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In 2011, miRNAs Move Beyond 'Scientific Curiosity' as Big Pharma Externalizes Oligo Drug Development


By Doug Macron

Amid an ever-growing body of evidence linking microRNAs to various biological functions and disease states, as well as new human data suggesting their therapeutic potential, advances with the non-coding RNAs proved to be the most notable milestone of 2011, according to industry watchers.

Meanwhile, over the past year the RNAi field saw big pharma adjust its stance to the gene-silencing technology and return to the more familiar approach of allowing small biotechs to handle early-stage research and development before taking an active role.

According to City of Hope researcher John Rossi, “microRNAs are turning out to be incredibly interesting biologically,” with roles that extend far beyond what may have initially been thought. For example, he pointed to a paper published by a team at Aarhus University showing for the first time that miRNAs can regulate gene expression by targeting non-coding antisense transcripts in human cells.

“That's a totally novel pathway for RNAi,” Rossi said, adding that he expects additional roles for miRNAs, ones that “are going to surprise us,” to be uncovered in the future.

Art Krieg, formerly the head of Pfizer's oligonucleotide therapeutics unit and currently an entrepreneur in residence at Atlas Venture, voiced similar sentiments.

Over 2011, he told Gene Silencing News, the field saw miRNAs move from “a scientific curiosity to something real,” with a “dramatic change in the perceptions of microRNAs as a therapeutic opportunity.”

Perhaps the biggest contributing factor to this change was the release of human data on Santaris Pharma's hepatitis C treatment miravirsen, a locked nucleic acid-modified phosphorothioate antisense oligo that targets miR-122. In a phase II trial, the drug was not only well tolerated, but triggered dose-dependent, prolonged reductions in HCV RNA (GSN 10/6/2011).

“I had thought that if you got a half-log reduction with an antisense approach, that would be pretty good — it's hard to get a 90 percent reduction in a target normally with antisense, even in the liver,” Krieg said. “Yet, the Santaris data [show a] … close to 3-log reduction in viral RNA. That's just incredible … [and] shows the power of targeting microRNAs in a way that should convince any skeptic.”

And Santaris was not alone in generating compelling miRNA data, he noted.

Miragen Therapeutics and collaborators at the University of Texas Southwestern Medical Center have conducted very encouraging research on therapeutically targeting miRNAs in the heart — work that helped the company land a major partnership with French pharmaceutical firm Les Laboratoires Servier (GSN 10/20/2011).

“This is particularly noteworthy because over the last decade or two of antisense development, the dogma had been that antisense oligos don't get into the heart and don't have biologic activity there,” Kreig said. “And yet, in the last year, we've seen data from multiple different groups that in disease settings, the functional activity of oligonucleotides in the heart is very real.”

But the impact miRNAs have had on changing the scientific community's way of thinking over the past year goes still deeper, according to Miragen President and CEO Bill Marshall.

“We want to be dogmatic, we want to find rules that fit,” he said. “We gain comfort from those rules.” And yet, miRNAs have helped show that “there is a whole lot more out there. Think about non-coding RNAs — how many years ago was it that this was all junk?”

During 2011, he said, there was a growing recognition that although “we tend to want to think about these things as all being alike … we have to think about the molecules [whether they be miRNA antagonists or siRNAs] as individual molecular structures that have very different properties … even if they don't change that much in structure.

“That recognition alone is really going to help the field,” he said.

Despite miRNAs' promise as drug targets, however, caution is still recommended, in large part because of the sheer number of targets these ncRNAs have.

Using miR-122 as an example, Rossi noted that the miRNA plays “a very important role in the liver. If you start knocking it down, you … may control HCV replication, but at the same time trigger enough dysregulation of genes in the liver that you end up getting other nasty side effects.

“How many targets does miR-122 have?” he asked. “I don't think anybody knows.”

Ultimately, highly selective delivery of both antagonists and mimics will be required for miRNAs to achieve their full therapeutic potential, Rossi said.

“If we start delivering [miRNA inhibitors] systemically all over the body, it's going to be like any other chemotherapy,” he warned. “Although it is targeting a selective target, if it is not targeting it in the right compartment, it's going to be potentially very toxic.”

To Krieg, “both the blessing and the curse of microRNAs [is] the fact that [they] affect so many different genes.

“It's not a highly specific approach,” he said. “That goes in the face of a lot of other trends in biology and drug discovery, where people were focused on the identification of a specific target.”

And yet, he remains optimistic. “When we look at the universe of drugs that have been successful in the clinic, many of the best drugs have actually affected multiple different targets,” he said. “I think that the microRNA space could be the extreme example of that.”

Course Correction

In late 2010/early 2011, the RNAi field was shaken by the decisions of two major pharmaceutical firms — Roche and Pfizer — to end their in-house development of nucleic acids medicines, each shuttering a number of research sites and eliminating thousands of jobs (GSN 11/18/2010 & 2/3/2011).

Many viewed the moves, along with Novartis' late 2010 decision not to exercise an option to Alnylam Pharmaceuticals' RNAi intellectual property and technologies (GSN 9/30/2010), as an indication that RNAi lacks potential as a therapeutic modality — a viewpoint that affected many RNAi drug shops' efforts at partnering and fundraising.

But to Marshall, there is more behind these developments than meets the eye.

“There is an enormous amount of pressure with patent expiration, regulatory pressures, and the general healthcare landscape that is causing these companies to think very carefully about their balance sheets and how they are going to spend money,” he explained. “This inherently drives them towards later-stage assets.”

Indeed, big pharma has traditionally relied on smaller companies to develop and de-risk novel technologies, oftentimes through late-stage clinical trials, before getting their toes wet. In the cases of both Roche and Pfizer, both pulled back on their internal development of RNAi drugs, but have said that they continue to maintain an interest in the field as smaller companies advance the gene-silencing technology.

A recent example of this return to externalization of R&D can be seen in Pfizer's December acquisition of antisense drug developer Excaliard Pharmaceuticals less than a year after it ended its internal oligo drugs activities.

“I don't think any of the things that occurred [among big pharmas] were a reflection that [RNAi] doesn't have legs or potential,” Marshall noted. “It's just a recognition that should have been there from the beginning that it needs longer to develop.”

To Krieg, no one should expect that “all of a sudden RNAi becomes a huge success that is going to demonstrate all of the potential in all areas that people hoped it would have. Rather, it's going to be a series of small advances.

“I would use as an analogy [of] … the monoclonal antibody field,” he said. “In the early days, everyone was using murine antibodies, then started using humanized antibodies, and then fully human antibodies. Then, antibodies that are fragments, and all kinds of new designs and innovations” occured.

“It wasn't a single enormous success in the development of monoclonal antibodies that made them the platform they are today,” Krieg noted. “It was a series of innovations from multiple companies, multiple academic groups … that gradually brought that field to enormous commercial success. What we're seeing in oligonucleotide therapeutics is very similar.”

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