Twice is quite nice

CAMBRIDGE, Mass.—With its patent count at 1,600 and 20 years of antisense research behind it, Isis Pharmaceuticals Inc. is once again betting on Alnylam Pharmaceuticals, with whom it has partnered since 2004, to move the therapeutic results of their joint research forward at a faster clip.

This time around, the focus is on the development of single-stranded RNAi (ssRNAi) technology. As part of the collaboration, Isis has co-exclusively licensed its ssRNAi technology to Alnylam in exchange for upfront payments, research and development milestone payments, and royalties. The alliance provides Alnylam with access to Isis' intellectual property and expertise regarding the development of ssRNAi antisense drugs, while both companies will have the opportunity to discover and develop drugs employing the new technology. In addition to the new collaboration, Isis and Alnylam also agreed to extend their broad cross-licensing arrangement regarding double-stranded RNAi that was established in 2004.

Antisense research has suffered from the curse of great promise. As it is known to occur in nature, the RNAi pathway is mediated by short double-stranded RNA oligonucleotides called small interfering RNAs or siRNAs. To date, efforts aimed at harnessing this pathway to silence disease-causing proteins have used double-stranded siRNAs. Many researchers consider the results disappointing.

Using its expertise in oligonucleotide chemistry and design, Isis has discovered strategies for designing single-stranded oligonucleotides that act through the RNAi mechanism. With further development, these chemically modified, single-stranded, RNA-like oligonucleotides could have improved properties for systemic administration while harnessing certain advantages of the RNAi mechanism.

"Our goal is to demonstrate that we can produce ssRNA drugs that we can take to man. At Isis, we have made significant breakthroughs showing that chemically modified single-stranded oligonucleotides can activate the RNAi pathway. Our strategy has been to identify all kinds of partners like Alnylam to whom we can parcel out the technology. This is an expression of the fact that there is more to do than we can take advantage of," says Dr. Stanley Crooke, chairman and CEO of Isis.

Also stressing the partnership as a path to meeting important therapeutic goals, Alnylam president Barry Greene calls it "co-opetition"—meaning that Alnylam actively cooperates with companies that can be considered competitors.

In 2001, Eli Lilly & Co. invested more than $200 million with Isis in turn for rights to a promising anti-cancer drug, Affinitak. Developed by Isis and Eli Lilly, its failure in Phase III trials for lung cancer was reported in 2006. Isis also suffered a Phase III failure with Alicaforsen, a drug targeted against Crohn's disease.

Now, under the terms of the licensing and collaboration agreement, Alnylam will potentially pay Isis up to $31 million in license fees, including $11 million on signing, $10 million in 18 months or earlier if in vivo efficacy in rodents is demonstrated sooner, $5 million upon achievement of in vivo efficacy in non-human primates and $5 million upon initiation of the first clinical trial with an ssRNAi drug. Alnylam will fund research activities at a minimum of $3 million each year for three years with research development activities conducted both at Isis and Alnylam. If Alnylam develops and commercializes drugs utilizing ssRNAi technology on its own or with a partner, Isis will receive milestones and royalties. Also, initially Isis is eligible to receive up to 50 percent of any sublicense payments due to Alnylam based on Alnylam's partnering of ssRNAi products, which will decline over time as Alnylam's investment in the technology and drugs increases. In turn, Alnylam is eligible to receive up to 5 percent of any sublicense payments due to Isis based on Isis' partnering of ssRNAi products. Both Isis and Alnylam are eligible to receive royalties from each other on any ssRNAi products developed by the other company.

Alnylam appears to have reason for optimism. Greene notes that an RNAi therapeutic for respiratory syncytial virus, which is the leading cause of pediatric hospitalizations, has completed Phase II studies, which showed it to be safe and well tolerated in healthy volunteers.

"And we're using liposomal nanoparticles to target two genes to treat both hepatocellular and secondary liver cancer," Greene adds.

This research moved into clinical trials in April 2008.