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Regulus Considers miR-21 Drug as Next Clinical Candidate amid Positive Alport Data


Regulus Therapeutics this week released new preclinical data showing that microRNA-21 is implicated in the fibrotic kidney condition Alport syndrome and indicated that the program could likely yield its next clinical candidate.

The company also released its third quarter financial results, which included a drop in its net loss amid increased revenues, and disclosed that it is nearing the completion of negotiations with partner Sanofi regarding taking a larger role in the miR-21 effort.

In 2010, Regulus inked a deal giving Sanofi the rights to develop and commercialize four miRNA-targeting therapeutics, including a fibrosis treatment targeting miR-21, in exchange for $25 million up front and the promise of a $10 million equity investment, research funding, milestones, and royalties (GSN 6/24/2010).

That alliance proceeded apace, generating new preclinical data — presented this week at the American Society of Nephrology’s Kidney Week 2013 meeting — implicating miR-21 in Alport syndrome.

The disorder is caused by mutations in three genes that affect production of the type IV collagen family of proteins. The result is a disruption to the structure of the glomerular basement membrane, increased expression of miR-21, an increase in fibrosis, and the loss of renal function, which ultimately leads to end-stage renal disease, Regulus CSO Neil Gibson explained during a conference call held to discuss the quarterly financials.

In a collagen 4A3-deficient mouse model of Alport syndrome, Regulus and Sanofi showed that inhibiting miR-21 "significantly decreased the rate of decline of renal fibrosis, restored the expression of key microRNAs involved in maintaining renal function, and increased the lifespan of the mice by 20 percent to 50 percent depending upon the genetic background of the collagen 4A3 mutation," Gibson said.

Based on these positive data, Regulus is leaning toward nominating the Alport syndrome program as next in line in its official drug-development pipeline behind the hepatitis C treatment RG-101, according to CEO Kleanthis Xanthopoulos.

"We're excited about the therapeutic opportunity that [targeting] microRNA-21 may have, and we expect to provide you with an update on this program in the coming months," he said during the call, adding that Regulus is on track to name a second clinical candidate before the end of this year

Before it does so, however, Regulus needs to complete ongoing toxicology studies and, perhaps most importantly, finish negotiations with Sanofi over how the miR-21 program is handled, Xanthopoulos said.

The partnership expired in June, but the companies agreed to an option agreement running through December that gives Sanofi an exclusive right to negotiate for the co-development and commercialization rights to certain of Regulus' unpartnered miRNA programs. In exchange, Regulus has the exclusive right to negotiate with Sanofi to get a bigger piece of the miR-21 program in both Alport syndrome and cancer.

Xanthopoulos said during the call that if the alliance is reworked the way Regulus would like, it would have "much more participation in the development of the program, as well as on the upside of the program."

He added that Sanofi is "positively inclined to these discussions," but noted that negotiations are ongoing and not likely to conclude until around the end of the year.

Should the companies fail to come to an agreement, Sanofi will retain the full rights to the miR-21 program, as agreed upon in the original deal with Regulus, he said.

Aside from RG-101, which is poised to enter phase I testing in the first half of 2014, and the miR-21 program, Regulus has been making strides with other, earlier-stage programs, Gibson noted.

Its glioblastoma program, which targets miR-10b, continues to move through preclinical testing and the company expects to have pinpoint lead candidates for further evaluation by the end of the year, he said.

Additionally, lead candidates with in vivo activity have been identified in Regulus' liver cancer effort, which focuses on silencing miR-221. "We are … working to optimize our ability to deliver those lead molecules … using lipid formulation and also GalNAc conjugation technology that has worked efficiently for us within the RG-101 program," Gibson said.

He added that Regulus is using its miRNA biomarker technology to identify miRNA signatures in the serum of liver cancer patients in order to identify those that overexpress miR-221 and would be best suited for treatment with the company's drug.


For the three-month period ended Sept. 30, Regulus' net loss fell to $2.2 million, or $.05 per share, from a year-ago loss of $5.7 million, or $.07 a share.

Contributing to the lower losses was a rise in third quarter revenues to $6.1 million from $2.8 million, which was helped by a $5.4 million payment from Sanofi in September tied to the extension of the deal until the end of 2013.

Research and development spending in the quarter edged up to $7.1 million from $5.2 million, largely due to work around preparing an investigational new drug application for RG-101. Regulus said that it expects its R&D expenses to increase over the coming quarters as it begins clinical trials and initiates additional IND-enabling activities.

General and administrative expenses in the third quarter rose to $1.9 from $1.1 million, largely due to the additional headcount and costs associated with being a public company. Regulus' initial public offering occurred in October 2012.

At the end of September, Regulus had cash, cash equivalents, and short-term securities totaling $123.9 million.