NEW YORK, Aug. 18 (GenomeWeb News) - About a year after reinventing itself as an RNAi company, Sirna Therapeutics (formerly Ribozyme Pharmaceuticals) appears to have gotten back into the swing of things.

The Boulder, Colo.-based company, which released its second-quarter results last Thursday, is conducting in vivo tests of its siRNA therapeutic candidates, and preparing to ask for the FDA's approval next year to begin clinical trials of at least one siRNA drug candidate, setting it up to possibly be the first to test the therapeutic possibilities of the technology in humans, according to company executives.

Sirna remains on-track to select a lead drug candidate in the two therapeutic areas it has chosen as its focus - hepatitis C and age-related macular degeneration - by year-end, and submit at least one IND by the end of 2004, said Nasseem Usman, the company's chief scientific officer.  Usman noted, however, that it is not yet clear whether the filing (if there is, in fact, only one) will be for a hepatitis C or AMD compound. 

The company is planning to release this year new data demonstrating systemic efficacy of its siRNA compounds in animal models. Data on the efficacy of local delivery, he added, is already available.  As it stands now, Usman said, the AMD program could be considered the more advanced, given that the drug is administered locally, which drastically simplifies delivery issues.

As for Sirna's ability to fund itself as it pursues these goals, Marvin Tancer, the company's chief financial officer, said the company has enough cash to last it for the next two or three years at its current monthly burn rate of between $1.2 million and $1.5 million.  According to its second quarter results released on Aug. 14, the company had cash, cash equivalents, and securities for sale worth $43.8 million, as of June 30.

Meanwhile, the company posted last week a lower second quarter loss amid higher revenues from contract manufacturing, despite an increase in operating costs.

The company's revenues for the period derived in part from contract manufacturing, came to $3 million, up from $1.6 million in the year-ago quarter.   Net loss for the second quarter was $7.8 million, versus $9.3 million a year ago. R&D expenses fell to $4.3 million from $7.9 million, reflecting the company's dropping its ribozyme programs and restructuring itself to focus on RNAi alone. 

Sirna's overall operating expenses rose about $1.6 million, as the company recorded a one-time non-cash charge of $5.3 million in deferred patent costs for patents that do not directly relate to RNAi.

Company RNAissance

In its previous incarnation, the company was focused on using ribozymes to cut up RNA encoding for disease-causing proteins. While Ribozyme managed to get three drug candidates into clinical trials, none of these ever proved to be effective, and the company, cash-strapped and with its shares trading at a fraction of the $361.88 peak they hit in March 2000, made the decision to turn its attention fully to RNAi.

And it did so rather gracefully. In 2001, the company brought in Tancer as CFO and promoted Howard Robin, its COO,to CEO, and the next year announced that it would be working on RNAi exclusively and shelving its ribozyme work.  In April this year, Ribozyme changed its name and stock ticker symbol (RNAI) to reflect its new focus, and then netted $45 million in a round of private financing that included venture capital firms The Sprout Group, Venrock Associates, Oxford Bioscience Partners, Techno Venture Management, and Granite Global Ventures -- all the while touting its RNA experience and IP estate as the keys to future success.

"The problems that Ribozyme had were clinical problems with their drugs.  There is some potential for RNAi to avoid the problems that were encountered in the clinic with ribozymes," said Douglas Fambrough, Sirna board member and principal at Oxford Bioscience, which invested about $8 million in the company for a mid-teens percentage stake.  "I didn't say there were big problems with the company itself.  The core scientific [expertise?] at Sirna is very strong and the capabilities they've built in RNA chemistry are unparalleled."

As for patents, Fambrough told GenomeWeb that "it's so early ...that it's hard to say anything that's definitive about IP.  What I can say is: we're comfortable with the IP position."

