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Santaris Reports Lower Q2 Losses on Lower Expenses, Data on Inflammatory Disease-Associated miRNA

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By Doug Macron

Santaris Pharma last week reported its second-quarter financial results, posting an almost 30 percent drop in its net loss for the three-month period amid a sharp decrease in research and development spending.

Meanwhile, this week, company researchers published data identifying miR-155, an miRNA involved in immune-system regulation, as a possible therapeutic target for chronic inflammatory diseases such as rheumatoid arthritis.

For the second quarter ended June 30, Santaris reported a decrease in its loss to DKK21.6 million ($4.1 million) from DKK29.8 million a year earlier.

Contributing to the decline was a 42 percent reduction in R&D costs, which fell to DKK28.7 million from DKK49.5 million, and a roughly 6 percent slip in administrative expenses, which dropped to DKK4.4 million from DKK4.7 million. Both decreases reflect the impact of a corporate reorganization initiated last year that included job cuts and a narrowing of the company's therapeutic focus to metabolic disorders and infectious disease.

Revenues in the quarter fell to DKK12.6 million from DKK23 million.

As of June 30, 2009, Santaris had cash and cash equivalents totaling DKK175.4 million, which the company said is expected to be sufficient to fund its operations beyond 2010.

Santaris added that it continues to expect to post a loss for 2009 in the range of DKK115 million and DKK125 million.

Separately, Santaris announced the advance online publication in Nucleic Acids Research of data detailing the in vivo and in vitro inhibition of miR-155 using the company's locked nucleic acid technology.

According to the paper, miR-155 is expressed on activated mature B and T lymphocytes, as well as in activated monocytes, "while studies using miR-155 knockout mice have directly linked this miRNA to functions of the immune system."

"In addition, miR-155 has been shown to regulate the production of cytokines, chemokines, and transcription factors, and to be induced by endotoxins, such as bacterial lipopolysaccharide," the paper states. Further, the miRNA has been shown to direct the generation of immunoglobulin class-switched plasma cells and to regulate activation-induced cytidine deaminase, which plays a role in antibody diversification.

"Altogether, these observations strongly imply miR-155 as a central regulator of the immune system," the paper's authors wrote.

To gain a better understanding of the miRNA's function during acute inflammatory response, the Santaris team treated cultured mouse macrophages and live mice with lipopolysaccharide, which has been shown to induce the transcription factor CCAAT/enhancer-binding protein-beta in monocytes and macrophages.

C/EBP-beta has also been implicated in the regulation of pro-inflammatory cytokines and other genes associated with macrophage activation and the acute phase response, they noted in Nucleic Acids Research.

The investigators found that exposure to lipopolysaccharide induced miR-155 expression in both the macrophages and in mouse splenocytes in vivo, and that treatment with a LNA targeting the miRNA led to de-repression of C/EBP beta in vitro and in vivo.

"Additionally, we find that antagonism of miR-155 leads to down-regulation of [granulocyte colony-stimulating factor], a regulator of granulopoiesis produced by activated macrophages during acute inflammatory responses," the research team noted.

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Previous studies have demonstrated that G-CSF is involved in inflammation and may contribute to the worsening of inflammatory diseases, the Santaris researchers wrote. Particularly, it appears to play a role in arthritis, with data showing that a G-CSF blockade can significantly reduce disease manifestations in mice.

At the same time, G-CSF has been shown to be elevated in the serum and synovial fluid of rheumatoid arthritis patients, and to correlate with disease severity.

But while G-CSF may be a potential target for inflammatory joint diseases, its down-regulation may lead to neutropenia, the authors caution.

"Thus, partial antagonism of endogenous G-CSF, as described in this study for LNA-antimir-mediated G-CSF down-regulation, might provide a positive outcome for arthritis patients without increased risk of severe neutropenia," they wrote.

Overall, in light of the importance of C/EBP-beta during macrophage activation and the role of G-CSF in stimulating granulopoiesis in bone marrow, "our data emphasize the potential of antagonizing miR-155 for modulating activation of macrophages and the number of circulating granulocytic cells with possible implications for treatment of inflammatory diseases," they concluded.

Still, it appears unlikely that this work will result in a full-fledged drug-development program for Santaris in the near term.

Currently, the company has just one miRNA-targeting drug in the clinic, the hepatitis C treatment SPC3649. A phase I, single-dose study of the agent in healthy volunteers was completed earlier this year, with data expected to be reported in the second half of 2009.

An investigational new drug application to start a second phase I trial of the drug, this time evaluating multiple doses in healthy volunteers, has been filed. That study is expected to begin before year end, according to Santaris.

And while the company remains interested in advancing other miRNA-antagonizing drugs, its only publicly disclosed effort in this area, which centers around unnamed oncogenic miRNAs, remains in the lead-discovery stage.

A Santaris spokeswoman confirmed in an e-mail this week that, in line with its new therapeutic focus, the company will not pursue development of miRNA-targeting drugs for cancer on its own, although it would consider doing so through collaborations.

Still, the company wants to maintain its strong position in the miRNA drugs space, she added, and therefore continues to "explore targets within cancer and inflammatory diseases."

In regard to its other in-house programs, Santaris has been focusing much of its attention on the use of LNAs to target mRNA. In its quarterly report, the company announced that its newest lead candidate, dubbed SPC4955, is designed to target apolipoprotein B mRNA and is advancing into preclinical testing. Clinical trials of the drug are expected to begin in early 2010.

Meanwhile, the company said that it has selected several lead LNA candidates targeting proprotein convertase subtilisin/kexin type 9, which is associated with cholesterol-level regulation, for pharmacological studies.

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