June 12, 1998

Crohn's patients soar through phase two clinical trials

Dr. Bruce Yacyshyn discusses phase two of a clinical trial of ISIS 2302 with media.

As a young nurse caring for a patient with Crohn's disease twelve years ago, Dori Vanstolk would thank her lucky stars she didn't have the debilitating condition herself. And then the unthinkable happened. She began to come down with all the symptoms -- bouts of diarrhea, swelling of the joints, and marks on her legs. Soon she was on a steroid treatment program almost as bad as the disease itself. She suffered mood swings, depression and weight gain "in the weirdest places."

Last summer, after having tried every conventional and alternative treatment she could find, Vanstolk heard about a clinical trial for a promising new drug run by U of A immunologist Dr. Bruce Yacyshyn. She signed on, and after only five days of treatment found most of the symptoms disappeared.

"It didn't happen the next day or anything, but over a period of two or three months I just kept feeling better...able to get off the steroids and start doing more of the things I enjoy doing," she says.

"One of the things it did is get me out of that rut. I was in a sort of a vicious cycle of spiraling downhill. Now I have the strength where if I have a bad day, well, tomorrow will be a better day and I can get on with it."

Last Monday Yacyshyn announced the completion of phase two of a clinical trial of ISIS 2302. After a single course of treatment (26 days, every other day), the drug produced remission in seven of 15 trial patients and significantly reduced or eliminated steroid requirements in the remaining eight. Steroid use can cause swelling of the body, deterioration of the bones, and can precipitate or exacerbate diabetes, says Yacyshyn. Prolonged use can result in osteoporosis and immune suppression.

Testing of ISIS 2302 is far from complete, but because it targets a specific human genome, so far it appears to cause none of the side affects associated with traditional drugs, aside from a slight and predictable increase in blood coagulation. Moreover, says Yacyshyn, benefits were still evident well after 140 days.

"We're able to use a molecule that gets in under the immune system and doesn't cause a problem in and of itself. That's the beauty of this new technology -- it potentially offers us a way to treat these conditions...without the patient being sick as a result

of the therapy." Discovered by ISIS Pharmaceuticals of California, the trial's sponsor, the drug is a chemically altered DNA molecule designed to block the RNA message responsible for producing inflammatory proteins.

Crohn's disease is a chronic condition causing inflammation of the colon and rectum. Common symptoms are abdominal pain, diarrhea and/or constipation, ranging in severity from mild discomfort to debilitating weakness and pain. Victims may also suffer weight loss, rectal bleeding and fever.

For some unknown reason, the disease is more prevalent in northern climates, says Yacashyn. It can affect anyone at any time, although it tends to hit people in their early 30s with higher frequency.

"It occurs at a time when these people are establishing families and careers. It causes problems at home and at work, and then comes and goes without warning over the course of a person's lifetime." Severe cases can be helped with surgery, but as medications improve, says Yacyshyn, invasive therapy will hopefully become less necessary.

The ISIS 2302 trial was the first time this class of drug, called "antisense," has been tested in humans. Yacyshyn says the new technology could potentially treat a number of diseases. In addition to Crohn's, it is now being tested in cases of rheumatoid arthritis, colitis and psoriasis. It also has potential use in transplantation, as an anti-cancer agent, and as an anti-viral treatment for infectious diseases.

Results of the second phase of the clinical trial have been published in the June edition of the medical journal, Gastroenterology, for global distribution. A third phase of the trial is now underway with 300 patients in 35 centres in Canada, the U.S. and

Europe. Yacyshyn is unable to say just when the drug will be available to the public, but hopes it will be "in the foreseeable future."

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