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Regulus Continues to Aim for Two INDs in 2014, Expects miRNA Biomarker Data in Q3

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Officials from Regulus Therapeutics this week said that the company continues to plan on filing two investigational new drug applications in 2014, one of which is for a microRNA-122-targeting hepatitis C treatment, but fell short of promising the goal would be met.

The comments, which were made during a conference call held to discuss Regulus' fourth-quarter financial results, contrast with those made by the executives in November, when they said they would nominate two clinical candidates before the end of 2013 and file two INDs the following year.

Meanwhile, Regulus' collaboration with Biogen Idec to identify blood-borne miRNA biomarkers of multiple sclerosis is poised to yield data by the third quarter of this year, Regulus President and CEO Kleanthis Xanthopoulos said during the call.

The milestone would set the stage for an extension of the arrangement, which was forged in August, he noted, and help validate the use of miRNAs as biomarkers for selecting patient populations for clinical trials and developing companion diagnostics, and as indicators of disease progression or relapse.

Despite the promising advances with the miRNA biomarker work, Regulus' core focus remains on therapeutic miRNA antagonists, and its miR-122 program remains at the head of the company's pipeline.

The miRNA has been established as key to the HCV lifecycle for some time, with researchers from the University of North Carolina reporting in 2005 that it facilitates viral replication, and, more recently, that it slows the decay of HCV RNA by recruiting the Argonaute 2 protein to its 5' UTR. Late last year, the same team published data describing the degradation pathways against which the miRNA protects the virus (GSN 12/20/2012).

Such data caught the eye of Santaris Pharma, which has its own miR-122 inhibitor, miravirsen, in phase II development (GSN 4/26/2012), as well as Regulus, which is working on its compound in collaboration with GlaxoSmithKline (GSN 2/25/2010).

According to Regulus CSO Neil Gibson, preclinical data indicates that the company's HCV agent is pan-genotypic and “shows activity against some of the known mutations that lead to resistance to the current oral HCV therapies in development.

“In addition, we have shown in rodent models that our lead candidate has a rapid onset of action and target gene derepression was sustained for longer than 28 days after a single subcutaneous dose,” he said during this week's call.

Gibson conceded that the market for HCV treatments continues to evolve, with a variety of new drugs under development, but said that Regulus sees “a clear market opportunity” for its candidate in niche populations including “difficult-to-treat patients, those who may have failed current therapies, or in combination with other anti-HCV agents.”

Xanthopoulos added that Regulus expects its drug's once-a-month dosing regimen would improve patient compliance since treatment could be administered during regularly scheduled monthly visits to health care providers, when viral load measurements are typically taken.

Gibson said that an HCV clinical candidate will be nominated in the first half of the year, with an IND in 2014. He also said that Regulus is in talks with a clinical contract research organization about the design of a phase I trial to determine “how quickly we can transition from healthy volunteers to HCV-infected patients.

“Depending on whether we do [a study] in Europe or the US, we could get into HCV-infected patients relatively quickly,” he added, and could “start to see clinical proof of concept towards the end of 2014.”

Meanwhile, Regulus continues to work on earlier-stage programs, including one targeting miR-21 for kidney fibrosis and, potentially, oncology, and another taking aim at miR-33 for atherosclerosis and metabolic disease.

Either one of these efforts could yield the company's next IND, Gibson said, although it is not entirely certain whether that filing would occur in 2014 as previously predicted.

Historically, it takes around 12 months from “selecting your clinical candidate to the filing of the IND,” he said during the conference call. “With our first effort in [miR-122], we're trying very hard to meet those types of timelines, and whatever we do with that first program will smooth the way for the filing of the second IND.

“If we can get the selection of the second clinical candidate early in the second half of [this] year, that would certainly position us to be in a strong position to file that second IND before the end of 2014,” Gibson continued. “If that [selection] happens later, towards the end of 2013 … we can still make that [goal], but we'd have a slightly higher level of risk.”

The Fourth Quarter Financials

For the three-month period ended Dec. 31, 2012, Regulus posted a jump in its net loss to $6.9 million from $2 million in the same period a year earlier.

The higher loss was in part due to non-cash charges from a $1.7 million loss on the extinguishment of debt associated with an amended and restated $5 million convertible promissory note originally issued to GlaxoSmithKline in 2010.

Revenues in the quarter slipped slightly to $3.2 million from $3.4 million, and consisted primarily of the amortization of up-front payments from collaborators.

Research and development spending rose to $5.6 million from $4.5 million, reflecting costs associated with strategic alliances and in-house programs, while general and administrative expenses climbed to $1.9 million from $800,000 as a result of Regulus' initial public offering in October (GSN 10/4/2012).

At the end of 2012, Regulus had cash, cash equivalents, and short-term investments totaling $98.1 million, which is expected to fund operations into 2016 and leave the company with at least $60 million in the bank at the end of this year.

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