National Editor

Boasting a patent estate that the company's CEO said "covers everything that can be done" in antisense, Isis Pharmaceuticals Inc. entered a strategic alliance with Alnylam Pharmaceuticals Inc. that combines the pair's knowledge and expertise in the burgeoning field of RNAi.

The hoped-for outcome, of course, is drugs.

"It's more than just exchanging [intellectual property]," Frank Bennett, vice president of antisense research, told BioWorld Today, adding that his firm's research already has "focused broadly on all antisense mechanisms, including RNAi."

Bennett, who has been with Isis for 15 years, said the Carlsbad, Calif.-based company has "a tremendous portfolio of chemistry, but we also have a lot of expertise in downstream events you have to consider when you want to develop these into drugs," such as toxicology and pharmacokinetics testing.

Isis' stock (NASDAQ:ISIS) rose 42 cents Friday to close at $9.10.

Isis licensed to Alnylam its patents relating to antisense mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics in exchange for a $5 million technology access fee, along with participation in fees related to Alnylam's partnering programs, and downstream milestone and royalty payments.

Access to the technology will be exclusive to Isis and Alnylam, with the companies also sharing proceeds of any licenses Alnylam grants under its InterfeRx program, if the deals include sublicenses to Isis patents.

InterfeRx is a program launched late last year through which the Cambridge, Mass.-based firm grants licenses on a target-by-target basis for development of RNA interference therapeutics under its patents relating to small interfering RNA molecules for use as drugs.

Isis also is making a $10 million minority equity investment in Alnylam, and will provide the company with access to Isis' capabilities for development and commercialization of RNAi drugs, including process development, bioanalytic methods, quality control and manufacturing.

Isis keeps certain rights to a limited number of targets for double-stranded RNAi drugs and, if it develops an RNAi-based drug that relies on Alnylam's technologies, would pay milestones and royalties.

Stanley Crooke, chairman and CEO of Isis, said the company would not be more specific about financial details, but assured investors during a conference call that the deal is "lucrative." Alnylam, for its part, is in a quiet period related to the filing of its initial public offering earlier this month. (See BioWorld Today, March 2, 2004.)

But Crooke freely elaborated on other aspects of the deal, which he said creates a "one-stop shop for access to double-stranded RNAi technology."

He said Isis "invented the medicinal chemistry of oligonucleotides, and of course RNAi drugs are oligonucleotides. So we've made available to Alnylam a portfolio of about 150 of our patents that cover basic chemistries and how you use those chemistries to design double-stranded RNAi drugs," which have been the subject of Alnylam's efforts.

RNAi surfaced in 1997 when Andrew Fire at the Carnegie Institute in Washington and Craig Mello at the University of Massachusetts Medical School found that by designing RNA with two strands they could silence targeted genes. The method since has been licensed in the U.S., Europe and Japan.

"The way to think about it is, you can deliver the antisense oligonucleotide as a double-strand or single-strand complex," Bennett said. "Most data suggest the double strand is more efficient, and that's how most people practice it."

But just about anything done in the space is covered by Isis' chemistry estate, the breadth of potential of which is "just enormous," Crooke said. "It means if you make a modification of an oligonucleotide of any sort, in our view, you're going to need our patents, most likely."

Alnylam's patent estate is not to be downplayed, he added, since the company has acquired intellectual property from the early inventors of double-strand RNAi. The two companies' joined arsenals "create a tremendously dominating patent position," he said.

"We're focused here at Isis primarily on single-strand antisense drugs with a variety of mechanisms," including RNAi and others, Crooke said, including the modulation of RNA splicing, which was the subject of a deal with Ercole Biotech Inc., of Chapel Hill, N.C., in May.

He said the Alnylam deal is "not significantly different" from the one with Ercole.

"Again, we had a lot of early pioneering work that covered splicing mechanisms," Crooke said. "They did a lot of really nice work in splicing. They needed access to our patents and our chemistry."

In the Ercole arrangement, each company will pay the other for certain preclinical, clinical and commercial achievements, as well as royalties. Ercole also got a license to Isis' Bcl-x preclinical antisense drug.

Isis' lead drug candidate, Affinitak, is in a Phase III program for non-small-cell lung cancer, and Alicaforsen is in Phase III for Crohn's disease. The latter also is being studied in a Phase II trial for ulcerative colitis.

The company has 11 antisense-based drugs in clinical trials, and Crooke called RNAi a mechanism of antisense.

"It's RNA-like antisense drugs that work through enzymes," he said, adding that "there are a number of ways to try and exploit these mechanisms," of which double-stranded RNAi is one - and Alnylam is "the center of excellence in the world" for such investigation.

"We'll participate in that through combined research activities and we'll participate in their successes financially," thanks to the new deal, Crooke said.

"We obviously are interested in all RNA-based drug discovery," he said, adding that "we have to compare all these potential mechanisms with each other, because we own them all."

Double-stranded RNAi, he allowed, "has to look a lot better than the other mechanisms that we're working on," but the approach will be to pursue drugs "based on as broad a range of mechanisms as possible, and let the data tell us which is the better solution." The Alnylam deal gives shareholders "maximum bang for their bucks," Crooke said.

How long might the world wait for an RNAi-based therapy? Bennett did not want to speculate.

"Right now there's not even a drug in clinical trials," he said. Although Alnylam expects to begin a clinical trial of its lead macular degeneration product candidate in 2005, Bennett said that "it's going to be several years before we know whether there are going to be RNAi drugs."