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Regulus Sets Bar High for HCV Program, Sees Alport Drug in Phase II by 2015

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NEW YORK (GenomeWeb) – Officials from Regulus Therapeutics this week provided updates for the company's two lead drug candidates, stating that a Phase I study of its hepatitis C treatment RG-101 is set to yield key data in the next few months, while the preclinical Alport syndrome therapy RG-012 is on track to enter human testing in early 2015.

Separately this week, Regulus announced that it has formed a new collaboration with Biogen Idec to identify microRNA biomarkers for multiple sclerosis (MS). The arrangement builds off of an alliance the companies forged in 2012.

Speaking during a conference call held to discuss Regulus' second-quarter financial results, CSO Neil Gibson indicated that the firm has set the bar high for RG-101, with the HCV landscape having changed significantly since the recent introduction of essentially curative treatments like Gilead Science's Sovaldi.

RG-101, a GalNAc-conjugated antagonist of miR-122, is currently in the fourth part of a Phase I trial, which is evaluating a single dose of the subcutaneously administered agent in HCV patients in order to assess safety and viral load reduction.

"By the end of the year, we expect to report human proof-of-concept results" from the trial, Gibson said, adding that anything short of a two-log reduction in viral load would "cause us to take a pause and think hard about the program."

Should the trial results be favorable, he said that they "may validate our microRNA technology platform and may set the stage for success in future clinical trials across the pipeline." No mention was made about the future of the HCV program itself, which was first called into question when Regulus partner GlaxoSmithKline changed its mind about co-developing RG-101 last year.

Meanwhile, work proceeds apace with the Alport syndrome treatment RG-012. The condition 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.

With preclinical data showing that inhibiting miR-21 can significantly decrease the rate of decline of renal fibrosis, restore expression of other microRNAs involved in maintaining renal function, and increase animal lifespan, Regulus is preparing to initiate in the next few weeks a natural history of disease study to gather information on the progression of Alport syndrome to guide its clinical development.

According to Regulus' newly minted Chief Medical Officer Paul Grint, the firm aims to begin Phase I testing of RG-012 in healthy volunteers in the first half of 2015, with a Phase II proof-of-concept study beginning later that same year.

Later this year, the company also plans to report preclinical data on the combination of RG-012 and an angiotensin-converting-enzyme (ACE) inhibitor. ACE inhibitors are commonly used to treat hypertension and congestive heart failure, but are also used in Alport syndrome because of their ability to reduce proteinuria and slow the progression of renal disease.

"We believe ACE inhibitors are not sufficient to treat the progression of Alport syndrome … and the preclinical combination data will be important in demonstrating the utility of adding a microRNA therapy to this emerging standard of clinical care," Grint said.

Gibson noted during the call that Regulus also expects to unveil a third clinical candidate by the end of 2014 as optimization work continues on various miRNA antagonists including ones against miR-21, miR-221, and miR-19 in oncology, and miR-103 and miR-107 in metabolic disease.

As this therapeutics work advances, Regulus is also maintaining a focus on its miRNA biomarker efforts, being conducted through its microMarkers division. Chief among these is its ongoing relationship with Biogen Idec.

The companies began working together in 2012 to find blood-borne miRNA signatures that can be used to help diagnose MS patients, as well as to guide their treatment and monitor disease progression and relapse, with particular emphasis on Biogen Idec's portfolio of MS therapies.

In late 2013, Regulus announced that it had thus far profiled 400 serum samples from MS patients and compared them to samples from healthy volunteers — a milestone that triggered an undisclosed milestone payment from Biogen Idec.

This week, the companies disclosed that they signed a new deal to replace the one inked in 2012, and that they would now focus on profiling miRNA signatures in a large number of whole blood samples from a cohort of MS patients who have been previously treated with one of Biogen Idec's drugs.

Regulus received $2 million upfront and stands to receive undisclosed milestones.

At the same time, the microMarkers division continues to look for biologically relevant miRNA expression patterns for use with Regulus' in-house drug programs. For instance, the unit has been looking for miRNA biomarkers in urine to support the RG-012 program — an effort Gibson discussed with Gene Silencing News in June.

Second-quarter financials

For the three-month period ended June 30, Regulus' net loss jumped to $12 million, or $.28 a share, from a year-ago loss of $7.3 million, or $.20 a share.

Driving the increased losses was a rise in research and development spending to $10.8 million from $7.7 million, as well as higher general and administrative costs, which rose to $3 million from $1.7 million.

Revenues in the quarter were $700,000 — a sharp drop from $4.8 million in the second quarter of 2013, which reflects decreases in recorded collaboration revenue from GlaxoSmithKline and Sanofi.

At the end of June, Regulus had cash, cash equivalents, and short-term investments totaling $103.5 million.

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