By Frances Bishopp

Isis Pharmaceuticals Inc. has signed an agreement with ophthalmic company CIBA Vision Corp. that grants CIBA Vision worldwide distribution rights for its lead product, fomivirsen, an antisense drug to treat AIDS-related cytomegalovirus (CMV) retinitis.

Under terms of the agreement, Isis will receive $20 million in a pre-commercial fee and milestones through the time of regulatory approval in the U.S. and Europe.

Isis will manufacture and sell fomivirsen to CIBA Vision at a price that will allow Isis, of Carlsbad, Calif., and CIBA Vision, of Atlanta, to share the commercial value of the product. CIBA Vision is a division of Novartis AG, of Basel, Switzerland.

Assuming the drug is approved, the companies have a "very complicated" formula for calculating how Isis will participate commercially, said Jane Green, senior director of investor relations at Isis. "It's intended roughly to provide for a 50/50 profit split."

CIBA Vision will market and sell fomivirsen worldwide and will be responsible for regulatory approvals outside the U.S. and Europe. Once regulatory approvals are obtained, CIBA Vision will hold the registrations.

Assuming all things go well, Green said, a new drug application will be submitted the first half of 1998.

Steve Martin, president of CIBA Vision's ophthalmic division, told BioWorld Today the agreement with Isis marks his company's first collaboration for a biotechnology drug.

Antisense drugs work at a genetic level to interrupt the process by which disease-causing proteins are produced. CMV retinitis is a late-stage opportunistic infection that affects 25 to 40 percent of AIDS patients. CMV retinitis destroys the retina, resulting in blindness.

All the work that keeps us going as living organisms is produced by proteins, and the proteins are produced by genes, Green explained. The vast majority of disease is caused by the misproduction, or misbehavior, of proteins, she continued.

Traditional drugs, which often have significant side effects, work at the level of the protein interacting via a receptor to either facilitate its activity or inhibit its activity, Green said. Antisense drugs are synthetic pieces of DNA-like molecules that bind very specifically and very tightly to the messenger RNA, which codes for a particular protein.

"Antisense drugs interrupt the process by which the disease-causing protein is produced in the first place," Green said.

Both Isis and CIBA Vision anticipate fomivirsen (ISIS 2922) will be the first commercialized antisense drug. It is currently in Phase III clinical trials, where it is being tested as both a single-agent therapy and a combination therapy for the treatment of CMV retinitis in AIDS patients.

Isis has presented data from the open-label, uncontrolled study of almost 100 patients with advanced CMV retinitis for whom other therapies have been unsuccessful. The data showed that many of the patients, when treated with fomivirsen, experienced progression-free periods.

The safety profile of fomivirsen has been shown to be attractive and the drug's intravitreal route of administration has been well tolerated by patients.

Peter Drake, an analyst with Vector Securities International Inc., of Deerfield, Ill., said he believes the deal to be positive for Isis, adding, however, the late-stage opportunistic infection market has slowed down due to the triple therapy now administered to AIDS patients.

Martin pointed out that although the triple drug combinations and the protease inhibitors are having a beneficial effect on AIDS patients, there is some concern about cross-resistance to the therapies. "That's why this is big news," Martin said. "There does not appear to be a cross-resistance that is effecting the Isis antisense product, since it works by an entirely different mechanism."

Under the agreement, CIBA Vision receives the option to acquire the exclusive license to market and distribute a second-generation antisense compound to treat CMV retinitis (ISIS 13312), which is currently in preclinical development by Isis.

In August 1996, Isis revised an earlier collaboration with Eisai Co. Ltd., of Tokyo, for fomivirsen, giving Isis full control of the continued development and commercialization of the product and Eisai royalties on sales.

Novartis is funding the development of two of Isis' cancer drugs: Isis 3521 and Isis 5132. Both drugs are currently completing Phase I clinical trials.

Isis also is developing Isis 2302, which is being studied for five different inflammatory conditions: renal transplant rejection, rheumatoid arthritis, psoriasis, ulcerative colitis and Crohn's disease.

Isis is collaborating with Boehringer Ingelheim, of Ingelheim, Germany, for Isis 2302 for Crohn's disease. The product is currently in a pivotal quality, 300-patient Phase IIb clinical trial, Green said, which was initiated after "very encouraging" results from the Phase IIa clinical trial were demonstrated.

Isis' stock (NASDAQ:ISIP) closed Tuesday unchanged at $14.125. *