors that normally defend against bacteria and other infectious agents. Scientists have long believed that particular types of T cells cause psoriasis by attacking the body's skin cells. Biogen's Amevive was approved for patients with "moderate to severe" psoriasis earlier this year. Genentech's Raptiva won similar approval on Oct. 27.
As in arthritis, however, Enbrel also emerged as a surprise contestant. Tests of the drug against psoriatic arthritis, a condition combining the joint degeneration of arthritis with the skin lesions of psoriasis, unexpectedly cleared the skin condition in many patients. Subsequent tests found that Enbrel may work as well as or better than Amevive or Raptiva against ordinary psoriasis.
"I don't think that anyone working in psoriasis, which was known to have a significant T-cell component, thought that [blocking TNF] would have the effect it does," says Roger Perlmutter, an immunologist who heads Amgen's R&D organization. Amgen applied in July for FDA permission to market Enbrel for psoriasis.
Johnson & Johnson and Abbott also are testing their TNF inhibitors, Remicade and Humira, in psoriasis, although neither has yet completed a large-scale trial. Enbrel may have an edge, according to some analysts, but its competitors plan to fight. Indeed, many dermatologists say the marketing effort for biotech psoriasis drugs is as intense as any they've seen.
Biogen, the first company to launch a bioengineered psoriasis drug, is advertising heavily in dermatology journals and hired Jerry Mathers, the 1950s star of "Leave It to Beaver" who has psoriasis, to speak to community groups and the media.
Genentech began its own educational campaign even before winning FDA approval for Raptiva. This past summer, the company began sponsoring a health section on Yahoo Inc.'s Web site devoted to psoriasis, mixing medical information from the National Psoriasis Foundation with Genentech ads that encourage patients "to learn how Genentech is working toward continuous relief from psoriasis symptoms." Now Genentech plans to reach dermatologists through ads in medical journals and a new 75-person sales force. It will advertise to psoriasis patients directly via its Web site and literature in dermatologists' offices.
Amgen maintains its own Web site as it waits for FDA approval to market Enbrel for psoriasis. And Amgen does have an important advantage: Its sales representatives can already pitch Enbrel to dermatologists for psoriatic arthritis. Some dermatologists are prescribing Enbrel for psoriasis itself, which is legal as long as the doctor takes the initiative. |
