Officials from Santaris Pharma, CytRx, and Targeted Genetics last week presented at the Acumen BioFin Rodman & Renshaw Global Healthcare Conference, providing some new details about their companies’ efforts in the RNAi and microRNA fields.
Keith McCullagh, president and CEO of Santaris, noted during his webcast presentation that his firm is currently transitioning into animal studies a program using locked nucleic acids against a liver-specific microRNA for the treatment of hepatitis C.
He also hinted that privately held Santaris may soon take steps toward becoming a public company through a possible initial public offering.
In a separate presentation, Tod Woolf, president and CEO of CytRx subsidiary RXi Pharmaceuticals, addressed the RNAi field’s closely watched intellectual property landscape and noted that his company’s core technology relies on a different set of patents and patent applications than those used by other players in the space.
As for Targeted Genetics, President and CEO H. Stewart Parker said during her presentation, which was also available online, that the company is aiming to leverage newly issued patents to strike an RNAi-focused collaboration this year.
Such a deal, she said, would build off of Targeted Genetics’ ongoing partnership with Merck subsidiary Sirna Therapeutics in Huntington’s disease, which is expected to reach clinical trials in 2008.
“MicroRNA dysregulation is now known to be a major part of disease pathophysiology, and you cannot inhibit a [disease]-inducing microRNA … through siRNA technology,” McCullagh said during his presentation. “You have to have a single-stranded approach … [and] we believe our drugs … are highly effective in vitro and in vivo.”
Those drugs, termed LNA-antimirs, are essentially nucleic acid analogs in which the ribose ring is locked by a methylene bridge connecting the 2'-O atom with the 4'-O atom. These features are designed to increase affinity and stability.
Santaris is already conducting clinical trials with LNAs targeting the mRNA of various disease-associated genes. But, as RNAi News reported last year, the company is also investigating whether the molecules can be used to block the action of miRNAs (see RNAi News, 5/4/2006).
While the company has discovery-stage programs evaluating LNA-antimirs against cancer-related miRNAs, its most developed program targets miR-122, an miRNA that is highly expressed in the liver and appears to play a role in cholesterol regulation and lipid metabolism.
A number of other companies have conducted early-stage research using miR-122 to evaluate potential miRNA antagonists including Alnylam Pharmaceuticals (see RNAi News, 11/4/2005) and Isis Pharmaceuticals (see RNAi News, 6/15/2006).
According to McCullagh, in vivo experiments have shown that daily administration of an LNA-antimir against miR-122 for three days in mice results in a dose-dependent reduction of the miRNA in the liver when compared to controls.
The LNA-antimir also resulted in a 40 percent reduction in circulating cholesterol that lasted up to 16 days, and “probably” out to 21 or 22 days, he said at the conference.
The cholesterol data, however, are “really pharmacological evidence that the drug is working,” McCullagh said. “We’re actually more interested in this drug for the treatment of hepatitis C … because microRNA-122 appears to be required to allow hepatitis C to replicate in normal human liver.”
He said that Santaris, in collaboration with academic partners, has generated data showing that inhibiting miR-122 can block hepatitis C viral replication, but noted that these data are only in cell culture.
“But if [they are] borne out in animal models, we’d like to take this drug to the clinic for [hepatitis] C,” he said. He did not provide a timeline for when a clinical trial might start.
During his presentation, McCullagh also indicated that Santaris might launch an IPO as it looks to build on a €40-million ($54 million) financing round that closed last March.
“The next financing will be raising money to take [our non-miRNA clinical] products into later-stage … trials,” he said. “That may well be an IPO, and we’re looking at that” option.
Officials from Santaris were not available for additional comment on the possible IPO.
With more and more RNAi-related patents being issued in the US and abroad, and with various companies claiming ownership of key pieces of the RNAi IP puzzle, RXi’s Woolf tried to assure the investment community that his firm has the IP to freely operate in the field.
RXi exclusively owns the therapeutic rights to the so-called Tuschl-1 IP, which covers the use of 21 to 23 nucleotide-long short-interfering RNAs to induce RNAi in mammalian cells, for indications that include diabetes, obesity, and amyotrophic lateral sclerosis.
Alnylam and Sirna co-exclusively own the IP for other indications, while the Tuschl-2 IP, which covers siRNAs with two-to-three nucleotide 3’ overhangs on their ends, is exclusively controlled by Alnylam.
Alnylam and Sirna have long maintained that these and other parts of their IP estates give them a level of control over the RNAi field that would require most other RNAi drug develops to sign IP-licensing deals.
Woolf, however, pointed out during his presentation that RXi is developing a different kind of RNAi technology that involves siRNAs 25 to 30 nucleotides in length, which fall outside of the Tuschl IP.
Additionally, RXi recently signed a non-exclusive license to acquire IP covering short hairpin RNAs, which can trigger an RNAi response when either directly delivered or expressed in DNA constructs. Company co-founder Greg Hannon developed this technology at Cold Spring Harbor Laboratory.
“So we have distinct [forms] of RNAi that we use, [and they are] highly effective in culture and in animals,” Woolf said.
“MicroRNA dysregulation is now known to be a major part of disease pathophysiology, and you cannot inhibit a [disease]-inducing microRNA … through siRNA technology. You have to have a single-stranded approach.”
David Haen, director of business development at CytRx, added during the CytRx presentation that RXi this year aims to identify lead RNAi compounds in its neurodegenerative disease and obesity/type II diabetes programs.
CytRx also plans to reduce its ownership in RXi from a majority stake this year through a stock dividend to its shareholders, he said.
Targeted Genetics first hit the RNAi radar in early 2005 when it signed a deal to combine its adeno-associated virus vector-based delivery technology with siRNAs developed by Sirna as a treatment for Huntington’s disease (see RNAi News, 1/14/2005).
According to Parker, her company is in the process of testing various delivery constructs “in preclinical models in order to pick the one that is the most optimal.”
As part of its arrangement with Sirna, Targeted Genetics will then begin manufacturing the drug with the goal of initiating clinical testing in 2008, she said during her presentation.
At the same time, Parker said that Targeted Genetics is hoping to find additional partners interested in using its AAV technology with RNAi drugs, and expects that the recent issuance of new US patents will help it do so sometime this year.
Key among those patents is No. 7,125,717, issued to Targeted Genetics last year. Entitled "Metabolically Activated Recombinant Viral Vectors and Methods for Their Preparation and Use,” the US patent covers the delivery of genes or small therapeutic genetic constructs including RNAi molecules, the company said.
“We intend to … work hard to leverage that AAV investment we’ve made into additional partnerships and licenses … [and] now we [also have] the opportunity to extend that into the RNAi space as well,” she said.