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Alnylam to Use MIT Delivery Tech In Cholesterol, Liver Cancer Programs

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Alnylam Pharmaceuticals will use a cationic lipid-based delivery technology developed at the Massachusetts Institute of Technology in both its hypercholesterolemia and liver cancer programs, RNAi News has learned.
 
The lipid nanoparticles on which the technology is based are approximately 50 to 60 nanometers in diameter and “encapsulate siRNA very efficiently,” David Bumcrot, director of research at Alnylam, said last week at Beyond Genome 2007 in San Francisco.
 
He added that Alnylam is “in the midst of” rodent and primate studies designed to support investigational new drug application filings for both its hypercholesterolemia and liver cancer programs.
 
By deciding to use the technology, which was licensed from MIT earlier this year (see RNAi News, 5/10/2007), Alnylam has opted against using a delivery method with which it has a fair amount of experience: the liposomal delivery technology licensed from Tekmira Pharmaceuticals, formerly Inex Pharmaceuticals.
 
According to Bumcrot, the choice was in part due to the efficacy with which the MIT technology is able to enter liver tissue.
 
In vivo, this material goes to the liver very efficiently, and shortly after administration in our tissue-distribution studies [we find] the majority of the drug in the liver,” he explained.
 
By comparison, larger molecules, such as those created using Tekmira’s technology, get “taken up much more readily by macrophages in the spleen and other tissues.”
 
Nonetheless, a broad partnership between Tekmira and Alnylam continues to move forward, Bumcrot noted.
 
Under that arrangement, which was expanded in January (see RNAi News, 1/11/2007),Tekmira will manufacture the clinical material used in both the hypercholesteremia and oncology programs, he said. Additionally, the companies will work to co-develop new delivery technologies.
 
Tekmira brings “a lot of expertise … to help us develop next-generation, lipid-based delivery technology that will have a bigger therapeutic window” than existing technologies, Bumcrot said.
 
Bumcrot declined to elaborate beyond his statements during his presentation.
 
At Beyond Genome, Bumcrot also provided a new insight into Alnylam’s selection of proprotein convertase subtilisn/kexin type 9, or PCSK9, as the target for its hypercholesterolemia program, rather than the cholesterol-metabolizing protein apolipoprotein B, which had been the focus of earlier efforts.
 
“In our hands, inhibiting apoB messenger RNA and protein very dramatically leads to an accumulation of triglycerides in the liver – fatty liver, basically — which is an effect we don’t want,” he said.
 
Previously, Alnylam officials had only said that the selection of PCSK9 was based on the large body of evidence validating the protease’s role in high cholesterol (see RNAi News, 12/7/2006). 
 
“I know that Isis [Pharmaceuticals] has a drug in the clinic where they have shown they can lower apoB without seeing this effect,” Bumcrot said, referring to Isis’ phase II antisense-based cholesterol drug Isis 301012. “So there must be a way to do that, but in our hands … we found an unacceptable elevation of fat in the liver when we targeted apoB that you don’t see with PCSK9 [inhibition].”
 
Liver Delivery
 
About a year ago, Alnylam published data in Nature showing that siRNAs, delivered systemically using a delivery technology developed by one-time Tekmira subsidiary Protiva Biotherapeutics could silence apoB in non-human primates (see RNAi News, 3/30/2006).
 

“In vivo, this material goes to the liver very efficiently, and shortly after administration in our tissue distribution studies [we find] the majority of the drug in the liver.”In vivo

That technology, called SNALPs, comprises a nucleic acid encapsulated by cationic and fusogenic lipids, all of which are surrounded by a polyethylene glycol coating. However, ownership of the technology is currently the subject of a protracted legal battle between Tekmira and Protiva (see RNAi News, 5/17/2007).
 
Despite its previous work with Protiva, Alnylam apparently sees Tekmira as the rightful owner of the technology: last year, Alnylam took an option to license the liposomal delivery technology from Tekmira. That option has since been exercised, and the companies’ arrangement has been expanded to include a research and manufacturing collaboration (see RNAi News, 1/11/2007).
 
In the end, however, it seems that Alnylam views the MIT delivery technology as superior to Tekmira’s — at least for therapeutics targeting the liver.
 
In already completed animal experiments, “the PCSK9 siRNA [leads] to dose-dependent reductions in PCSK9 messenger RNA in the livers of mice given a single bolus injection of the lead siRNA formulated” using the lipidoid technology, Bumcrot said.
 
“Duration of action is somewhat reminiscent of what we’ve seen with [our] apoB [experiments] in mice, lasting for 10 days or so,” with a 25- to 30-percent reduction in total cholesterol levels being maintained over this period, he said. “A slightly higher dose, 7.5 mg/kg, [resulted in] a prolonged duration of action over several weeks.”
 
Based on these and other data, “we’ve identified our lead siRNA [against PCSK9 and] we’ve optimized a novel, proprietary liposomal formulation,” he said. “We plan to file an IND at the end of this year and enter the clinic early next year with this program.”
 
The same liposomal formulation, Bumcrot added, is also going to be used with Alnylam’s liver cancer therapeutic, called ALN-VSP01. The company expects to file an investigational new drug application on the drug next year (see RNAi News, 4/19/2007). 

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