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Alnylam Says Liver Cancer Drug Is Its First Systemic Candidate; Delivery Question Lingers

Alnylam Pharmaceuticals last week announced that it has selected its preclinical liver cancer treatment ALN-VSP to be its lead systemically administered RNAi-based drug candidate, and that it remains on track to file an investigational new drug application for the compound before the end of the year.
In choosing to move forward with ALN-VSP, Alnylam has pushed back slightly the development of its investigational hypercholesterolemia drug ALN-PCS, which had previously been in the running to be the first systemic RNAi drug for which the company would file an IND (see RNAi News, 11/8/2007).
During a conference call held last week to discuss Alnylam’s second-quarter financial results (see RNAi News, 8/7/2008), CEO John Maraganore said that while both the liver cancer and hypercholesterolemia programs are “progressing very actively,” it was the company’s plan to file an IND for just one of the two drug candidates this year, and IND-enabling studies for ALN-VSP are more likely to be completed in time to meet that goal.
Good Laboratory Practice studies conducted to “support INDs in oncology are quite different than the nature and flavor of GLP studies that are needed and used to support clinical trials for a hypercholesterolemia program,” he said. “So there really are some differences there that edged in favor of the VSP program from a timing execution standpoint.”
Also driving Alnylam’s decision to move on ALN-VSP are data showing that the drug can trigger significant, dose-dependent silencing of its two targets, kinesin spindle protein and vascular endothelial growth factor, in a mouse model of liver cancer, Akshay Vaishnaw, Alnylam’s vice president of clinical research, added during the call.

GLP studies conducted to “support INDs in oncology are quite different than the nature and flavor of GLP studies that are needed and used to support clinical trials for a hypercholesterolemia program. So there really are some differences there that edged in favor of the VSP program from a timing execution standpoint.”

In addition, Alnylam researchers observed in treated mice histologically documented evidence of cell cycle arrest due to KSP silencing, a reduction in overall tumor growth as measured by quantification of a tumor-specific gene, and marked reduction in the size of liver tumors as observed by gross pathology, he added.
Still, data from the ALN-PCS program has been promising enough that Alnylam expects an IND for the drug could be filed sometime in 2009.
ALN-PCS targets proprotein convertase subtilisn/kexin type 9, a gene associated with regulation of low-density lipoprotein receptors.
This week, a team of investigators from Alnylam, the University of Texas Southwestern Medical Center, Roche, and the Massachusetts Institute of Technology published data in the Proceedings of the National Academy of Sciences showing that four siRNAs designed to silence the gene could cut PCSK9 mRNA levels by 50 percent to 70 percent when delivered to mice and rats in a lipidoid nanoparticle.
Additionally, the reduction in PCSK9 transcript was associated with up to a 60 percent reduction in plasma cholesterol concentrations — an effect shown to be mediated by RNAi using 5’-RACE.
In cynomolgus monkeys, meanwhile, a single bolus injection of nanoparticle-formulated siRNAs triggered, on average, a greater than 50 percent drop in LDL cholesterol levels, with the effects lasting three weeks.
“We are very encouraged by the significance of these findings, including data in non-human primates, which continue to validate PCSK9 as an attractive target for a systemic RNAi therapeutic approach given its ability to achieve acute and durable reductions in LDL cholesterol," Victor Kotelianski, Alnylam’s vice president of research, said in a statement.
SNALP Decision
Although the nanoparticles used in the PNAS study were based on lipidoid technology Alnylam licensed from MIT (see RNAi News, 5/10/2007), it remains unclear if the company will use the technology, or aspects of the technology, in its actual drug candidate.
About a year ago, David Bumcrot, director of research at Alnylam, told attendees at the annual Beyond Genome conference in San Francisco that the company would use the MIT technology in both its liver cancer and hypercholesterolemia programs (see RNAi News, 6/28/2007).
SNALPs, or stable nucleic acid lipid particles, have been key to the RNAi drug-development efforts of various companies over the past few years. Notably, Alnylam and Protiva Biotherapeutics — which merged with Tekmira earlier this year (see RNAi News, 4/3/2008) — published data in 2006 showing that SNALPs could be used to deliver siRNAs against another cholesterol target, apolipoprotein B, in non-human primates (see RNAi News, 3/30/2006).
But at Beyond Genome, Bumcrot said that Alnylam had opted to use the MIT technology for the two systemic RNAi programs instead of SNALPs in part because of its ability to effectively enter liver tissue.
However, last week Alnylam collaborator Tekmira Pharmaceuticals announced that ALN-VSP would “include [its] SNALP delivery technology.”
But in a press release detailing its second-quarter financials, Alnylam was less committed, stating only that “data from [the ALN-VSP] program were generated in collaboration with Tekmira using their … SNALP technology.”
A Tekmira spokesman told RNAi News via e-mail this week that the company’s statement had been approved by Alnylam and “accurately describes the use of Tekmira’s technology … in support of the IND application for ALN-VSP.”
He added that the company was contractually unable to provide additional details.
An Alnylam spokeswoman, meanwhile, said in an e-mail to RNAi News that ALN-VSP “comprises small interfering RNA molecules delivered systemically using Tekmira’s SNALP technology.”
She did not return a request for clarification or comment on whether ALN-VSP would include MIT’s lipidoid technology.

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