New IBD surgical advances

Options Expand for Crohn's Disease Patients Drugs on Market and in Trials Show Promise in Treatment; Surgery Gets New Attention

By AVERY JOHNSON January 9, 2007; Wall Street Journal Page D1

After decades of relying on little more than steroids, victims of a painful digestive disease are starting to see a wider range of treatment options, from new drugs to promising surgical techniques.

Crohn's disease, a debilitating and incurable digestive ailment, affects about one million people world-wide -- a 10-fold increase since World War II by some estimates, which doctors speculate is due to a confluence of environment and genetics. Crohn's is an immune disorder that causes inflammation deep in the lining of the digestive tract. Symptoms generally start in adolescent patients as stomach cramping and diarrhea, but can result in an inability to digest food, leading even to death from malnutrition.

Patients have largely been treated with steroids, which are powerful suppressants of the immune system. But these drugs can produce an array of side effects, including rashes, weight gain and osteoporosis. Other drugs, such as methotrexate, have run into problems with efficacy and side effects. Surgery to remove sections of diseased intestine has been another option, but that can leave the digestive tract so short that it can no longer easily absorb nutrients.

The latest major advancement is a category of drugs called anti-TNF medicines. The drugs target a compound known as tumor necrosis factor, which is overproduced in many patients with inflammatory disease. So far, most of these medicines are approved mainly for rheumatoid arthritis, though they can be used "off-label" for Crohn's. Only Johnson & Johnson's anti-TNF drug Remicade is approved by the Food and Drug Administration specifically to treat Crohn's.

Some patients develop a resistance to Remicade because it's made in part from mouse cells, which the human body may reject, doctors say. A spokesman for Johnson & Johnson says that any time a foreign protein is injected into the human body it can elicit an allergic response. The drug also requires a trip to the hospital every eight weeks for an intravenous infusion. Other anti-TNFs hold the promise of being more convenient and better-tolerated, says Jonathan Braun, a professor at UCLA's medical school. Still, anti-TNFs don't work for everyone, can come with increased risk of infection and blood cancer, and are costly -- often over $1,000 a month. "The anti-TNFs have revolutionized care for patients, but they're not a magic bullet for everyone," says Warren Strober, chief of the mucosal immunity section of the National Institute of Allergy and Infectious Diseases.

Here's a look at what's on the horizon for Crohn's patients:

New Access to Existing Drugs

The anti-TNF category has been a huge growth driver for drug makers. Credit Suisse Equity Research estimates that the world-wide market for biologic auto-immune medicines, which includes mostly anti-TNFs, will grow to $17.1 billion in 2010, from $8.3 billion in 2005. A Cowen & Co. report estimated J&J's revenue alone from Remicade in Crohn's and a related condition, ulcerative colitis, was $700 million last year.

Recently, there has been progress getting more anti-TNF drugs to Crohn's patients. Remicade was approved in May for Crohn's in children. Humira, Abbott Laboratories' blockbuster anti-TNF medicine for rheumatoid arthritis, has been accepted for a "fast-track" FDA review for Crohn's, which means it could be available in the first half of the year. Humira is injected with a syringe rather than infused intravenously, and patients can administer the shot themselves at home every two weeks. Humira, which is completely made out of human cells, could also provoke less resistance in patients than other therapies. Ginger Gray, a 59-year-old housewife from Westtown, Pa., who was diagnosed with Crohn's about 40 years ago, is one patient who got well on Remicade and then developed a resistance to it. Already she had spent almost 20 years on steroids -- which she says gave her cataracts and a "moon face that made me look like Charlie Brown" -- and had five surgeries. Lately, her doctor has prescribed Humira off-label, which has driven her disease into remission, for now.

"I'm hopeful with all the research going on that I won't have to stay on Humira," she says. She worries that "you are fooling around with your immune system."

Besides anti-TNFs, there is a rheumatoid arthritis drug from Bristol-Myers Squibb, called Orencia, that is being studied for Crohn's disease. The drug works on inflammation earlier in the process than do anti-TNFs. Bristol started the final phase of human testing of Orencia against Crohn's last month and is currently enrolling patients in a trial. Tysabri, a multiple-sclerosis drug co-marketed in the U.S. by Elan Pharmaceuticals Inc. and Biogen Idec Inc., has demonstrated effectiveness against Crohn's, especially in the half of patients who don't respond to the anti-TNF drugs, according to Elan. But Tysabri was withdrawn from the market in 2005 after it was tied to a rare brain infection. It was reinstated last summer with tightened restrictions on prescribing. The companies are still pursuing FDA approval for Crohn's, and submitted the drug for consideration last month. Lars Ekman, Elan's president of global research and development, says the brain infection occurs in about one in 1,000 patients, and that other medicines for Crohn's also have side effects.

Drugs in the Pipeline

J&J and Abbott are working on drugs that inhibit two proteins called interleukin-12 and interleukin-23. Both companies are in the middle stages of human testing. Dr. Strober, of the National Institute of Allergy and Infectious Diseases, says the benefit could be tackling inflammation much earlier in its development than the anti-TNFs do, but that the drugs could carry an increased risk of infection.

Belgium's UCB SA filed last year with the FDA for approval of its new anti-TNF drug, Cimzia, for Crohn's and the FDA recently responded, asking the company for additional clarification. Cimzia is a once-a-month shot, which patients will have to go to the doctor to get at first. Cimzia is made with 98%% human cells and may also provoke less resistance.

Osiris Therapeutics, based in Baltimore, just got approval from the FDA to go into the third and final phase of human testing on a Crohn's drug that uses adult stem cells. The company says the agency gave the drug fast-track status, which means it could come to market as early as 2008. The drug is thought to work by correcting inflammation only where it's taking place -- which could help avoid excessive immune suppression.

Surgery

For patients whose disease requires surgery, a new bowel-sparing procedure for advanced Crohn's is gaining attention. The surgical technique, developed by Fabrizio Michelassi, chief surgeon at New York Presbyterian Hospital-Weill Cornell Medical Center, has been shown to restore function of the bowel. In an article last month in the journal Diseases of the Colon & Rectum, Dr. Michelassi found that the procedure is being reproduced with good results by other surgeons.

Instead of cutting out narrowed portions of the bowel and shortening the gut, the new procedure creates a new enlarged intestinal passageway, allowing nutrients to be absorbed again. Further research is being conducted by Dr. Michelassi to confirm that the disease disappears after the procedure.