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Regulus Selects HCV Drug Candidate, Will Develop without Partner GSK

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Regulus Therapeutics this week announced that it has selected its first drug candidate, RG-101 for the treatment of hepatitis C. However, the company said it will develop the compound on its own despite an ongoing collaboration on the disease with GlaxoSmithKline.

Speaking during a conference call held to discuss Regulus’ first-quarter financial results, company officials also provided details about a new program in hepatocellular carcinoma.

RG-101 is an antagonist of miR-122, which has a well-established role in HCV infection. In 2005, it was shown that the miRNA is key to the virus’s lifecycle, and last year researchers from the University of North Carolina published data demonstrating how the miRNA slows the decay of HCV RNA.

That same team reported in late 2012 on additional functions of miR-122 that are viral for HCV replication (GSN 12/20/2012).

In 2008, Regulus and GSK began working together on miRNA-targeting drugs to treat inflammatory diseases (GSN 4/17/2008), and in 2010 expanded their alliance to include miR-122 for HCV (GSN 2/25/2010).

And while the partnership has now yielded a clinical candidate in RG-101, GSK has stepped back from the drug in order to let Regulus advance it on its own, according to Regulus President and CEO Kleanthis Xanthopoulos.

That said, “we and GSK remain committed to the existing alliance and the overall microRNA-122 program,” Xanthopoulos said during the call, adding that the companies will amend their deal to indicate that RG-101 is fully owned by Regulus, but that they will continue to work together to develop other miR-122-targeting drugs to treat HCV.

He also noted that GSK cannot pursue such drugs without Regulus, pursuant to their arrangement.

Commenting on the development of RG-101, which incorporates Alnylam Pharmaceuticals’ GalNAc conjugate delivery technology, Regulus CSO Neil Gibson said during the conference call that the drug’s active oligonucleotide has shown efficacy against “specific HCV genotypes, as well as some of the known mutations that may cause resistance” to existing treatments.

Additionally, “we have shown in rodent models that RG-101 has a rapid onset of action, and that target gene derepression was sustained for longer than 28 days after a single, subcutaneous dose,” he said.

In light of these data, Regulus expects to develop RG-101 as once-monthly treatment in difficult-to-treat patient populations. Xanthopoulos noted that such a dosing regimen matches well with the standard once-a-month visits of HCV patients to their physicians for viral load monitoring.

Regulus is preparing to initiate a GLP toxicology program for RD-101 in the next few weeks, and expects to begin phase I testing in early 2014 with a single, ascending dose study in healthy volunteers, Gibson said.

This trial will be followed by a multiple-dose study in healthy volunteers, and then a single dose trial in HCV patients.

“We anticipate that these studies could be completed by the middle of 2015,” he said. “At that time, we expect the competitive landscape in HCV to have clarified, allowing us to identify the niche populations likely to benefit from a novel mechanism” of action such as RD-101’s.

As it works to meet its stated goal of identifying two clinical candidates before the end of 2013, Regulus this week also said that it has begun evaluating miR-221 as a target for its new HCC program.

There is much data in the literature linking the miRNA to cancer, and “overexpression of miR-221 in HCC is known to be associated with poor prognosis,” Gibson explained. “We’ve already identified potent lead candidates that inhibit miR-221 and have shown that naked oligonucleotides formulated in saline can inhibit the growth of HCC tumor models that overexpress miR-221.

“We are working to optimize our ability to deliver these lead molecules … using a variety of formulations including a lipid formulation … and the GalNAc technology,” given that human HCC samples have been shown to express the glycoprotein receptors that facilitate intracellular delivery of the conjugates, he added.

“We expect to have a more robust data package for the miR-221 program in the next six months.”

The Financials

For the three-month period ended March 31, Regulus posted a net loss of $7.2 million compared with a year-ago loss of $2.2 million.

Revenues were $3.2 million in the quarter, versus $3.3 million in the same period the year before, while research and development spending jumped to $6.9 million from $4.6 million.

Meanwhile, general and administrative costs climbed to $1.9 million from $900,000, in part reflecting the expenses associated with operating as a public company following its late 2012 initial public offering (GSN 10/11/2012).

At the end of the first quarter, Regulus had cash, cash equivalents, and short-term investments totaling $90.7 million, which is expected to be sufficient to fund operations into 2016.

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