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Wyeth Becomes Latest Big Pharma to License Santaris LNA Tech, But Has No Plans to Pursue miRNAs Yet

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Santaris Pharma this week announced that it had signed a deal giving Wyeth access to its locked nucleic acids for use in developing RNA-targeting drugs, marking the second time in roughly two years that a big pharma has licensed the technology.

Despite the potential of LNAs as microRNA antagonists, however, Wyeth has no immediate plans to use the technology against the small, non-coding RNAs, a company official told RNAi News this week.

Under the terms of the three-year deal, Wyeth will select up to 10 targets against which Santaris will create LNA-based drug candidates.

In exchange, Santaris will receive an upfront payment of $7 million, as well as a $10 million equity investment by Wyeth. Santaris also stands to receive milestones of up to $83 million for each drug developed through the alliance, plus royalties on worldwide sales.

Wyeth, which has the right to extend the agreement for an additional two years, will be responsible for all development and commercialization activities. Additional terms were not disclosed.

LNAs 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 — features designed to increase the molecules' affinity and stability. Santaris holds the exclusive, worldwide rights to LNA for therapeutic applications.

Already, the molecules have become some of the most promising for therapeutically targeting miRNAs, and last May Santaris announced that it had advanced its first LNA-based miRNA drug, the hepatitis C treatment SPC3649, into phase I testing (see RNAi News, 5/29/2008).

But for Wyeth, the miRNA field is simply too new for it to jump into — at least for now.

According to Bob Abraham, vice president of oncology discovery research at Wyeth, the company plans to initially take an antisense approach, using LNAs to directly target messenger RNAs.

"MicroRNAs are incredibly intriguing in human disease … [for] diagnostics, as well as potential therapeutics," he told RNAi News this week. Still, "right now … we're somewhat sitting on the sidelines with respect to microRNAs and [the LNA] technology."

Abraham said that the main driver behind this decision is the fact that miRNAs have shown to regulate multiple genes, raising the specter of off-target effects. Further complicating things is research suggesting that miRNAs may be responsible for regulating up to one-third of all human genes (see RNAi News, 1/21/2005).

"The microRNA-targeted therapy [space] is very promising," he noted. Yet, "given the fact that this whole field is young in terms of designing therapeutics that work in vivo, getting them to the tissue of interest, and so forth … we felt that the additional complexity of trying to go after a microRNA with potential multi-targeting activity was biting off a little more than we wanted to chew at this stage."

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Instead, Wyeth plans to apply the LNA technology to an area where the path to market appears shorter and more straightforward.

"This [LNA] platform, in general, brings in a whole slew of targets that were previously considered undruggable," he added. "This made us think that if we took genes that are extremely well-characterized in cancer but previously considered to be undruggable, our chances of a proof-of-concept drug coming out in a timely fashion would be better than [by] targeting a microRNA."

Still, the big pharma has not turned its back on the miRNA field.

Abraham stressed that the arrangement with Santaris does not preclude Wyeth from selecting an miRNA as one or more of the ten targets covered under the arrangement.

"As the [technological] obstacles are overcome, microRNAs [become] very appealing targets," he said. And although Wyeth is "taking a wait-and-see attitude [to miRNA-targeting therapeutics] in one sense … in another [sense] we're following this field very closely.

"If druggability proves to be feasible, we'll be all over microRNAs," he added.

Keeping Options Open

Santaris' deal with Wyeth follows a similar arrangement signed in 2007 with GlaxoSmithKline, under which the companies agreed to discover, develop, and market LNA-based drugs for viral diseases (see RNAi News, 12/20/2007).

As with the Wyeth alliance, the GlaxoSmithKline partnership did not expressly cover miRNAs, a Santaris official told RNAi News at the time. But also like Wyeth, GlaxoSmithKline left the door open to the possibility that it may add miRNAs to the mix.

Specifically, GlaxoSmithKline was granted the option to develop and commercialize SPC3649, which targets miR-122, the most abundantly expressed miRNA in the liver and one that appears to play a role in cholesterol regulation, lipid metabolism, and HCV replication.

A spokesman for Santaris told RNAi News this week that the company is "not able to give an update on the status [of the SPC3649] at the present time." Officials from GlaxoSmithKline were not available for comment by press time.

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