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Santaris Releases Phase II Data Showing Its HCV Drug Is Well Tolerated, Effective

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By Doug Macron

Santaris Pharma this week released new data from an ongoing phase IIa study of its microRNA-targeting hepatitis C treatment miravirsen, showing that the drug is well tolerated and can trigger “continuous and prolonged” antiviral activity that extends beyond the time of active treatment.

As previously reported by Gene Silencing News, the company hopes the findings, which are slated for formal presentation at next month's American Association for the Study of Liver Diseases meeting, will attract a bigger partner that can help Santaris move miravirsen through to commercialization.

Miravirsen is a locked nucleic acid-modified phosphorothioate antisense oligo that targets miR-122, a liver-expressed miRNA shown to play a role in HCV replication, cholesterol regulation, and lipid metabolism. The drug has already been tested in two phase I trials, and in both cases led to “dose-dependent, long-lasting reductions” in cholesterol similar to what it showed in preclinical models, a company official said last year.

With those data in hand, Santaris last year moved miravirsen into phase II testing (GSN 9/23/2010). The ongoing study is designed to evaluate weekly doses of the drug at either 3 mg/kg, 5 mg/kg, or 7 mg/kg administered over 29 days via subcutaneous injection in treatment-naive chronic HCV patients.

Patients in the lowest-dose cohort are evaluated after three weeks, and patients in the other two cohorts are evaluated after six weeks, at which point a physician may also begin treating them with standard interferon therapy.

According to the phase IIa data, patients in the first two cohorts, 18 of whom received miravirsen and six of whom received a placebo, have completed the trial. No serious adverse events were observed, and side effects included headache, coryza, and diarrhea, though they were “infrequent and mild.”

Meantime, there were no clinically significant changes in laboratory test results, vital signs, or electrocardiograms. Biomarker signals of miR-122 inhibition were also observed, including decreases in cholesterol, apolipoproteins A and B, and increases in alkaline phosphatase.

Importantly, miR-122 treatment was associated with dose-dependent, prolonged reductions in HCV RNA, Santaris said in the abstract for its upcoming AASLD presentation. These reductions continued even after the completion of miravirsen therapy.

For instance, in the 5 mg/kg dose group, the mean maximum change from baseline in HCV RNA over the first ten weeks was -2.710 log10 IU/mL among miravirsen-treated patients compared with -0.152 log10 IU/mL for those receiving placebo, according to the abstract. Five patients in this cohort had a 2-log or greater decrease from baseline to week 10, and one patient's levels of HCV RNA were undetectable at 10 weeks after receiving the final dose of the drug, even without the addition of interferon.

Based on these data, miravirsen “has the potential to be a once-weekly treatment of chronic HCV infection,” Santaris said in the abstract.

Still, it is unlikely that that company will pursue development of the drug as a single-agent therapy.

Santaris CSO Henrik Orum told Gene Silencing News this week that “given its unique combination of subtype-independent potency, long-lasting effect and very high resistance to viral breakthrough, we believe miravirsen could be the centerpiece in a interferon-free cure for HCV. Accordingly, combination studies with [direct-acting antivirals] are the next likely studies we will undertake.”

Last month, Orum said that “for competitive reasons, this drug is best served by finding a big partner,” adding that discussions are ongoing with undisclosed parties. This week, he confirmed that talks are continuing, but said that Santaris has “the means to conduct [additional clinical trials] ourselves if required.”

Muddled IP Landscape

Complicating matters, however, is an uncertain intellectual property landscape surrounding miR-122 and HCV.

Regulus Therapeutics is also developing an HCV treatment that targets the miRNA, and has long touted its access to related IP including patents and applications licensed from Stanford University and the Max Planck Institute. The company has publicly stated that it believes these pieces of IP are required for treating HCV by inhibiting miR-122.

Tellingly, Santaris partner GlaxoSmithKline had once held an option to in-license miravirsen, but ultimately let it expire (GSN 12/3/2009). The big pharma later partnered with Regulus on its HCV program (GSN 2/25/2010).

Other hints that miravirsen might face IP problems can be found in a lawsuit Santaris filed in a Danish court against startup Mirrx Therapeutics, which is developing an miRNA-inhibition technology called Blockmirs.

According to legal filings obtained by Gene Silencing News, Mirrx charges that Santaris is using litigation to obtain access to the Blockmir technology as an alternative approach to inhibiting miR-122 since miravirsen is “blocked by a patent held by … Regulus.”

For its part, Santaris maintains that Blockmirs were developed using its trade secrets.


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