Alnylam Pharmaceuticals said this week that it has accelerated its systemic RNAi delivery collaboration with Inex Pharmaceuticals, and the companies have now begun looking at applying Inex’s delivery technology to gene targets not examined in the first phase of their partnership.
Alnylam indicated, however, that it has not yet exercised its option to take a broad, exclusive license to Inex’s delivery technology, suggesting that the RNAi drug developer may still be awaiting the outcome of a legal dispute over the ownership of the technology.
Separately this week, Alnylam also said it has signed a deal with the University of Texas Southwestern Medical Center to discover novel RNAi-based therapeutics for hypercholesterolemia, with a focus on a gene known to be involved in low-density lipoprotein metabolism.
Research conducted with UT Southwestern is expected to build off of earlier work by Alnylam in which siRNAs were used to silence apolipoprotein B, also known to be involved in cholesterol metabolism.
The Inex Delivery Deal
In March, Alnylam took an option to exclusively license from Inex a liposomal-based drug-delivery technology for use with certain undisclosed gene targets in exchange for option fees, license fees, milestone payments, and royalties on future product sales (see RNAi News, 3/30/2006).
In conjunction with that deal, Alnylam also began conducting early-stage research with Inex to evaluate the delivery technology with siRNAs.
"Very rapidly, our scientific teams have made tremendous progress in achieving systemic delivery of Alnylam siRNAs formulated in Inex liposomes," John Maraganore, Alnylam’s president and CEO, said in a statement this week. "Given the results to date, we are confident that we will be able to achieve potent and specific gene silencing with systemically delivered siRNAs.”
"It is very gratifying to see such promising results after only a few months of working with Alnylam and we are pleased to enter the next phase of our collaboration ahead of schedule,” Inex President and CEO Timothy Ruane added in the statement.
In connection with the accelerated partnership, Alnylam said it will pay Inex $1.9 million, $1 million of which relates to “an option to take a broad, exclusive license to Inex’s technology.” The remaining $900,000 is related to license option fees for certain undisclosed targets and research funding.
Additional details of the arrangement were not disclosed.
Alnylam did note in its announcement, however, that it continues to hold onto an “option to take worldwide, exclusive licenses to use Inex’s technology for RNAi therapeutics directed to specific gene targets,” and that “any exclusive license agreement would include upfront license fees, future milestone payments, and royalties.”
"Very rapidly, our scientific teams have made tremendous progress in achieving systemic delivery of Alnylam siRNAs formulated in Inex liposomes. Given the results to date, we are confident that we will be able to achieve potent and specific gene silencing with systemically delivered siRNAs.”
Stopping short of stating that it has exercised its licensing option, Alnylam appears to be holding off on fully committing itself to Inex until a dispute over the ownership of the liposomal delivery technology is settled.
Currently, Inex is embroiled in a legal battle with Protiva over the technology, with each company claiming ownership to it in the RNAi field (see RNAi News, 3/30/2006 and 5/4/2006).
The technology, called SNALPs by Protiva for stable nucleic acid lipid particles, involves the encapsulation of oligos by cationic and fusogenic lipids, which are surrounded by a polyethylene glycol coating to prevent clearance of the positively charged cationic lipid from the bloodstream. Earlier this year, Alnylam and Protiva published data in Nature showing that SNALPs could be used to systemically deliver siRNAs in non-human primates (see RNAi News, 3/30/2006).
Although it is agreed that the foundation for SNALPs was built at Inex, Protiva claims that when it was spun out of Inex in 2001 it was given ownership of a gene-delivery technology that was eventually developed into SNALPs. For its part, Inex maintains that Protiva had limited rights to the delivery technology and was obligated to license back to Inex any improvements made to it — including those that allow it to be used with siRNAs.
Both Protiva and Inex have filed lawsuits against each other over the issue in the Supreme Court of British Columbia.
By holding off on a formal licensing contract with Inex, Alnylam seems to be protecting itself from being pulled into the legal wrangling with Protiva, while at the same time maintaining its freedom to strike a deal with whichever company ultimately ends up with the rights to the delivery technology.
Officials from Inex and Alnylam did not return requests for comment.
And the UT Discovery Deal
Under their collaboration, Alnylam and UT Southwestern will co-discover RNAi-based drugs targeting proprotein convertase subtilisn/kexin type 9, a gene that produces a protein responsible for breaking down the LDL receptor.
“PCSK9 is a compelling target for potential breakthrough treatments of hypercholesterolemia and complications of acute coronary syndromes,” Victor Kotelianski, Alnylam’s vice president of research, said in a statement. PCSK9 “has been a difficult protein to target using traditional drug discovery approaches. Therefore, we believe it is an ideal target for a systemic RNAi approach in light of our recent progress with systemic delivery of RNAi therapeutics."
According to Alnylam, UT Southwestern researchers have shown that reducing PCSK9 protein levels can lead to significant reductions in serum LDL, and that mice lacking PCSK9 have significantly decreased cholesterol with no other adverse phenotype.
“Human mutations in PCSK9 that increase PCSK9 activity are linked with an autosomal dominant form of hypercholesterolemia,” the company said, adding that recent data indicates that human polymorphisms that lower PCSK9 function are associated with an 88-percent risk reduction in coronary heart disease.
Alnylam said it will use “systemic RNAi technologies” such as those described in the Nature paper the company published with Protiva, but did not provide additional information regarding those technologies.