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At JP Morgan Conference, Sirna Says Cancer Next Preclinical Focus, Probably

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Sirna Therapeutics last week named oncology as the third disease area in which it will most likely be focusing its RNAi-based drug development efforts, an announcement that might not come as much of a surprise to those keeping a close watch on the company.

Speaking last week at the JP Morgan Healthcare Conference, the year’s first major healthcare meeting for the financial community, Sirna president and CEO Howard Robin said for the first time publicly that cancer would probably join age-related macular degeneration and hepatitis C on the company’s list of preclinical drug programs. While he did not commit fully to the indication, it’s increasingly looking like a done deal, given the hints that have been cropping up: in August, Robin said at another financial conference that Sirna was looking to expand its pipeline “to include areas of oncology, to include inflammation, [and] metabolic disease.” He also added in a breakout session at that event that the company was seeing opportunities in cancer, at one point citing company’s work with telomerase inhibition. (See RNAi News, 9/26/03).

Sirna’s IP estate also holds clues, including two recently published patent applications covering the use of nucleic acid molecules to modulate the expression of epidermal growth factor receptor genes. (See RNAi News, 10/10/03).

Robin told RNAi News this week that although “we haven’t publicly stated what [our] third program would be — we’re still working on whether it might be in the area of CNS or the area of oncology or anti-inflammatory [diseases] … [preclinical data indicate that] oncology is an important area. Oncology is a likely candidate.”

These data include those from blinded experiments using modified siRNAs targeting vascular endothelial growth factor receptor-1 (VEGFR-1) in a mouse models of the 4T1 breast cancer cell line. In the tests, mice were given either the siRNAs or inverted controls through intravenous injections. “We can show after 21 days, compared to inverted controls, a 50 percent inhibition of tumor growth,” Robin said at the JP Morgan conference. “Follow[ing] that up with molecular marker activity … we’ve measured soluble VEGF receptor-1 and we see a 48 percent inhibition of soluble VEGF receptor-1 compared to inverted control.”

He added during the presen- tation that the company also measured soluble VEGF receptor-2, but found no change. “That was not the target, so we feel very comfortable that we’re having very important effects here … [with] systemic administration of siRNAs,” Robin said.

At the conference, Robin stressed that a specific target for the oncology program has not been named yet, but added that “we felt it was very important to … demonstrate that through Sirna’s chemistry, we can modify siRNAs and show efficacy against solid tumors in various animal models.”

So while the signs coming out of Sirna all point to cancer — especially its decision to present new oncology data at JP Morgan rather than data from another indication — Robin is still hedging his bets, conceding that Sirna’s public status restricts what he can make public and when.

“We’re going through a very formal process by exploring all the different possibilities [for preclinical candidates] and making a judgment as to what is the next best target for use of an siRNA,” he told RNAi News. “The process … is a combination of internal discussion where a number of scientists all have very good ideas and they come forth with their plans and proposals, and we also meet with outside experts,” Robin added.

Robin noted that a decision on the third preclinical disease area will be made before the end of the year.

AMD and Hep C

Robin also touched on Sirna’s other preclinical programs during the JP Morgan conference, stating that studies show a .5 microgram dose of the company’s AMD drug candidate, which targets VEGF receptor-1, has demonstrated the ability to cut neovascularization by 66 percent over saline in mouse models of the eye disorder. He added that additional analyses using RT-PCR and Western blotting showed reductions in VEGFR-1 mRNA and VEGFR-1 protein, respectively, after administration of the drug, which has been named Sirna-027.

As for Sirna’s hepatitis C program, Robin said at the meeting that the company has demonstrated significant mRNA knockdown in the hepatitis C Replicon system with its modified siRNAs compared with inverted controls. In hepatitis B plasmid mouse models, intravenously administered siRNAs targeting hepatitis B resulted in a roughly 90 percent knockdown of hepatitis B DNA levels at a dose of about 3 mg/m² compared with inverted controls.

“This is the first demonstration of antiviral efficacy by systemic delivery of an siRNA,” Robin said during his presentation, but he cautioned that “there’s still a lot more work that needs to be done here.” He said at the conference that Sirna intends to select a preclinical hepatitis C candidate before the end of 2004, but told RNAi News that it is unclear what the timing of an IND filing would be after that. “It could be six months, it could be eight months, it could be nine months — it depends on a number of very tech- nical factors. An IND somewhere in ‘05 is realistic, but it’s not likely to be the beginning of ‘05,” he added.

Robin also noted during his JP Morgan presentation that Sirna is projecting a monthly burn rate of about $1.5 million in 2004. He added that the company had a cash position of $41.3 million as of the end of September 2003, translating into about two years of cash “at this moment.”

—DM

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