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Lorus Publishes Preclinical siRNA Data; Firm Eyes Collaborations as Key to Clinic

Lorus Therapeutics last week reported the publication of preclinical data on its lead siRNA cancer drug, siRNA-1284, marking the first formal announcement of the company’s intention to play in the RNAi-based drugs arena.
According to Jeff Lightfoot, project manager at Lorus, the company has been working on expanding beyond antisense into RNAi for about three years, primarily focusing on molecules that target R2, a subunit of the enzyme ribonucleotide reductase, which is required for DNA synthesis and repair.
After testing several siRNAs, the company settled on siRNA-1284 as the most promising and has put the drug candidate at the top of its RNAi pipeline, he told RNAi News this week. He added that the drug is expected to be used to treat solid tumors such as those associated with renal, skin, and colon cancers.
However, Lorus doesn’t expect to rush the RNAi drug into the clinic. Saeid Babaei, associate director of corporate affairs at Lorus, noted that the company is currently prioritizing its research and development projects and expects to focus on those drug candidates already in the clinic. These include the antisense drug GTI-2040, which also targets R2 and is in six phase I and phase II studies for various cancers.
“A major effort [is underway] and resources are being spent for 2040, trying to move the compound forward,” Babaei told RNAi News. “We don’t have a defined timeline [for the RNAi program] that I can share. It [might] be some time in ’08, [but] it would be too premature to comment” on exact timing.
The Data
According to Lorus’ paper, which was published online this week in Anti-Cancer Drugs, siRNA-1284 was successfully used to inhibit the expression of R2 in cancer cell lines and resulted in a significant inhibition of cell proliferation in vitro.
In vivo testing, meanwhile, showed the siRNA was able to significantly inhibit tumor growth in three different mouse models of cancer — renal carcinoma, melanoma, and adenocarcinoma.  
“Dose-dependent anti-tumor effects correlating with dose-dependent target down-regulation were also demonstrated in at least one tumor model,” the paper’s authors stated, adding that the “observed inhibition of tumor growth correlated with R2 suppression.”
Cell-cycle analysis indicated that cells transfected with siRNA-1284 “were blocked in S-phase,” the authors wrote. “This arrest in S-phase likely contributes to the observed anti-proliferative and anti-tumor effects in siRNA-1284-treated tumor cells and xenograft models, and is a consequence of suppression of R2 and therefore inhibition of RNR activity.”
In the Anti-Cancer Drugs paper, the Lorus researchers note that in their in vivo experiments siRNA-1284 was administered in an unmodified form via an intravenous bolus injection. “Though highly effective in preclinical animal models, chemical modification of siRNA-1284, along with the identification of an efficient delivery system, may be required to achieve the same efficacy in the clinic,” they wrote.
Road to the Clinic
Echoing the paper’s authors, Babaei said that while Lorus would like to move siRNA-1284 “forward at a reasonable rate to the clinic,” securing an R&D partner — especially one with an effective siRNA delivery technology — would likely be a necessity to do so.

We don’t have a defined timeline [for the RNAi program] that I can share. It [might] be some time in ’08, [but] it would be too premature to comment” on exact timing.

Lightfoot said that about a year ago, Lorus was in partnership discussions with a company touting an oral delivery technology, but that these negotiations ultimately broke down.
“This is how these things go,” he said. “You start discussions with someone [and] you find out a bit more about their technology. But there has to be a compelling reason to proceed with co-development.”
He declined to comment on why a deal never materialized or disclose the company with which Lorus had been in discussions. One RNAi company, Cequent Pharmaceuticals, has an RNAi delivery technology it claims can be used orally, but Lightfoot said that Lorus has not discussed an alliance with this firm.
Despite the priority of its later-stage programs, Lorus anticipates striking a deal for its RNAi program, and making an announcement “in terms of our plans for 1284,” some time this year, Babaei said.
Once this loose end is tied up, Babaei said that Lorus will turn its attention to securing the intellectual property rights it needs to bring siRNA-1284 to market.
“One of the things we’re working on right now [is], obviously, the IP situation with [the] appropriate partners,” he said, adding that Alnylam Pharmaceuticals and Merck, which recently acquired Sirna Therapeutics (see RNAi News, 1/4/2007), are the two main IP holders with which Lorus is in talks. 
“They’re not the only ones, but they’re the main ones we’re talking to,” he said.

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