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as Alnylam Picks Inex s Platform Over Protiva s Despite Co-Authoring Study Supporting It in RNAi

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Alnylam Pharmaceuticals said this week that it has obtained an option to exclusively license a liposomal-based drug-delivery technology from Inex Pharmaceuticals, even though that technology is at the center of a legal thicket that raises doubts about who actually owns the rights to license it.

Interestingly, the agreement comes soon after Alnylam and Inex spin-out Protiva Biotherapeutics published data supporting the use of Protiva's drug-delivery technology for systemic RNAi applications. Protiva, Inex, and Alnylam rival Sirna Therapeutics are principals in the legal skirmish that aims to identify the true owner of the technology for siRNA applications (see accompanying story, this issue).

Alnylam's deal with Inex calls for the companies to evaluate the delivery technology, which involves encapsulating oligonucleotides with lipids, for use with therapeutic siRNAs. Alnylam has the right to exclusively license the technology worldwide for use with certain undisclosed gene targets in exchange for option fees, license fees, milestone payments, and royalties on future product sales.

Alnylam announced the Inex deal shortly after it and Protiva published data in Nature this week showing that lipid-encapsulated siRNAs targeting the gene for apolipoprotein B, a protein involved in cholesterol metabolism, could be used with clinical efficacy after systemic administration in non-human primates.


The deal comes soon after Alnylam and Protiva published data supporting the delivery technology. Protiva, Inex, and Alnylam rival Sirna Therapeutics are principals in a legal skirmish that aims to identify the true owner of the technology.

According to the paper, Alnylam researchers used Protiva's SNALP, or stable nucleic acid lipid particle, technology to deliver its apoB-targeting siRNAs. The SNALP technology comprises a nucleic acid encapsulated by cationic and fusogenic lipids, all of which are surrounded by a polyethylene glycol coating.

It remains unclear why Alnylam chose to collaborate with Protiva on the research published in Nature but signed its licensing deal with Inex, or how Inex's and Protiva's delivery technologies differ, if at all. Officials from Alnylam and Inex declined to comment for this article.

Nature Calls

Alnylam said that the data in the Nature paper reinforce its expectation that it will be able to initiate a clinical trial of a systemically administered RNAi-based drug within 18 to 24 months, although that study would not necessarily be for an apoB-targeting agent.

According to the Nature paper, the researchers encapsulated apoB-targeting siRNAs in Protiva's SNALPs. A single dose of the RNAi drug, either 1 or 2.5 mg/kg, was then administered intravenously to cynomolgus monkeys.

"A single siRNA injection resulted in dose-dependent silencing of apoB mRNA expression, with maximal silencing of over 90 percent," Alnylam said. "In addition, plasma apoB levels were reduced by more than 75 percent, cholesterol levels by more than 60 percent, and [low-density lipoprotein] levels by more than 80 percent. In the study of 18 animals, the treatment was well tolerated with only transient liver enzyme elevation observed at the highest dose."

John Maraganore, president and CEO of Alnylam, noted during a conference call this week that "these results were dramatic, fast-acting, and durable. Specifically, these effects were evident after 24 hours of a single dose and lasted for over 11 days, which was the last time point measured in our study."

He added that in the animal study, 5' RACE analysis was used to demonstrated that the "silencing of the apoB mRNA was mediated by RNA interference."

However, Maraganore stressed that Alnylam has been using apoB "as a model system and [we] have not yet decided what specific target of the many potential targets we can go after to pursue in our first systemic RNAi clinical program. We are currently considering many potential opportunities, including treatments for systemic viral infections, metabolic and cardiovascular disease, and cancer," he said.

But the CEO added: "ApoB as a potential clinical target is of interest to us, and there clearly are a significant number of patients that are refractory to existing drugs for the treatment of hypercholestremia — and these are very large drugs," he said.

Maraganore noted that "apoB is simply undruggable with small-molecule or antibody drugs, [and] … the effect on cholesterol and LDL levels [from the primate study] greatly exceed the effects seen with the world's largest-selling drug, an over $12 billion annual sales drug, called Lipitor, even when that drug is combined with other ant-cholesterol agents."

Maraganore said that additional details about Alnylam's systemic RNAi program would be made public as the company's research in the field develops.

— Doug Macron ([email protected])

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