USA TODAY with a testimonial report on ENBREL
08/28/00- Updated 11:13 AM ET
One drug helps young and old
By Steve Sternberg, USA TODAY
When Katie Emmerson was 10, she wrote a little book describing, as she puts it: "A girl who wasn't able to do things, so she locked herself away and lived through things she saw through her window."
Called Window on the World, the book tells the thinly disguised story of Katie herself, and what life is like when illness steals away your childhood. Katie's trouble was juvenile rheumatoid arthritis, an ailment that erodes joint cartilage so severely that bone soon grinds against bone.
The friction produces inflammation, with its classic symptoms of redness, swelling, heat and pain. Standard medicines didn't help her, Katie says. Instead, they heaped on new side effects.
Two years ago, Katie's doctor suggested she try a new drug, etanercept, sold as Enbrel. Then under study in children, Enbrel unlocked Katie's skeleton and set her free.
Now the West Covina, Calif., teen is every bit as active as her friends, swimming competitively at Nogales High School and performing in the school's show choir. A few days ago, Katie, 16, tossed out the ceremonial first pitch at a Seattle Mariners-Detroit Tigers game in Seattle, courtesy of Immunex, the firm that makes Enbrel.
Sherman Long praises Enbrel, too. Yet Long, 51, a retired IBM systems analyst from Clairton, Pa., isn't taking Enbrel for arthritis. Long takes Enbrel for heart failure, the result of a massive heart attack.
Why give the same drug to people with such different ailments? Because people with juvenile rheumatoid arthritis and congestive heart failure have something in common. One key feature of their immune systems — the biochemical switch that turns off inflammation and promotes tissue repair — is stuck in the "on" position.
The result can be chronic, crippling inflammation of the joints or heart muscle. "Inflammation, while a good thing when getting rid of infections, can be really damaging when it attacks essential parts of the body, like the joints and heart," says immunologist Philippa Marrack of National Jewish Medical and Research Center in Denver .
Enbrel, one of roughly 25 approved immune-based therapies now on drugstore shelves, shuts the system down.
Katie Emmerson and Sherman Long are reaping the benefits of dual revolutions in genetics and immunology -- the latter spurred in part by the growing intensity of research into Acquired Immune Deficiency Syndrome, or AIDS — that promises to produce dozens of new immune-based treatments.
"This is one of the most exciting, potentially explosive fields in medical research," says Anthony Fauci, director of the National Institute of Allergy and Infectious Disease. "What's happened over the last 20 years is amazing, but I think it's going to be even more amazing over the next decade or two."
On the simplest level, the immune system serves as an invisible shield against threats from the environment. When bacteria, viruses and toxins breach the barrier of the skin and enter the bloodstream, the immune system counterattacks. In most cases, it triumphs.
But the body's defenses don't always work as they should. Juvenile rheumatoid arthritis (JRA) and congestive heart failure result from the loss of control over the body's tissue repair mechanism.
Central to this failure is a protein known as tumor necrosis factor, or TNF, which is produced in the human body by white blood cells, stalwarts of the immune system. Named for its ability to literally melt tumors in mice, TNF at first delighted researchers who thought the body's pharmacy naturally produced a potential cancer killer. But in the 1980s, therapeutic doses of TNF proved too toxic for use in humans, and interest waned.
But by the 1990s, the revolutions in genetics and immunology were well underway. Teams of researchers across the USA vied to identify and catalog the complex roster of cells and proteins that the immune system relies on to do its job. Researchers at Immunex Corp. decided to take another look at TNF and the role it played in the body.
"We thought we could study its biology and perhaps develop therapeutics," says Ray Goodwin, a pioneering TNF researcher at Immunex. "We hadn't specifically decided what disease to work on at that point. But there were plenty of diseases to choose from."
Why? Many ailments involve inflammation, Goodwin says, and TNF promotes inflammation. In small doses, TNF also helps damaged cells to repair themselves. This makes TNF a critical player in wound healing and tissue repair. But TNF production sometimes continues after its job is done, and it destroys healthy tissue.
