Officials from RNAi drug newcomers Nastech Pharmaceuticals and RXi Pharmaceuticals this week provided a few new details about their companies’ development activities at the BIO CEO and Investor meeting in New York.
Speaking for Nastech, CFO Philip Ranker touted the strength of his company’s intellectual property position within the RNAi space, highlighting Nastech’s recent licensing deal for City of Hope’s novel Dicer-substrate RNAi technology.
He also confirmed that Nastech is using the technology to develop an RNAi-based influenza therapy, a move that seemingly safeguards the drug-development program from possible IP infringement issues.
Tod Woolf, meanwhile, made his first public appearance as RXi’s CEO during a presentation covering CytRx, which spun out RXi last month. He also gave an overview of the company’s pipeline, as well as a sneak peek at its proprietary delivery technology.
Woolf also provided some additional details about RXi’s management and advisory team.
Co-developed by COH and Integrated DNA Technologies, Dicer-substrates are 27-nucleotide long RNA duplexes that have been shown to be up to 100 times more effective at silencing genes than conventional 21 nucleotide-long siRNAs without inducing an interferon response or activating protein kinase R in cells. to be up to 100 times more effective at silencing genes than conventional 21 nucleotide-long siRNAs without inducing an interferon response or activating protein kinase R in cells.
Since the Dicer-substrate molecules are 27-mers rather than 21-mers, they apparently fall outside of the scope of most of the RNAi field’s IP — including the Tuschl-2 patent family, which covers siRNAs between 19 and 25 nucleotides in length, as well as overhangs on the 3' ends of dsRNAs, and is controlled by Alnylam Pharmaceuticals (see RNAi News, 1/19/2006).
Alnylam is developing its own RNAi-based influenza drug for which it expects to file an investigational new drug application this year.
As first reported by RNAi News, late last year Nastech provided an overview of various RNAi technologies it was developing, including 27-mer RNAi duplexes, the therapeutic rights to which are owned by COH (see RNAi News, 10/12/2006).
Although Nastech officials declined to confirm at the time that the company had licensed the technology, about a month later the firm announced that it had (see RNAi News, 11/9/2006).
“We believe [the Dicer substrate technology] is the second-generation siRNA technology,” Ranker said at BIO-CEO this week. “Through our license with City of Hope, we have acquired access to exclusive rights to five as-of-yet undisclosed targets, as well as broad non-exclusive access to all mammalian targets.”
Though officials from Nastech have previously declined to specify whether the company was applying the Dicer-substrate technology to its flu program, Ranker confirmed this was the case during his presentation, noting that in vitro experiments have shown the 27-mers to be comparable to, if not better than, 21-mers in silencing an influenza target.
In in vivo testing in mice, “the Dicer-substrates were significantly more active in knocking down the viral titer for influenza than the corresponding 21-mer,” he added.
Nastech President and CEO Steven Quay told RNAi News this week that the company’s flu drug will most likely be a Dicer-substrate molecule, but that the decision to use the 27-mer technology in the program was not because of any perceived IP issues.
“We’re doing it primarily because of efficacy — they’re more potent,” he said. “It was a scientific decision, not a legal decision.”
Nastech is planning on filing an IND for its lead flu drug candidate, G101, early this year.
As first reported by RNAi News, CytRx’s spin-out of its RNAi therapeutic programs into a new subsidiary has long been in the works as part of a bid to gain better traction in the field against more established players such as Alnylam and Merck subsidiary Sirna Therapeutics (see RNAi News, 11/11/2005). But it wasn’t until last month that CytRx finally did so and created RXi.
At the time the spin-out was announced, CytRx said that the new company would initially focus on neurodegenerative disease, oncology, type II diabetes, and obesity.
During his BIO-CEO presentation, Woolf said that the company’s neurodegenerative disease program is expected to begin with amyotrophic lateral sclerosis, and provided a brief glimpse at some recent work in the area by scientific advisor and University of Massachusetts Medical School researcher Tariq Rana.
“We believe [the Dicer substrate technology] is the second-generation siRNA technology.”
In experiments conducted last year, Rana used an implantable pump to deliver into murine spinal columns siRNAs targeting the gene SOD1, a mutant form of which is responsible for familial ALS.
“After infusion for seven days … [there was] excellent inhibition of the target with the RNAi [agent] compared to controls” at both 100 microgram and 200 microgram dose levels, he said. “We’re following up on this and moving to develop this into a clinical compound.”
Woolf did not say when the company might begin testing an ALS compound in the clinic, but CytRx President and CEO Steven Kriegsman said during the presentation that lead compounds in RXi’s neurodegeneration and diabetes/obesity programs are expected to be identified some time in 2007.
While RXi has yet to decide on drug candidates, it appears likely that they will all incorporate a delivery technology, so-called nanotransporters, that was developed by Rana and exclusively licensed from the University of Massachusetts for all therapeutic indications.
A nanotransporter is “basically a molecular structure that complexes with the RNAi” agent, Woolf explained. “It is very small [in] size, which leads to good tissue distribution, [and] it’s readily formulated.
“Unlike many other delivery technologies where you have to extrude and you form mixtures of compounds, with this delivery method, all you have to do is mix the delivery carrier … with the RNAi [agent] and treat the animal,” he said.
In mouse studies, nanotransporters have been able to deliver an RNAi payload into the liver, spleen, lung, and fat tissues, he noted, all with “excellent activity.”
For example, siRNAs targeting CDK9 and systemically delivered with the nanotransporter technology into mice at 1 milligram per kilogram results in “greater than 90 percent inhibition of the target,” Woolf said. “In the same experiment, if you use uncomplexed RNAi, you obtain no [silencing] activity at all, even at 50 mgs per kg.”
Supporting RXi’s further development of the nanotransporter technology and its clinical development programs are Nicolas Dean and Robert Brown, Woolf said at BIO-CEO.
Brown, a member of CytRx’s scientific advisory board, is a professor of neurology at Harvard Medical School. According to Woolf, Dean held various vice president positions at antisense drug developer Isis Pharmaceuticals.
Dean is “an expert in getting oligonucleotide drugs into the tissues in the animal, and that’s the core challenge of an RNAi therapeutics company,” he said.
Woolf also added that RXi’s management team has been expanded to include Helena Correia as vice president of regulatory affairs. Correia has previously held similar positions at Acambis, Serono, and Boston Scientific, according to RXi.