First it was Sirna Therapeutics (formerly Ribozyme Pharmaceuticals), then it was CytRx. Now another drug developer, New Zealand-based Genesis Research and Development, has turned to RNAi to fill in its pipeline after its development of other biotechnologies failed.
Genesis, which is traded on the New Zealand and Australian stock exchanges, was established a decade ago as a biotechnology firm focused on developing biological treatments for immunological disorders. While the company had advanced three product candidates through phase II testing — including ones for asthma, psoriasis, and eczema — they all were ultimately dropped amid poor clinical results.
"After the first [drug candidate] failed [in 2002], we looked at our pipeline and realized that we needed to re-stock it as quickly as we could," Stephen Hall, CEO of Genesis, told RNAi News this week. "We looked at our capabilities, where the market was, and where technology was headed, and we felt RNAi therapeutics was an area we could apply our skill to quite usefully and develop products more quickly than with some other routes."
According to Hall, Genesis has been working with RNAi for years through its agricultural biotechnology unit, AgriGenesis. As such, around late 2003, the company began investigating whether it could translate its use of RNAi as a functional genomics tool in plants into a therapeutic modality in humans.
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"Part of [Genesis'] general corporate strategy has always been to outlicense and partner at the right stages. … At this stage, we're very happy with the program proceeding internally." |
"We had done some very early experiments testing RNAi in mammalian cells prior to the … [Thomas] Tuschl-type papers" in 2001, Genesis CSO Greg Murison told RNAi News. "That was really born from our interactions with our plant scientists. As health scientists, we were jealous of what they were able to do with RNAi, so we had a crack at it in mammalian cells and saw that it worked."
"Some of that data was actually used by Benitec in some of their patenting activities," Hall added.
But as its RNAi drugs research was ramping up, Genesis was still dealing with the clinical setbacks of its other products, the most recent of which occurred late last year. In order to control costs, over the last 12 months Genesis has executed a series of lay-offs that have cut the number of employees in its ag-bio unit to 10 from about 65, Hall said.
The lay-offs, however, "had very little impact on the health science" operations of the company, he noted, adding that Genesis now has just over 40 employees total.
While the headcount reductions might have helped Genesis free up resources for its RNAi work, the company is also expecting a cash infusion from the settlement of a legal dispute with ArborGen. Under the terms of that arrangement, Genesis stands to receive $5.5 million in exchange for transferring certain ag-bio technmology to ArborGen, and ending all forestry-related activities.
This money, Hall said, is expected to be received in a matter of months and will give Genesis enough capital to operate for three years at its current monthly burn rate of about $276,000.
RNAi
With its coffers filling up, Genesis continues to advance its RNAi programs, which Murison said accounts for about 90 percent of the company's drug development efforts. (The other 10 percent primarily involves Zyrogen, a preclinical therapeutic target for autoimmune disorders and osteoporosis that the company is looking to outlicense.)
Specifically, Genesis is hoping to use RNAi to treat asthma and atopic dermatitis by targeting immunoglobulin E (IgE) and IgE receptor pathways, Hall said.
"Our major focus [recently] has been screening RNAi drug candidates … and we have selected lead candidates," Murison added. "We've developed some pretty neat technology for testing those in primary cell types. It's difficult to do that testing in hematopoietic cells — just getting RNAi [compounds] or genes into those cells is a challenge — but we've met that challenge and have some good in vitro assays that we've developed in-house that allow us to do" the testing.
Murison noted that the company is testing both siRNAs and shRNAs, in both delivered and expressed formats, as part of its "strategy [of developing] a therapeutic quickly without getting bogged down in one particular technology."
The company's most developed RNAi drug candidate — an siRNA — is currently being tested in mice for both asthma and atopic dermatitis, he said. "In tandem, we're developing drug delivery vehicles for that [while] also testing other people's drug delivery vehicles in our mouse models."
According to Anand Kumble, Genesis' head of product development, the company is investigating a number of direct-to-lung delivery approaches and topical delivery technologies for its asthma and dermatitis programs, respectively.
"What we've chosen to do is identify companies that have delivery technologies [that] can package either the [siRNA] or [shRNA] and deliver it via a pulmonary route into the lungs," he said. "We have identified companies, and have spoken to them, and are moving ahead in that area" through pilot testing programs.
"Likewise in atopic dermatitis, we have decided upon whom we are going to collaborate with and we are in advanced stages of getting that underway as well … for a topical route of delivery," Kumble added.
Hall declined to identify the companies with which Genesis has struck technology-testing arrangements, but he said they include ones in both the US and abroad. Among the names in the RNAi space working on direct-to-lung delivery are Alnylam Pharmaceuticals, Insert Therapeutics, and Galenea. Companies working on topical delivery of RNAi drugs include Sirna subsidiary Sirna Dermatology and SR Pharma subsidiary Atugen.
Hall noted that Genesis also has developed its own delivery technology, which is being tested against other companies'. Kumble declined to provide details about Genesis' delivery approach.
Kumble also said that no decision has been made on whether Genesis will develop its RNAi drug in-house or whether it will find a development partner. "At the moment, we think it would be wise to first test [the drug candidates] out in feasibility studies," he said.
But Hall indicated that the company would likely pursue partnerships down the road. "Part of our general corporate strategy has always been to outlicense and partner at the right stages because it brings not just access to money but access to technology and rigor in decision-making," he noted. That said, "at this stage, we're very happy with the program proceeding internally."
Although for the near-term RNAi has become the chief R&D focus for Genesis, Hall stressed that the company does not intend to limit itself to this technology.
"Our core capability is … the understanding of immune disorders," Murison noted. "We have an extensive in vitro discovery platform … as well as in vivo models of inflammatory disorders. So our feedstock, if you like, at the moment is the RNAi-type drugs … but we see that we can feed that engine with biologics or even, in the future, with small molecules of the right shape and size."
Similarly, Hall said, Genesis does not plan on restricting itself to immunological indications. "We have other targets in mind for further development" under the company's RNAi program, he said, declining to go into further detail.
And within the immunology space, "we have a panel of siRNAs and shRNAs that we're testing against … targets [other than IgE and Ige receptors]," Murison added. "So it's not like a one-off shot with our lead candidate. It's a process where we've got a number of candidates coming through for the different targets."
— Doug Macron ([email protected])