By Charles Craig

Isis Pharmaceuticals Inc. has begun what could be the first of two pivotal clinical trials of a systemically delivered antisense compound, ISIS 2302, in the treatment of Crohn's disease, an inflammatory bowel disorder that affects approximately 200,000 people in the U.S.

The Phase IIb study, which will involve 300 patients at 40 medical centers in North America and Europe, follows a successful 20-patient Phase IIa trial completed in December 1996. That study showed ISIS 2302 achieved a statistically significant effect on disease remission and reduced reliance on the standard therapy, corticosteroids, which have toxic side effects and often are ineffective against the disorder.

Jane Green, spokeswoman for Carlsbad, Calif.-based Isis, said the first pivotal trial could take up to 18 months to complete, based on the pace of patient enrollment. After about half the 300 patients have been through the treatment regimen, data will be reviewed and, if the drug is working as expected, a second pivotal study will get under way. Results from both pivotal trials will support a new drug application with the FDA.

Isis is collaborating with Boehringer Ingelheim GmbH, of Ingelheim, Germany, on development of antisense drugs targeting cell adhesion molecules involved in inflammatory disorders.

Antisense compounds are oligonucleotides designed to block the function of messenger RNA to prevent production of proteins linked to disease. ISIS 2302 attempts to block intercellular adhesion molecule 1, a protein whose over-expression on endothelial cells lining blood vessel walls allows white blood cells to migrate into tissues, causing damaging inflammation.

Drug Targets Four Other Disorders

In addition to Crohn's disease, ISIS 2302 is in Phase II trials for renal transplant rejection, rheumatoid arthritis, psoriasis and ulcerative colitis. Data from those four studies are expected this year.

Successful completion of the Phase IIa trial in Crohn's disease in December 1996 yielded the first indication an antisense compound, delivered systemically, could hit its target. The study also demonstrated the drug was safe and well-tolerated.

In the current Phase IIb trial, the treatment protocols and follow-up observation cover six months. Patients will be divided into three groups and receive treatments -- either ISIS 2302, a placebo or a combination of drug and placebo -- every other day during the first and third months.

One group will receive ISIS 2302 for all treatments. A second group will receive the drug for two weeks and a placebo for the other two weeks. And the third group will receive only a placebo.

Endpoints for the study are remission of the inflammatory disorder and reduction in steroid dependency.

Crohn's disease causes diarrhea, fever and pain and eventually leads to a thickening of the bowel wall.

Isis' stock (NASDAQ:ISIP) closed Monday at $13.875, down $0.875. *