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Santaris Pharma to Begin Phase II Development of miRNA-Targeting HCV Drug

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By Doug Macron

Santaris Pharma said this week that it has been cleared by the US Food and Drug Administration to advance its microRNA-targeting hepatitis C drug miravirsen into phase II testing.

But while the company remains optimistic about the drug's potential, questions remain as to whether Santaris has the intellectual property necessary to bring it to market.

According to Santaris, the planned phase IIa study will be a randomized, double-blind, placebo-controlled, ascending multiple-dose trial designed to assess the safety and tolerability of miravirsen as subcutaneous injections administered weekly or every other week for four weeks.

The study is expected to enroll up to 55 treatment-naive patients with chronic hepatitis C virus genotype 1 infection. Secondary endpoints include pharmacokinetics of miravirsen and its effect on viral load.

"We are extremely pleased with the results of the phase I trials and excited to progress miravirsen into phase II clinical trials," Santaris CSO Henrik Orum said in a statement. "Because of its unique mechanism of action and tolerability profile, miravirsen has the potential to be an effective treatment option for patients with HCV."

The drug, formerly known as SPC3649, is a locked nucleic acid targeting miR-122, a liver-expressed miRNA shown to play a role in HCV replication, cholesterol regulation, and lipid metabolism. In mid-2008, it became the first miRNA-targeting drug to enter human testing with a phase I study (GSN 5/29/2008).

In that trial, 64 healthy volunteers initially received single doses of the drug up to 6.4 mg/kg. The study's protocols were later amended to include 9 mg/kg and 12 mg/kg doses. No significant adverse events were observed, and Santaris said it saw evidence of a pharmacological effect as measured by reductions in serum cholesterol.

Santaris recently completed a second phase I study examining multiple doses of miravirsen, but has yet to publicly release the data. But Orum told Gene Silencing News earlier this year that the company was "happy with the results" and had been planning to move the drug into phase II trials (GSN 4/29/2010).

Both phase I studies were conducted in Denmark.

Non-human primate data on miravirsen were also recently published. In December, company researchers reported in Science that intravenous administration of the agent could silence its target microRNA in chimpanzees infected with the virus without triggering resistance or adverse effects (GSN 12/3/2009).

"Receiving [investigational new drug application] acceptance from the FDA to conduct the first clinical trials with a microRNA-targeted drug in the United States brings Santaris Pharma one step closer to potentially providing a growing number of patients chronically infected with HCV with a more effective and better tolerated treatment option," Arthur Levin, chief development officer and president of Santaris' US operations, added in a statement.

But miravirsen's path toward the market may not be straightforward as questions linger about the IP needed to commercialize an HCV drug targeting miR-122.

Santaris rival Regulus Therapeutics currently holds the exclusive rights to US patent families related to miR-122, and is developing its own HCV drug that targets the small, non-coding RNA.

According to Regulus, its IP claims methods of use of anti-miR-122 to inhibit HCV replication, the use of miRNA antagonists targeting miR-122 as inhibitory agents, and compositions of matter for miR-122 and complementary oligonucleotides.

Tellingly, GlaxoSmithKline held an option to miravirsen as part of a broader alliance with Santaris, but let it expire and shortly thereafter partnered with Regulus on its HCV drug (GSN 2/25/2010).

In addition, Santaris recently sued Mirrx Pharma over a miRNA-inhibition technology dubbed Blockmirs (GSN 5/6/2010). Santaris charges that the technology is based on its own inventions, but Mirrx has countered that Santaris is simply trying to gain control of the Blockmir technology because it would provide a workaround to the IP controlled by Regulus.

In an e-mail to Gene Silencing News, Levin said that Santaris "believes that it has freedom to operate with its miR-122 targeting compound miravirsen for the treatment of hepatitis C.

Santaris "does not speculate on [other companies'] intellectual property positions," he added, noting that the company has "freedom to operate and substantive intellectual property coverage that includes ownership of patent families which cover the LNA chemistry, manufacturing, therapeutic uses in patients and animals, and optimal drug designs and drug formats.”

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