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With Positive Phase II Data on HCV Drug, Santaris Aims for Another Clinical Trial by the Summer

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Having just released phase IIa data demonstrating the antiviral activity of its microRNA-targeting hepatitis C treatment miravirsen, Santaris Pharma is preparing to begin within a few months another phase II study that will examine the drug in combination with direct-acting antiviral agents, a company official said.

“Miravirsen is certainly doing what it says on the bottle … [demonstrating] a high barrier to resistance [with] good saturation and distribution within the liver,” Santaris CMO Michael Hodges told Gene Silencing News this week.

“We're very confident that miravirsen will be able to prevent resistant virus from spinning off and infecting the uninfected hepatocytes when we give it in combination with a DAA,” he said.

Miravirsen is 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).

In the five-week phase IIa trial, treatment-naive patients with HCV genotype 1 received once-weekly subcutaneous doses of the drug at 3, 5, or 7 mg/kg. The mean of the maximum decline from baseline in HCV RNA for the 5 mg/kg group was 2.9, and was 1.2 for those receiving the lowest dose.

Notably, four out of nine patients in the highest dose cohort became HCV RNA undetectable after the five-week treatment regimen. Hodges noted that a clinician participating in the study suggested one patient, in which the viral remains undetectable “many weeks after the last treatment,” may have been cured.

“Of course, it is a little bit premature to go all the way and talk about cures,” he cautioned.

Meantime, Santaris conducted HCV genome sequencing through the trial and did not observe any nucleotide changes that would be indicative of genotypic resistance, Hodges said.

Given this apparent high barrier to resistance, Santaris views miravirsen as “ideally suited to be combined with a DAA,” he said, which is precisely what the company aims to prove in the upcoming study.

“Our drug takes a few weeks to work,” but once it does, “you get very prolonged antiviral activity,” Hodges explained. DAAs, meanwhile, “work very quickly, with a three- to four-log drop” in viral load, but the virus soon rebounds with resistant strains.

By combining the agents, Santaris expects it can address both issues.

“The DAA does the heavy lifting [and] knocks down the virus,” he said, while miravirsen will prevent resistant-associated variants from “spinning off and infecting the uninfected hepatocytes.

“Miravirsen will be able to fully saturate within the liver and sequester miR-122, which is critical for the virus to take hold in the uninfected cells,” he noted. “So even if there were any resistant virus present when the DAA was given, it's got nowhere to go to — it can't get into the cells.”

Whether miravirsen will actually work in this fashion remains to be seen, so Santaris is putting the final touches on the protocols for a planned phase II study that will examine its drug in combination with either one or two DAAs over a three-month period.

“It's been very well tolerated over five doses, [and] there is nothing in our database or animal toxicology studies that would show it would be unsafe over 12 weeks,” Hodges said of miravirsen. “But, of course, we have to demonstrate this.”

The miR-122 inhibitor has thus far proven to be safe and well tolerated, and although combining drugs can often trigger adverse reactions, Hodges doesn't expect this to be the case with miravirsen.

“It's important to note that all these DAAs, just like in an HIV treatment, are very difficult to combine with one another because of the drug-drug interactions that occur by them all being metabolized by the P450 enzyme system,” he said. “Miravirsen is devoid of this. It does not need the P450 system to metabolize, so we should be able to freely give miravirsen without any … contraindications to other DAAs.

“It's almost like an ideal partner of choice” for existing antivirals, he said.

The exact design of the upcoming trial has yet to be finalized, but Hodges said that it is expected to test the drug cocktail in patients with both subtypes of HCV genotype 1 who have not responded to first-line treatment.

“In the future, once we have experience with treatment failures and have shown that miravirsen does what it says on the side of the bottle [and] can get a high cure rate … then there are opportunities to go into the treatment-naive patient population,” he added.

Santaris also plans to treat patients in the next study with a 7 mg/kg dose of miravirsen, the highest tested in the now-completed phase IIa trial, given its antiviral activity and safety, he said.

“Some of our advisors have said that [the drug] has been so safe, you can go higher,” Hodges noted. But “miravirsen's role in this will be preventing the resistance from occurring, so we think that one or two DAAs combined with [7 mg/kg of] miravirsen should be able to effect a cure across all … genotypes.”

Later on, Santaris may actually want to examine lower doses, which could prove to be more effective with a low viral load, he added.

“I don't think miravirsen needs to get a three-log drop to do its business; it's got such a high barrier to resistance and it's easy to combine with DAAs, I think it can do its job with a lesser viral load drop,” he said.

“But hey, I'll take a bigger viral load drop if I can get it.”

The planned phase II trial is expected to start by the summer.

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