Tancer told GenomeWeb that Sirna has taken licenses to the fundamental Fire-Mello patents being non-exclusively licensed by the Carnegie Institution and the University of Massachusetts, and is taking a serious look at the Tuschl patent applications held by MIT.  Aside from this kind of "base technology" IP, he said, Sirna has, as a result of its earlier work with RNA, 30 issued patents "in the areas of chemical stabilization, process development, and manufacturing, which make [siRNAs] real as potential therapeutics."

The company also has filed 50 patent applications covering, among other things, oligo stabilization, delivery technology, and individual drug targets in areas such as cancer and metabolic diseases, according to whom?  "We have identified targets, we've made the RNAi constructs, we've stabilized those constructs, we've knocked out the targets, and filed the IP," Tancer said.

He noted, however, that this timeline could change if Sirna's active pursuit of collaborations, which are part of the firm's "strategic plan", pays off.  This is not to say, though, that Sirna intends to throw itself at the first potential partner it comes across.

"We're interested in collaborations.  But...we want to make sure that we align ourselves with not just with a company that's going to put up money, but a company that has a real strategic interest and a capability in an area where we can take advantage."

Translation: "Basically, we're looking at the larger pharma companies and the larger, more-established biotech companies" and are interested in ones with strong clinical development and commercialization capabilities that compliment siRNA.

But before any commercialization or clinical trials can begin, Sirna, like all companies trying turn RNAi science into medicine, needs to overcome the drug delivery hurdle.  Currently, Tancer said, the company is looking at "organ systems or targets where oligos generally tend towards, such as the liver," as well as local delivery of siRNAs, two areas he terms "the lower hanging fruit." 

"When it comes to targeting specific organs that oligos don't naturally go towards, we need to begin thinking about more sophisticated targeting and delivery mechanisms."  As such, Sirna is also on the look out to ink an alliance with a firm that has "superior delivery technology." 

Acacia Research said last week that its CombiMatrix unit has introduced a program, called siRNA Solutions, offering customers and collaborators an integrated siRNA gene silencing service for drug discovery. 

According to the Newport Beach, Calif.-based company, siRNA Solutions will allow for the design and synthesis of custom siRNA pools, and assist researchers in designing, conducting, validating, and reiterating gene silencing experiments in days for any gene in any organism.

Looking to address the problem of off-target gene silencing often associated with RNAi, Dharmacon introduced last week new siRNAs, in which the sense strand of the oligo has been inactivated but the efficacy of the antisense strand maintained.

"SiRNAs are not as specific as we thought they were, so there are off-target effects and the siRNA can hit multiple genes," Dharmacon co-chairman and chief scientific officer Steve Scaringe explained to Genome Web.  "What this product does is address perhaps one of the...major causes of non-specific effects."

Scaringe said that Dharmacon found that "putting a couple modifications on the five-prime end" of the dsRNA's sense strand would inactivate it, keep the antisense strand functional, and reduce by half the potential for off-target effects.  He declined to comment specifically on the sense strand modifications as the company is in the process of preparing patent filings for the technology, but noted that papers detailing the technology are expected to be submitted to peer-reviewed journals in the "next couple of months."

Despite their putative superiority, Scaringe said he does not anticipate the On-Target oligos replacing Dharmacon's standard siRNAs, at least not just yet.

"Some people just simply want to go with the old platform," he said.  "That's what they're comfortable with, that's what they're getting results with, they stay with it."

Additionally, On-Target will carry a slightly higher price tag than Dharmacon's regular siRNAs, roughly $75 more per order regardless of unit size, so while it may be useful to some people, others may be satisfied with what they have already and not willing to pay the extra cost, he said.

But as the RNAi space develops and research becomes more sophisticated, Dharmacon expects the need for highly specific siRNA, such as On-Target, to increase.  "Our goal is that, six months from now, this becomes the standard."

RNA interference innovator Craig Mello of  Medical School was honored in Boston at the Drug Discovery Technology conference last week along with his collaborator Andy Fire of the Carnegie Institute of Washington with an award from Aventis for their studies on the gene silencing technique. See the GenomeWeb story filed from the conference filed from the conference.