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Santaris Starts New Phase II Trial of HCV Drug, Plans Others Before Phase III

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Santaris Pharma this week announced that it has completed patient enrollment in a phase II trial of its microRNA-targeting hepatitis C treatment miravirsin, and that it has begun enrollment in a new phase II study of the drug.

The news comes just a few months after Santaris published the results of an earlier phase II study in the New England Journal of Medicine.

Despite the progress with miravirsin, the company is not yet making plans to move the compound into pivotal human trials, according to Santaris CMO Michael Hodges. "We're not jumping into phase III after these two ongoing studies," he said.

Such a move will require further dose-ranging work, he told Gene Silencing News, and potentially additional phase II studies testing miravirsin's activity in patients with HCV genotypes not examined in previous trials — "for example, genotype 3 and genotype 4, which historically have been hard to treat."

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. The subcutaneously administered drug is the first miRNA antagonist to enter human studies and is Santaris' most advanced product candidate.

In 2010, following the completion of phase I trials, including one that combined miravirsen with the direct-acting antiviral telaprevir, Santaris launched a phase IIa study examining multiple ascending doses of its drug — 3 mg/kg, 5 mg/kg, and 7 mg/kg — in 36 treatment-naive subjects with chronic HCV genotype 1 infection.

As reported earlier this year in NEJM, patients receiving the drug showed prolonged, dose-dependent reductions in HCV RNA levels with no dose-limited adverse events or escape mutations in the miR-122 binding sites of the virus' genome.

In 2012, the company initiated another phase II study, this one testing nine doses of miravirsen alone in 10 chronically infected HCV genotype 1 patients who had not responded to previous treatment with pegylated interferon alpha and ribavirin. Subjects in the trial receive five weekly doses at 7 mg/kg, then four biweekly doses at 5 mg/kg.

According to Hodges, Santaris has now completed enrollment in this study, putting the firm on track to release data as early as November at the American Association for the Study of Liver Diseases' annual Liver Meeting.

Should Santaris not have the data ready in time for this conference, it is aiming to present them at the European Association for the Study of the Liver's International Liver Congress in April 2014, he noted.

Hodges stressed that it is too soon to draw conclusions about the outcome of the ongoing trial, but said that thus far, "the results are looking encouraging."

Meanwhile, Santaris has just kicked off a third phase II trial that will enroll up to 20 chronically infected HCV genotype 1 patients who have failed previous treatment. In addition to telaprevir and ribavirin, study subjects will receive either five weekly doses of miravirsen at 7 mg/kg, followed by six biweekly doses at 5 mg/kg; or five weekly doses of the drug followed by three monthly doses, all at 7 mg/kg.

In addition to testing whether the drug cocktail can trigger a sustained virological response, a key measure of the new study will be whether miravirsen can help prevent viral resistance, Hodges said.

While Santaris believes that miravirsen could possibly be positioned as a monotherapy, the company's primary goal is to bring it to market as the "backbone" to salvage therapy, combining it with one or two other direct-acting antiviral agents in this hard-to-treat population.

He said that initial data from this study could also be available by next year's International Liver Congress, but added that Santaris isn't necessarily waiting until then before starting additional clinical trials for miravirsen.

However, the next few steps for the drug will not be in phase III, as Santaris still needs to gather additional phase II data, he cautioned.

Hodges hinted that the company may also be hoping to land a partnership with a bigger company before taking the plunge into pivotal studies.

"We believe the data from these two ongoing [phase II] studies would be enough to entice partners to the table for discussion," he said. "Whether that is enough for actually signing on the paper [to complete a deal] is yet to be seen."

At one point, Santaris had been close to inking an agreement for its HCV drug with GlaxoSmithKline, which had picked up an option to miravirsen as part of a broader collaboration to develop LNA-based antivirals (GSN 12/20/2007).

However, GlaxoSmithKline ultimately let the option expire, choosing instead to link up with Regulus Therapeutics, which is developing its own miR-122-target drugs for HCV (GSN 2/25/2010). Notably, Regulus recently announced that GlaxoSmithKline had passed on the first compound to come out of that effort, although the alliance remains in effect (GSN 5/16/2013).

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