By Doug Macron
On the heels of promising phase II data on its microRNA-122-targeting hepatitis C treatment miravirsen, Santaris Pharma is making plans for a second phase II trial — possibly to begin this year — that will examine the drug in combination with an existing direct-acting antiviral agent, company officials told Gene Silencing News this week.
And while questions linger over whether miravirsen infringes intellectual property controlled by rival Regulus Therapeutics, Santaris remains “comfortable” with its patent position for its compound, CSO Henrik Orum said.
Notably, Santaris has also filed an opposition to one of Regulus's key miR-122 patents with the European Patent Office.
Miravirsen is a a locked nucleic acid-modified phosphorothioate antisense oligo that inhibits miR-122, a liver-expressed miRNA shown to play a role in HCV replication. Recently, independent researchers demonstrated that the virus binds to the miRNA in association with the Argonaute 2 protein, which helps it maintain infection by slowing the decay of its genome in infected cells (GSN 1/5/2012).
Late last year, Santaris released data from a phase II trial that showed the drug was well tolerated and triggered “continuous and prolonged” antiviral activity that extends beyond the time of active treatment in treatment-naive HCV patients.
Specifically, patients received weekly doses of the drug at either 3 mg/kg, 5 mg/kg, or 7 mg/kg administered over 29 days via subcutaneous injection. Of the nine patients treated at the highest dose, four became HCV RNA undetectable during the study. Additionally, the therapy resulted in a mean reduction of 2 to 3 logs from baseline RNA levels, which was maintained for more than four weeks after the end of treatment.
“We're really pleased” with the outcome of the study, Orum said this week.
The clinical results, along with data from preclinical animal studies, suggest that miravirsen “could become the centerpiece of a [once-monthly] HCV treatment … and that it may do so by being combined with as little as a single DAA,” he said.
“It has a unique barrier to resistance … [and] is a true pan-genotypic compound” that can attack all of the different genotypes of HCV since its target is exploited by all forms of the virus, he added.
As such, Santaris expects to run a second phase II trial of miravirsen, Orum said. The exact nature of the study is still being worked out, but he said that it may have two arms, one continuing to examine the drug as a monotherapy and another testing it in combination with a selected DAA.
He also said that Santaris is still deciding on the best patient population for the upcoming trial, noting that while the drug is expected to ultimately be positioned as a therapy for HCV genotype 1, the most common form of the disease in the US, it may initially be commercialized in sub-markets. These could include patients with other genotypes, patients co-infected with HCV and HIV, and those who relapse or don't respond to the standard of care.
Santaris CFO Henrik Stage said that the company expects to finalize the next steps in its clinical strategy for miravirsen “in the first half of this year and, hopefully, be able to have top-line results [from the next trial] in the course of this year” or in early 2013.
Like just about every other small biotech, Santaris is also hoping to score a partnership with a bigger player, and Orum said that discussions are underway amid “quite of a lot of interest from third parties.” Still, the company isn't pinning all its hopes on an industry alliance, especially since a potential deal with GlaxoSmithKline failed to materialize when the British big pharma let an option to miravirsen expire and instead chose to work with Regulus on a miR-122-targeting HCV treatment in early 2010 (GSN 2/25/2010).
“We are prepared to advance [miravirsen] into additional phase II clinical trials ourselves,” Stage said. “We are looking to partner it, [but] whether it becomes something that we do now or at the end of the next studies is not clear at this point.”
Though GlaxoSmithKline never commented directly on the decision to pass on miravirsen, some have speculated that the key factor may be Regulus's exclusive access to US and European patents and patent applications related to the use of miR-122 for treatment HCV. The centerpiece of Regulus's miR-122 IP portfolio is the so-called Sarnow patent estate, which includes two US patents — Nos. 7,307,067 and 7,838,504 — and one European patent — No. 1747023.
Regardless of what prompted GlaxoSmithKline to choose Regulus over Santaris, Orum said that his company has the freedom to operate when it comes to miravirsen. Still, the company appears to be hedging its bets and last year filed an opposition to the European Sarnow patent with the EPO.
According to documents filed with the patent office, Santaris claims the patent does not disclose “the alleged invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art;” that the invention claimed lacks novelty in light of prior art; and that the patent “amounts, at best, to a discovery and/or scientific theory.”
Regulus representatives were not available for comment.
As the wrangling over the European Sarnow patent progresses, there may be another IP showdown brewing between Santaris and Regulus.
Early last year, Santaris acquired from Massachusetts General Hospital certain IP related to the use of miR-33 as a target for cardiovascular diseases including hypercholesterolemia (GSN 3/3/2011). At the time, Orum told Gene Silencing News that the company had then added the miRNA target to its official drug-development pipeline.
Around that same time, Regulus announced that it had struck a deal acquiring the exclusive rights to IP related to methods of modulating miR-33a and miR-33b for metabolic diseases including atherosclerosis, and touted work with collaborators showing that dysregulation of the miRNA family members was associated with diseases such as dyslipidemia (GSN 3/31/2011).
Orum said this week that work developing LNA antagonists of miR-33 is progressing, but offered no timing on when a clinical candidate might be ready.
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