Drug Firms Target Arthritis Treatment
By the end of 1998, Jeanne Harrison thought she had lost a 20-year battle with rheumatoid arthritis. Her wrists had fused and her right elbow had locked at a 45-degree angle. She couldn’t dress without help from her husband.
The medication she took to slow the disease, a powerful chemotherapy drug called methotrexate, left her nauseated and tired. It was painful to walk and to hug her two children.
Then she started taking a drug called Enbrel and everything changed. She can straighten her elbow and dress herself, and she no longer is fatigued. The pain in her joints is gone.
Three weeks ago, she enrolled in a jazz dance class near her home in Westlake Village. “This medication has truly been a miracle drug for me,” said Harrison, 48.
But Enbrel is no magic bullet. It does not work for everyone and it is not a cure. To keep their disease in check, patients may have to take the drug for the rest of their lives at a cost of $12,000 a year. People who take the drug face an increased risk of infection, and the effects of long-term use aren’t known.
For those reasons, doctors tend to prescribe Enbrel for patients who have not been helped by standard therapies. Still, the drug represents a breakthrough for patients and drug makers.
Enbrel is among an emerging class of drugs that attack rheumatoid arthritis on a molecular level. These drugs target specific proteins that direct the assault on cartilage and bone. The new “targeted” drugs appear to work in other chronic disorders that affect more than 8 million Americans, in addition to the 2.1 million people with rheumatoid arthritis.
That makes the business of rheumatoid arthritis treatment tempting to drug makers. Enbrel’s huge sales potential prompted Amgen Inc. to pay $16 billion for Immunex Corp., which developed the drug. The deal, announced in December, is expected to close this summer.
Amgen predicts that Enbrel’s annual sales will more than quadruple to $3 billion by 2005, driven in part by new uses for the drug. The Food and Drug Administration has approved its use in psoriatic arthritis. Immunex has been studying the drug as a treatment for psoriasis and ankylosing spondylitis, an arthritic condition that causes the vertebrae to fuse.
Amgen’s immediate rival will be Centocor, the Johnson & Johnson unit that markets Remicade, a drug similar to Enbrel. The Centocor drug is approved as a short-term treatment for Crohn’s disease, a chronic bowel inflammation that affects nearly 500,000 people in the U.S. It also is approved to treat rheumatoid arthritis, and Centocor is studying it as a treatment for ankylosing spondylitis.
But a broader competition is underway among drug companies racing to develop second-generation medications. The result for patients may be drugs that not only are better but also cheaper. Scios Inc. is testing a drug in clinical trials that it believes will be as good as Enbrel but with fewer side effects. The Scios drug, Scio-469, is cheaper to make than Enbrel and could cost 50% less.
“Enbrel is a good drug, but we can avoid the side effects at a significantly lower price,” Scios Chief Executive Richard Brewer said at a recent investment conference. “I think we will take the market.”
With at least a dozen drugs in various stages of testing, it is too soon to say how the category will shake out. It is a safe bet that some experimental medications won’t make it out of the laboratory.
Still, industry executives say there is plenty of room for those therapies that manage to reach the marketplace. Less than 6% of rheumatoid arthritis patients use the targeted drugs, which, besides Enbrel and Remicade, include Kineret, an Amgen medication approved in November.
An aging population will further expand the opportunity for drug makers. Decision Resources, a market research firm, said the number of Americans with rheumatoid arthritis will increase by 19% this decade, to 2.8 million. The disease chiefly strikes people between ages 40 and 60 and affects twice as many women as men.
In rheumatoid arthritis, the body’s immune system attacks the tissues that line and cushion the joints, eventually causing the cartilage, bone and ligaments around the joints to erode. It also can inflame the membranes around the lung and the sac around the heart. The cause of the disease isn’t known.
Relief From Pain Worth the Risks
The new medicines target proteins that orchestrate the immune assault on joint tissue, thereby preventing further damage and reducing inflammation. One protein, tumor necrosis factor--or TNF--comes into play early, sending signals to cells in the immune system like a molecular Paul Revere.
Interleukin-1, a protein produced by cells in the connective tissue, similarly rallies cells.
Enbrel and Remicade work by binding to TNF molecules, so they can’t dock on cells and nudge them into attack mode. Enbrel, a modified copy of the TNF receptor found on the surface of cells, acts as a decoy for free-floating TNF molecules. Remicade is a bioengineered antibody that latches onto TNF molecules and also plugs the receptors.
Kineret prevents interleukin-1 from docking on cells by plugging the receptor for that molecule.
But the signaling proteins, called cytokines, are not all bad. They also prod the immune system to fight disease. Interleukin-1 fends off bacterial assault and causes fever. TNF can kill cancer cells, at least in test tubes, and is believed to resist viral invaders. Because the new drugs neutralize these cytokines, people who use the medications face a greater risk of infection.
To patients such as Richard Van Antwerp, who tried five conventional drugs and such folk remedies as bee stings, relief from pain is worth the risk. Before he started getting daily injections with Kineret, Van Antwerp couldn’t grasp a steering wheel. On some mornings, he was so stiff that he stayed in bed. Now he splits logs at his ranch near Yosemite National Park, where he is building a rail fence.
Kineret “restarted my life,” he said.
But physicians worry about the long-term effects of powerful immune suppressors. In August, after 84 patients developed tuberculosis, Centocor warned that Remicade users face an increased risk of the disease--three years after the FDA approved the drug. The Enbrel label says there have been rare reports of multiple sclerosis.
