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In Another First, Intradigm Announces Publication of RNA Interference Drug Data


Vying for its own place among the growing number of RNAi-therapeutics firsts, Intradigm said this week that it is the first to publish data “in preclinical disease models of clinically viable systemically administered RNAi therapeutics.”

The company’s statement comes about a month after one of its RNAi-based drug peers staked a similar claim to primacy in the field, and underscores the notion that being first depends a lot on how one defines the race being run.

According to Intradigm, its first-place status stems from the publication of data in two peer-reviewed journals: Nucleic Acids Research and the American Journal of Pathology. In the first paper, researchers from the company, Utrecht University, and Groningen University reported that siRNAs targeting murine vascular endothelial growth factor receptor-2 were able to inhibit tumor cell angiogenesis and growth rate when delivered intravenously using Intradigm’s nanoparticle technology.

In the second, researchers from the University of Tennessee detailed how they used systemically administered siRNAs incorporating the nanoparticle technology to target either murine VEGF, VEGFR1, VEGFR2, or a combination of all three. The siRNAs were able to reduce ocular neovascularization induced by CpG oligodeoxynucleotides, according to the researchers.

“The two papers are basically efficacy studies with [the drug] ICS-283, [which is a] systemically administered nanoparticle that’s targeted to neovasculature and delivers VEGF-pathway siRNA,” Martin Woodle, Intradigm’s CSO, told RNAi News this week. In the studies, “we’ve generated … [a] demonstration that the target gene is being down-regulated [as is] the phenotypic effect.”

Woodle noted that in the ocular study, “we attained very nice results with a single dose and with the use of just two doses. The effects persisted for the better part of two weeks and perhaps even longer with some of the studies.” In the tumor growth study, “we used dose administration every three days … and the study occurred over a two-week period,” he said.

Both the ocular and cancer experiments used 40 micrograms per 20-gram doses, Woodle said. “Those doses and dose frequencies are very amenable to go into humans,” he added. “It’s quite straightforward to envision using those kinds of doses and schedules to translate them into a clinical regimen.”

Intradigm is currently evaluating ICS-283 as a treatment for cancer and ocular diseases such as wet age-related macular degeneration and diabetic retinopathy.

The company said that it expects to move the drug into phase I testing by late 2005 as a cancer therapeutic. “The phase I [study] may be in a broad [spectrum of cancer] indications,” Woodle said. “Very likely, [the trial] will be looking at kidney cancer patients, but the exact nature of it needs to be defined by the clinical investigator” for an investigational new drug application.

To prepare for the IND filing, Intradigm is currently in the process of completing the necessary preclinical work, such as pharmacology and toxicology studies. Additionally, the company is still finalizing the design of ICS-283, determining what siRNAs will make up the drug, Woodle noted. “We are undertaking the process of converting the mouse versions of the siRNA agents to ones for human genes,” he said. “In addition, we are working to determine whether we limit ICS-283 to the current form with siRNA for a single gene, not yet announced, or to expand it with siRNA for multiple genes.” He declined to provide a timeline for this determination.

Intradigm is also in the process of figuring out where ICS-283 will be made. Woodle said that the siRNA portion of the drug is expected to be produced by a contract manufacturer, but that the company is undecided on whether the nanoparticle formulation will be produced in-house or not.

He declined to comment on whether a deal has been struck with an outside manufacturer for the siRNAs yet.

One thing Intradigm will not have to deal with in preparing the IND for ICS-283 is pinning down the exact modifications to make to its siRNAs; its drug does not feature any. ICS-283 instead relies on the company’s nanoparticle technology termed TargeTran, which Woodle said comprises “a polymer that contains three domains: one domain is a peptide ligand for the integrin that is upregulated on new blood vessels; another is a polymer that forms a steric shell around the particle; and the third is a polymer that is positively charged and acts as a carrier for the siRNA — it binds the siRNA and forms the core particle.

“Nanoparticle systems are very attractive to move [siRNAs] rapidly without need for chemical modification to the oligo … [so] we’re not looking to use chemically modified siRNA,” Woodle added. “We continue to see the nanoparticle with unmodified RNA as the best way to move the field forward in an aggressive manner.”


Intradigm’s announcement about the publication of preclinical data on ICS-283 comes on the heels of Alnylam Pharmaceuticals reporting that it had become the first to publish data demonstrating “RNAi-mediated gene silencing in mammals by a method that potentially can be applied to systemic RNAi therapeutics for human disease.”

As RNAi News reported, Alnylam’s statement caused a minor backlash, with one industry analyst calling the claim “false” in light of previous publications, including ones from rival Sirna Therapeutics (see RNAi News, 11/19/2004).

Ultimately, in an e-mail sent to RNAi News in November, Alnylam qualified its statement by saying that “the reasons that [its data are] a first are: in vivo silencing of an endogenous gene using a clinically relevant route of administration with confirmation of RNAi-mediated cleavage of mRNA using 5’ RACE.”

As Sirna Therapeutics’ COO Nassim Usman pointed out to RNAi News last month, “with the modifier ... the confirmation of cleavage ... [Alnylam’s claim] is technically true. However, endogenous gene silencing without confirmation of cleavage, but with molecular RNA and protein knockdown, has been published.”

According to an e-mail sent to RNAi News this week from Woodle, “the other published work we have seen … doesn’t appear ready for clinical development. Consequently, it looks clear that these recent publications on … ICS-283 are the first demonstration of [an RNAi-based drug] candidate using systemic administration for clinical development.”

Apparently, there is room for several number ones in the RNAi therapeutics field, as long as each is defining itself differently.

Commenting on the situation, Woodle took a diplomatic tack: “There’s been a lot of nice work and results that have continued to support the point that we’ve been trying to make: that systemic delivery is possible,” he said.

— DM


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