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Regulus Stock Surges on Positive Phase I HCV Data; Phase II on Deck for 2015

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NEW YORK (GenomeWeb) — Regulus Therapeutics this week released interim results from an ongoing Phase I study of its microRNA-targeting hepatitis C therapy RG-101, which showed that a single subcutaneous dose of the drug could trigger an average 4.1-log reduction in viral loads in patients — a number on par with current treatments.

On the better-than-expected data, shares of Regulus rocketed up more than 115 percent, hitting $14.60 during Wednesday afternoon trading on the Nasdaq.

Speaking during a conference call held to discuss the data, Regulus President and CEO Kleanthis Xanthopoulos said RG-101 has the potential to disrupt the existing market for HCV treatments, particularly given its potential for a once-a-month dosing regimen. Recently approved therapies such as Gilead Sciences' Sovaldi (sofosbuvir) and Janssen's Olysio (simeprevir), in contrast, are pills taken once a day for between one and three months.

He added that Regulus is aiming to file an investigational new drug application with the US Food and Drug Administration for RG-101 in the first quarter of 2015, which would allow the company to start a Phase II study combining its drug with an approved direct-acting antiviral (DAA) in HCV patients. The Phase I trial is being conducted in the Netherlands.

RG-101 is an antagonist of miR-122, the most abundant miRNA in the liver and one that has been show to play a key role in HCV replication and infection. The Phase I trial comprises four stages, with the first three examining single and multiple doses of the drug, as well as single doses in combination with the approved oral direct-acting antiviral agent Olysio.

The fourth arm of the study, which was reported on this week, tested single doses of RG-101 ranging from 2 mg/kg, 4 mg/kg, and 8 mg/kg in a variety of HCV patients including ones with genotypes 1, 3, and 4, as well as treatment-naive patients and ones who have experienced viral relapse after receiving interferon-containing treatments.

All 14 patients in the 2-mg/kg-dose group who received treatment experienced a virological response, with a mean 4.1-log viral load reduction at day 29. The range of viral load reductions among these patients was 5.8 log to 2.3 log.

Further, six of the patients had HCV RNA levels fall below the limit of quantification by day 29, with three patients from this group still experiencing these undetectable levels at day 57. Patient response to treatment was rapid, Regulus noted, with viral load reductions occurring within the first 96 hours after treatment.

Xanthopoulos said during the call that Regulus has amended the Phase I study's protocol so that patients can be followed up to six months after dosing, rather than the one month that the trial's design originally called for, to examine whether a single dose of RG-101 can achieve a viral cure. He noted that data from the 4-mg/kg cohort is expected to be released early next year, with 8-mg/kg-dose group data coming later in 2015.

Thus far, there have been no serious adverse events reported in any of the study arms, and no drug-drug interactions observed in those receiving RG-101 and Olysio. As such, Regulus expects it will receive FDA approval on its IND in time to begin the Phase II combination study by the second quarter of 2015.

Getting to market

In early 2008, Regulus inked a deal to collaborate with GlaxoSmithKline to co-develop miRNA-targeting drugs for inflammatory diseases. Two years later, the companies signed another deal, partnering on miR-122 inhibitors including RG-101.

By 2013, however, the alliance started to break down, with GlaxoSmithKline backing away from RG-101 but still interested in other miR-122 agents. During this week's call, Xanthopoulos disclosed that its relationship with GlaxoSmithKline has now "come to its natural conclusion" after the big pharma decided that the partnership did not fit in with its "overall research priorities."

Regulus continues to have full ownership of RG-101, and now has reacquired all other targets and compounds that were part of the arrangement, he said.

Although Regulus has known for over a year that it lost its partner for RG-101, Xanthopoulos said that the company's plans for taking the drug to the market are still up in the air given the "extraordinary results" in the Phase I study.

"We're currently [working] very intensively to develop a plan that moves [RG-101] forward in combination with direct-acting antivirals for a variety of patients," he said. "Those plans will be finalized over the next few months."

The competition

When Regulus first disclosed it was pursuing HCV through its collaboration with GlaxoSmithKline, the company immediately put itself in competition with Santaris Pharma, which already had its own miR-122 inhibitor for the disease, miravirsen, in Phase I testing.

But based on this week's data, it appears that Regulus has an edge over its rival.

Although Santaris announced the completion of enrollment in its second Phase II trial of miravirsen a little over a year ago, the most advanced human data the company has released on the drug is from the initial Phase II study that was completed in 2011.

In that trial, treatment-naive genotype 1 HCV patients received weekly doses of miravirsen at doses of 3 mg/kg, 5 mg/kg, or 7 mg/kg over 29 days, and were then followed for 14 weeks. While there were no serious adverse events reported, the company achieved a maximum of a 2.73-log reduction in HCV RNA levels at the highest dose tested.

This, Xanthopoulos said, was "nowhere close to what we've seen" with RG-101, and required weekly injections compared with the single monthly dose that Regulus reported on this week. Further, optimal HCV RNA reductions with miravirsen took weeks to reach, significantly longer than RG-101's onset of action.

During this week's conference call, Regulus CSO Neil Gibson chalked up RG-101's rapid effect to its use of the GalNAc conjugate delivery technology Regulus has licensed from former parent firm Alnylam Pharmaceuticals.

"We know from preclinical studies that when you compare the non-conjugated oligonucleotide with the conjugated oligonucleotide, you can get more efficient delivery into hepatocytes," Gibson explained. "So the ability to load the hepatocyte and get active drug into the cytoplasm to target the microRNA is much more efficient with GalNAc conjugates."

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