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Regulus Provides Details on AstraZeneca Alliance, In-house Pipeline Programs

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A little less than a year after it lost its partner for its preclinical hepatitis C therapy RG-101, Regulus Therapeutics announced last week that AstraZeneca has stepped away from the companies' program to develop an atherosclerosis drug targeting microRNA-33.

The firms will, however, continue to work together on drugs for metabolic diseases and cancer, and AstraZeneca retains the right to substitute a new target in lieu of miR-33 under their ongoing alliance.

Meanwhile, Regulus said it continues to advance RG-101 on its own, with company officials breaking out the details of an upcoming phase I study in the Netherlands, while it lays the groundwork for the clinical development of its Alport syndrome candidate RG-012 with a planned natural history study of people with the disease.

Regulus and AstraZeneca first began working together in mid-2012 under a deal that gave AstraZeneca the exclusive rights to miRNA drugs against three targets, the first of which was miR-33. About a year later, the companies announced that AstraZeneca had selected an undisclosed oncology target for the partnership.

Last week, however, Regulus said that the companies had dropped miR-33. During a conference call held to discuss Regulus' fourth-quarter financial results, CSO Neil Gibson said the decision stemmed from "certain technical challenges" facing the program, as well as "increasing complexity in the competitive landscape for atherosclerosis."

Noting that Regulus' relationship with AstraZeneca remains in full effect, Gibson characterized the move as a rebalancing of their collaborative efforts, which will now focus on the previously selected cancer target — revealed to be miR-19 — and miR-103/107 for metabolic diseases.

"AstraZeneca also has replacement rights for the miR-33 target," he added.

The miR-33 changeup follows GlaxoSmithKline's decision last year to end its involvement with RG-101. As with AstraZeneca, Regulus continues to work with GSK. However, while Regulus gave no indication that it will continue to pursue miR-33, the company continues to press ahead with RG-101 on its own.

During last week's call, Regulus President and CEO Kleanthis Xanthopoulos announced that the company has received clearance from regulators in the Netherlands to begin phase I testing of RG-101.

The trial, expected to begin shortly, will comprise four stages. In the first, single ascending doses of the drug will be examined in healthy volunteers. Assuming a positive outcome from those experiments, healthy volunteers will be enrolled to receive multiple ascending doses.

The third part will test in healthy volunteers single doses of RG-101 in combination with an oral direct-acting antiviral (DAA) drug already approved to treat HCV. The fourth phase of the study will then assess the effects of single doses of RG-101 in genotype I and genotype III HCV patients in order to establish human proof of concept.

The primary endpoint of the study, which is expected to enroll up to 100 people in total, is safety and tolerability, Regulus said. Secondary objectives include the evaluation of pharmacokinetics, viral load reduction, and any impact an oral DAA may have on the pharmacokinetics of RG-101.

Notably, Regulus is not planning to initiate phase II testing of RG-101 on its own, but rather partner the drug with a company that would develop it as an adjunct to an oral DAA once proof of concept has been demonstrated, Xanthopoulos said.

"We already have started a number of discussions [to] potentially find an appropriate home for RG-101," he added.

Following just behind RG-101 in Regulus' pipeline is its candidate for Alport syndrome, a rare kidney disease 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, according to the company.

Although Regulus has shown in vivo that silencing miR-21 was able to decrease the rates of decline of renal fibrosis while increasing the life span in mouse models of the disease, Gibson cautioned last week that the "clinical and regulatory path [for RG-012] is unclear."

As such, the company is planning to kick off a natural history of disease study in the third quarter to "gather greater information about the actual progression of patients with Alport syndrome, as this is not well described in the current literature," he said.

"Our learnings from … the natural history of disease study and our ongoing discussions with the regulatory agencies will help us establish clinical endpoints for our upcoming trials amidst the unclear clinical path," Gibson noted.

He added that glomerular filtration rate — a calculation of the kidneys' ability to filter blood — may be an appropriate clinical endpoint for studies of RG-012, and that this will be assessed further "as we learn more about the progression of disease" through the natural history study.

The natural history study is expected to enroll between 30 to 50 Alport syndrome patients, who will be followed for up to 24 months. Xanthopoulos noted during the call that Regulus does not plan to wait for the completion of that study before beginning phase I testing of the drug, which is currently slated to begin in the first half of 2015.

Fourth quarter financials

For the three-month period ended Dec. 31, 2013, Regulus' net loss dropped to $1.9 million, or $0.05 per share, from $6.9 million, or $0.49 a share, the year before. Impacting the comparison of the company's year-over-year losses per share is the change in number of shares outstanding following its late 2012 initial public offering.

Revenues for the fourth quarter were $5.5 million, up from $3.2 million, and included a $4.5 million payment from partner Sanofi.

Research and development spending increased to $8.2 million from $5.6 million, primarily due to increased activities associated with RG-101's preparation for the clinic. General and administrative costs, meantime, were essentially flat in the quarter at $1.9 million.

Regulus said it expects to end 2014 with $75 million in cash, cash equivalents, and short-term investments.

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