In rheumatoid arthritis, excess TNF thins the cartilage that cushions bones. In congestive heart failure, excess TNF gradually kills off the muscle cells that power the heart's contractions. As in JRA, TNF also attacks the connective-tissue "struts" that hold muscle cells together, thinning the heart's wall, enlarging the heart and forcing it to work harder.
"It's as if the heart were encased in cement," says Baylor College of Medicine cardiologist Douglas Mann, who helped tease out the protein's role in heart failure.
Small-scale studies of Enbrel in heart failure so far have yielded positive results, indicating that the drug at least slows the breakdown of heart muscle. Two larger trials, Renaissance and Recover, have begun to test Enbrel in 1,800 heart-failure patients in North America, Europe and Australia. The results are expected sometime next year.
Goodwin says that TNF triggers inflammation by locking into special receptors on the cell surface, which cues a kind of bucket brigade of signaling molecules to convey a message from the cell's surface to the genes in its nucleus.
Receptors' role in this process makes them a valuable target for drug discovery, he says. If you know the TNF receptor's makeup, you can create a decoy receptor that will lock up any extra TNF that's around, preventing it from triggering the signaling cascade.
This is the same tactic that cells use in nature to keep inflammation in check; they release TNF receptors from their surface to mop up excess TNF. "A lot of companies were going after the TNF receptor," Goodwin says.
Goodwin and his colleagues worked out a way to prompt TNF-receptor genes to make the receptor on demand. Immunex scientists initially tried using the receptor to block overwhelming infections of the bloodstream. It didn't work.
But clinical trials in more than 1,000 patients indicated that the decoy TNF receptors in Enbrel dramatically reduced pain and inflammation in adults with rheumatoid arthritis (RA). In 1998, Immunex won government permission to market Enbrel to treat RA in adults. Enbrel isn't cheap; it costs about $13,000 a year.
Even as the adult trials were going on, Immunex rheumatologist Barbara Finck urged her bosses to try Enbrel in children. "The FDA was pushing to get companies to study drugs in children in parallel with studies in adults," she says. "Enbrel looked like a fairly safe drug. It did what we thought it would in adults, and we couldn't see withholding it from children."
Still, it was a risk. "If a child had died or there was a severe adverse event, a whole development program could go down the tubes," Finck says. Nevertheless, she says, "I predicted it would work."
It did, in most of the adults and children who used it. The government approved Enbrel for use in children last year. But about 15% of people with rheumatoid arthritis don't respond to the drug, she says, suggesting that other inflammation promoters may be at work.
Enbrel's chief competition is a genetically engineered antibody called infliximab, or Remicade, which seeks out TNF, latches onto it, and prevents it from attaching to cells. Unlike Enbrel, Remicade has not been approved as a first-line RA therapy in adults or for use in children, though Centocor of Malvern, Pa., plans to apply for those approvals, says Chris Allman, the firm's spokesman.
Remicade has been approved, however, for use in people with Crohn's disease, a TNF-mediated inflammation of the gut. It will soon be tested in people with congestive heart failure, Allman says.
Sherman Long is pleased with Enbrel's performance. "It worked wonders for me," says Long, who's been on the drug for 14 months. "I'm not going to tell you I'm 100% better, because I'm not. But I'm having more good days than bad; before (Enbrel) I was having many more bad days than good ones.
"And since I'm taking the drug, guess what? No aches and pains in my knees."
Until Enbrel came along, Katie Emmerson masked her pain with a brave face. "You don't want people feeling sorry for you, so you have to hide things with a smile," she says. These days, Katie's smile is genuine. So is her gratitude.
On Aug. 13, the firm flew Katie — who has been an unpaid spokesperson for Enbrel — and her parents to Seattle so she could thank Goodwin and Finck. The firm also arranged for her to toss out the first pitch at the Mariners-Dodgers game that evening. After viewing a video of her ordeal, 48,000 fans gave Katie a standing ovation.
Even a standing ovation did not move her as profoundly as the opportunity to thank her heroes, Goodwin and Finck. "How do you thank someone who gave you your life back?" Katie said, before her visit. "I think I'll just cry."
She did. |