“These drugs are being positioned as something patients use indefinitely,” said Dr. Doyt Conn, director of allergy, immunology and rheumatology at Emory University. “The drug companies want patients to stay on the drugs forever. I really question that strategy when we don’t know what the effects will be.”
Physicians have relegated the new medications to the back of the disease arsenal, at least for now. That is in part because there is little evidence that these new biologics are more effective than a standard course of methotrexate in treatment of early disease. And methotrexate, a generic, has the advantage of being 85% cheaper than Enbrel and other anti-cytokines.
Drug makers are pushing their own slant on the price gap. A study presented at a recent rheumatologists’ convention asserted that Remicade, which can cost $25,000 a year, is more “cost effective” than methotrexate, with annual costs of $2,000, when “quality of life” is considered. The research was funded by Schering-Plough Corp., Centocor’s marketing partner.
Until recently, Centocor had on its Web site a work sheet that helped doctors to compute profits per Medicare patient. Remicade is the only rheumatoid arthritis drug covered by the government plan for the elderly.
Conn isn’t convinced. “I don’t think the cost benefit [relationship] has been proven. We can’t use drugs just because they are there.”
Dr. Bevra Hahn, chief of rheumatology at UCLA, said 40% of patients with severe rheumatoid arthritis either don’t respond to methotrexate or stop taking it because the side effects--hair loss, nausea and a risk of birth defects--become intolerable. For those patients, she said, the new medicines “are a good addition to the arsenal.”
Unfortunately, few patients do as well on the new drugs as Harrison. A large number of patients--40% to 60%--do not improve on the anti-cytokines. Kineret offers the least benefit and Enbrel, the most. That has set off a race among drug companies for better targets and better drugs.
“This is going to be a battle for efficacy,” said Dr. Roger Perlmutter, Amgen executive vice president for research and development. “Everyone is looking for improved efficacy, I think. The drugs we have today are not nearly good enough.”
The experimental Scios drug takes aim at an enzyme called p38. The p38 enzyme awakens other molecules, triggering a chain reaction that leads to excess production of TNF, interleukin-1 and a third inflammatory protein, Cox-2. This molecular alarm is normally silent, but not in people with rheumatoid arthritis and other autoimmune diseases.
Scios Chief Scientific Officer Dr. George Schreiner said a drug that blocks p38 should break the cycle that leads to bone tissue destruction. But it shouldn’t interrupt production of TNF and interleukin-1 in amounts needed to fight infection. What’s more, a drug that blocks the p38 enzyme can take the form of a pill, which is cheaper to manufacture than the anti-cytokines. The drug is in the early stages of clinical testing, and it is too soon to predict whether it will work. The p38 molecule belongs to a family of enzymes with diverse functions, so a drug that inhibits a related enzyme could cause serious side effects. Vertex Pharmaceuticals recently dropped a p38 inhibitor because at high doses it caused nervous system complications in animals.
But such a medication has the potential to dramatically change the rheumatoid arthritis drug market and siphon sales from existing drugs, according to Decision Resources.
Drug Makers Look for New Targets
“It would be revolutionary,” said Dr. Larry Moreland, a University of Alabama-Birmingham immunologist who works closely with the National Institutes of Health.
Amgen also is looking at new targets, including p38 and specific T-cells, white blood cells that function as foot soldiers in the immune assault. But its chief focus is on developing better drugs that block TNF and interleukin-1, targets its scientists understand well. A team of Immunex scientists in the early 1990s was among the first to realize that TNF, first studied as an anti-cancer agent, could be useful as an immune modulator. Amgen is the first company to market a drug that blocks interleukin-1.
High on Amgen’s list is an improved version of Kineret, whose sales are expected to total $80million this year. By comparison, Enbrel should break $1billion. Perlmutter wants to develop a more convenient interleukin-1 blocker that can be taken weekly instead of daily.
More important, he wants to offer a version that can be safely used with Enbrel. Currently, patients who combine Kineret with a TNF blocker face a threefold risk of serious infection. If Amgen can reduce the hazard, it can sell more medicine while offering patients a potent combination therapy. Kineret costs $11,000 annually.
Amgen also must work out the kinks in Enbrel production. Immunex expects to open a $500-million factory this year in Rhode Island that should alleviate a chronic shortage of Enbrel. The situation got so bad in December that Immunex stopped supplying new patients and recently warned that 60,000 Enbrel users may face delays getting their prescriptions filled. The shortage should ease by June.
Patients soon will have more choices. In the next two years, analysts said, Abbott Laboratories and Pharmacia Corp. will launch injectable TNF blockers that last longer than Enbrel and cost less than Enbrel and Remicade. Their arrival should ignite a marketing war in a disease category long dominated by generics.
Abbott’s D2E7, the drug furthest along, doesn’t work much better than Enbrel. But lower prices--Decision Resources forecasts a 15% discount--would be good news for patients, who have seen their drug expenditures soar overall. Abbott hasn’t commented on price. If the market leaders are worried about the next round of competition, they aren’t saying. Immunex Chief Operating Officer Peggy Phillips predicts that sales of medications that target tumor necrosis factor alone will reach $10 billion by 2005, leaving plenty of room for new drugs.
“If they can supply the market, they can sell it,” said Scott Habig, Centocor marketing vice president. “That’s true for all of us. These are very big markets.”
