By Mary Welch

Isis Pharmaceuticals Inc. regained all rights to ISIS 2302, its compound in a pivotal trial for Crohn's disease, from Boehringer Ingelheim International GmbH, its five-year developmental partner, and is close to linking up with another partner to take 2302 to market.

"We are very excited to have 2302 back and are now in the process of finding a new marketing partner with a presence in the gastrointestinal market with a strong sales and marketing penetration," said Christopher Keenan, manager of corporate communications for Carlsbad, Calif.-based Isis. "We get all the rights to the antisense compounds, and Boehringer will receive royalties on anything commercialized. But we are particularly pleased to have 2302 back in all formulations and indications."

Under the modified deal, Isis will be solely responsible for the development and marketing of ISIS 2302 and other antisense inhibitors of cell-adhesion molecules discovered during the past five years, with Boehringer Ingelheim having a similar arrangement with the small molecules under development.

Isis will continue to receive funding until the end of the year. Isis now will continue the development of 2302 for four indications: Crohn's disease, renal transplant rejection, ulcerative colitis and psoriasis. A fifth potential indication - rheumatoid arthritis - failed in a Phase II trial. A Phase II trial in renal transplant rejection is near completion. The compound is expected to enter clinical studies in the other two indications within nine months, the company said.

Isis' stock (NASDAQ:ISIP) gained $1.375, or 14 percent, Thursday to close at $11.438.

When the two companies first signed the deal in 1995, the intent was to combine their cell-adhesion programs. Boehringer, of Ingelheim, Germany, made an up-front $28.5 million equity investment and pledged access to a $40 million line of credit as well as milestone payments and research and development money. The deal, if played out fully, would have been worth about $100 million to Isis. (See BioWorld Today, March 2, 1995, p. 1.)

"We got about $60 million from Boehringer and they own 9 percent of our company," Keenan said. "We would like our next partnership to be simpler rather than the 50-50 deal we had. We also would like for equity not to be involved."

Sushant Kumar, an analyst with Mehta Partners LLC, of New York, said, "It's important to remember that this was a research and development deal. Isis is very committed to ensuring the commercial success of 2302. One of the issues was that Boehringer Ingelheim does not have a presence in the gastrointestinal area and no sales force."

Both Kumar and Keenan said it may have been better had Isis considered Boehringer's lack of presence in the gastrointestinal field before committing to the partnership in the first place.

"It was a broad R&D collaboration that focused on cellular adhesion molecules," Keenan said. "We were all trying to learn as much as possible about them and what came out was 2302, which looked like it had a wide variety of potential indications. I think rheumatoid arthritis may have been Boehringer's strategic focus at the beginning but the reality was that, after the Phase II trial, 2302 didn't warrant further development for rheumatoid arthritis but did for Crohn's disease."

Kumar agreed. "As soon as Isis realized they had the potential to make it with this compound, they started thinking seriously and apparently did have some negotiation with Boehringer," he said. "There were some deficiencies in Boehringer's lack of experience in gastrointestinal and Boehringer was not excited about Crohn's disease. They were more interested in 2302 for rheumatoid arthritis and asthma. It was a mutual decision."

Isis 2302 is an antisense oligonucleotide designed to block intercellular adhesion molecule 1 (ICAM-1), a protein whose overexpression on endothelial cells lining blood vessel walls allows white blood cells to migrate into tissues, causing damaging inflammation. Cell adhesion molecules, implicated in a number of inflammatory diseases, make up a large family of related proteins involved in a variety of cell-to-cell interactions.

The company completed its enrollment of 300 Crohn's disease patients in a pivotal trial that started in May 1997 and involved 40 medical centers in North America and Europe. The trial's endpoints were disease remission and a reduction in steroid dependency. It is expected to end by the end of the year with the company filing a new drug application (NDA) most likely in the first quarter of 2000, Keenan said. (See BioWorld Today, April 22, 1997, p. 1.)

In a Phase II study of 20 patients, 47 percent treated with Isis 2302 were in disease remission vs. none in the placebo group at the end of the one-month treatment phase. (See BioWorld Today, March 3, 1997, p. 1.)

"Although interim data [of the Phase IIb trial] was not released, we understand that the data is considered to be good," Kumar said. "We expect the drug to do well. We haven't updated our figures but we have estimated 2302 could be a $300 million drug."

With a potential NDA in Isis' near future with 2302, Keenan said it is "safe to say we've had an incredible level of interest from pharmaceutical companies. We're talking with companies who know the gastrointestinal area and have an established sales force. They may have complementary or non-competing compounds."

A partnership announcement could come as early as a few weeks, he said.