By Mary Welch

Two years ago, Hybridon Inc. entered into a potential $200 million alliance with G.D. Searle & Co. for antisense drug development; today, that deal is going strong as Searle expanded the collaboration to include another gene target and the possibility of adding more targets in cancer and cardiovascular disease.

The original area of research was in inflammatory diseases. In addition, Cambridge, Mass.-based Hybridon initiated another program with Searle that will focus on the oncogene MDM2. Searle, of Skokie, Ill., is the pharmaceutical division of Monsanto Co., of St. Louis.

"There are several key points to this," said Andy Grinstead, Hybridon chairman and CEO. "Searle has extended the timetable through 2000 and has expanded the scope of the collaboration into cancer and cardiovascular diseases. And in the area of MDM2, they've acquired the rights to our intellectual property. We have made quite a bit of progress on MDM2, and it's obvious that Searle thinks it's a potentially exciting target."

The 1996 agreement called for Hybridon to use its antisense technology to develop compounds for up to eight molecular targets identified by Searle. The drug maker purchased $10 million in stock for the first compound. It agreed to pay fees, contribute research funds and make equity investments totalling $130 million for compounds directed as six other molecular targets. Identification of a drug directed at the eighth target, which is associated with cancer, is worth another $26 million. Searle also agreed to pay $10 million in milestone payments during the development of the drugs. (See BioWorld Today, Jan. 18, 1996, p. 1.)

Joint Venture Could Bring Another $50M

"We get $600,000 each year plus costs and costs of materials," said Grinstead. "We have the opportunity to get $20 million in equity and licensing for each target they (Searle) select. They also have the right to enter into to a manufacturing joint venture with us."

If the joint venture were formed, Searle would add another $50 million to Hybridon's coffers. Hybridon also would contribute $50 million, but the cash would be reduced based on the value of its technology.

Antisense molecules are synthetic segments of DNA or RNA designed to mirror specific messenger RNA sequences and block disease-associated protein production.

Hybridon stopped a Phase II trial of its lead antisense product, GEM91 for advanced HIV infection after three of the nine patients experienced platelet count decreases that required dose interruption. GEM stands for gene expression modulator. (See BioWorld Today, July 28, 1997, p. 1.)

A few months later, the company lost partner Hoffman-LaRoche Ltd., of Basel, Switzerland, when the pharmaceutical company decided not to pursue Hybridon's lead compounds against both hepatitis C and human papillomavirus. (See BioWorld Today, Sept. 5, 1997, p.1)

The company has moved forward with its antisense projects not only with Searle, but with two Hybridon spin-out companies — MethylGene Co. and OriGenix Therapeutics Inc., both of Montreal. In addition, Hybridon itself has four antisense products in preclinical testing.

In the research on the MDM2 oncogene, Hybridon already has achieved activity in animals with a compound. The company has worked on MDM2 with academic collaborators at Louisiana State University Medical Center, in New Orleans, and the University of Alabama, in Birmingham.

The research completed by Hybridon and the universities were presented to Searle for its own animal testing. "They will validate and expand the research," Grinstead said. "It will also accelerate the pace because they can bring more resources to the table than we can. This will be successful."

Gene amplification and overexpression of the MDM2 oncogene occur in major tumors. MDM2 inhibits apoptosis in these tumors by inactivating the p53 tumor suppressor gene.

MDM2 stands for "mouse minute-double." It was discovered in mice and refers to an oddball, paired extrachromosomal element, without a centromere (a true chromosome's wasp-waisted mid-section), which turns up in many drug-resistance genes. (See BioWorld Today, Jan. 6, 1998, p. 1.)

"MDM2 is a very important missing piece of the gene world," said Grinstead. "I know of at least three other major companies working on MDM2 and objectively, I would say we're as far along — if not farther — than those companies. It's a hot target."

Hybridon's stock (OTC:HYBN) closed Monday at $1.625, unchanged. *

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