By Matthew Willett

Isis Pharmaceuticals Inc. dosed the first patient in its pivotal Phase III trial of ISIS 3521 for non-small-cell lung cancer in combination with the chemotherapeutics carboplatin and paclitaxel.

Researchers are attempting to reproduce survival results from a Phase II trial now nearing completion that produced a median survival of 19 months in patients with stage IIIb or stage IV non-small-cell lung cancer, a survival rate more than double the typical median survival rate.

ISIS 3521, an antisense protein kinase C-alpha (PKC-alpha) inhibitor, binds to an mRNA sequence specific to PKC-alpha to inhibit that kinase's production without stopping other proteins in the PKC-alpha family.

PKC-alpha's family of kinases plays a role in normal cell function, acting as a signal-transduction agent, modulating cellular responses to environmental stimuli. In cancer patients, PKC-alpha is implicated in abnormal cell growth.

"This protein kinase family has about 12 or 13 members, depending on the way you count them, and we've made inhibitors of each member and demonstrated that although they're closely related to each other, the inhibitor is specific for each one," Isis Chief Medical Officer Andrew Dorr said. "That's the dramatic difference between antisense and small-molecule technology: Small molecules can't reach this level of specificity."

Dorr said the Phase III trial may yield results that could support a new drug application submission in 2003.

Isis' stock (NASDAQ:ISIP) gained 75 cents Wednesday, closing at $10.25.

"We've done a trial of 3521 with carboplatin and paclitaxel, the two most commonly used combination chemotherapeutics in the U.S., and we've seen a very nice response rate, quite a remarkable prolongation in survival compared to any other data we've seen," Dorr said.

The two-arm, 600-patient Phase III trial has similar enrollment eligibility requirements as the Phase II trial, and an identical primary endpoint of survival. Usual survival rates for non-small-cell lung cancer are about eight months, Dorr said.

Preliminary results from the Phase III trial should be available about six months after enrollment is completed in 15 to 18 months, he added, depending on the survival-promoting therapeutic's efficacy.

Isis has sole ownership and rights to 3521, Dorr said, and the market for a therapeutic for non-small-cell lung cancer is a significant one with few treatment options.

"There are about 150,000 new cases of lung cancer annually," he said, "Of those, about 80 percent are non-small-cell, but most of those are in the late stages, the vast majority, so the incidence rate being what it is, the death rate isn't far off that.

"On a simple basis, all those who die are potential candidates for this. And the population in Europe is a similar number."

Isis' only commercialized product is Vitravene (fomivirsen) for the treatment of cytomegalovirus-induced retinitis in AIDS patients, approved in 1998. (See BioWorld Today, Aug. 28, 1998.)

The company has a total of 11 products in its development pipeline, five of which are in Phase II clinical trials.

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