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Regulus On Track for HCV Phase I in ’14, Renegotiating Sanofi Partnership

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Regulus Therapeutics remains on track to filing an investigational new drug application for its microRNA-targeting hepatitis C treatment RG-101 next year, with a second candidate — likely for fibrosis or cancer — to be added to the company's formal pipeline before the end of 2013, officials said this week.

Speaking during a conference call held to discuss Regulus’ second-quarter financial results, the executives also provided an update on the firm’s partnership with Sanofi, stating that while their original agreement expired in June, negotiations are underway about continuing the relationship.

RG-101 is an antagonist of miR-122, a miRNA with a well-established role in the HCV lifecycle and the ability of the virus to infect cells. Earlier this year, Regulus announced that it had selected the drug as the first candidate it will move into human testing, although not with GlaxoSmithKline despite the companies’ ongoing collaboration on the disease (GSN 5/16/2013).

Regulus said that it is currently conducting toxicology studies on RG-101, which is formulated with Alnylam Pharmaceuticals liver-targeting GalNAc conjugation technology, and expects to file with regulators to begin phase I testing in the first half of 2014.

“We are planning a single ascending dose study in healthy volunteers that will be followed by a multiple-dose study in healthy volunteers,” Regulus CSO Neil Gibson said during the call. In parallel with the multi-dose trial, the company aims to run a single-dose study in HCV patients to demonstrate human proof of concept.

As it gears up for these studies, Regulus is also working to unveil a second clinical program before the end of this year, President and CEO Kleanthis Xanthopoulos said. Although a final decision has yet to be made, he indicated that the next candidate will likely be either a miR-21-targeting agent for liver cancer and kidney fibrosis, or a miR-221 inhibitor for hepatocellular carcinoma.

In 2010, Regulus and Sanofi agreed to partner on the development of four miRNA inhibitors, including ones designed against miR-21 (GSN 6/24/2010). That deal expired in June, but Xanthopoulos said that the companies signed an exclusive option agreement, which gives them until the end of December to hammer out a new contract.

According to a filing with the US Securities and Exchange Commission, Regulus received $2.5 million in exchange for giving Sanofi the exclusive rights to renegotiate the rights to the miR-21 program in oncology and the fibrotic disease Alport’s syndrome, as well as make offers for the rights to certain other unpartnered programs.

Xanthopoulos said during the conference call that while the original agreement called for Sanofi to take over the miR-21 program once Regulus had filed an IND on a candidate, going forward “we want to have a little more say in how the program develops” — an issue now under discussion between the companies.

He added that he expects the two firms to come to ultimately continue their partnership on miR-21 in fibrosis and oncology, and was optimistic that Sanofi would decide to partner on other miRNA targets, as well.

As for the miR-221 effort, Gibson said that Regulus has “identified potent lead candidates” that inhibit the miRNA both in cell-based models and in vivo tumor models. Additionally, he said, the company has shown that naked oligonucleotide formulated in saline can impact the growth of tumors in HCC models that overexpress the miRNA.

However, Regulus is also exploring the use of GalNAc conjugates and lipid nanoparticles to deliver its miR-221 antagonists, he added.

Despite the likelihood that miR-21 or miR-221 will be chosen as Regulus’ next clinical target, the company continues to make progress with earlier-stage programs including one focused on miR-10b in glioblastoma, Gibson said.

He noted that the firm has begun collaborating with Harvard University’s Anna Krichevsky, who has been studying the role of miRNAs in brain cancer for some time (GSN 9/16/2005), to examine miR-10b in different brain cancer models.

Q2

For the three-month period ended June 30, Regulus reported a surge in its net loss to $7.3 million, or $0.20 a share, from a year-ago loss of $2.6 million, or $10.78 a share. The comparability of Regulus’ loss per share in each period is affected by its initial public offering and stock issuances in October 2012.

Revenues in the quarter rose to $4.8 million from $3.3 million — an increase primarily due to a $1.1 million payment from GlaxoSmithKline that was recognized earlier than expected after the companies amended their alliance to allow Regulus to develop RG-101 on its own.

Research and development spending in the quarter jumped to $7.7 million from $4.9 million, while general and administrative costs climbed to $1.7 million from $1 million last year.

At the end of June, Regulus had cash, cash equivalents, and short-term investments totaling $82.7 million. As a result of a recent stock offering, Regulus said that it has increased its year-end cash guidance to $110 million.

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