Isis Pharmaceuticals Inc. shares (NASDAQ:ISIS) extended a slow recovery Wednesday as investors took note of phase II data showing that the company's experimental antisense drug, ISIS-GCGRRx, helped patients with type 2 diabetes improve control of the disease, even when they're unable to do so with metformin.

Patients treated with ISIS-GCGRRx in the study achieved absolute mean reductions in HbA1c greater than 1 percentage point when given 100 mg of the drug and greater than 2 percentage points compared to baseline after 13 weeks of treatment with 200 mg, comparing favorably to approved therapies. Treated patients also experienced increased blood plasma levels of glucagon-like peptide-1, a hormone that preserves pancreatic function and enhances insulin secretion.

Isis CEO and chairman Stan Crooke called the results "unprecedented," noting that at first, when Isis unblinded the small double-blinded, randomized, placebo-controlled study, "we didn't believe it" given the short trial period. A typical 26-week phase III trial could show even greater impact on HbA1c he said, but noted that it's hard to know what that would look like at this stage.

Several small-molecule inhibitors of glucagon receptors, including efforts at Merck & Co. Inc., Bayer AG and Eli Lilly and Co. have been discontinued over the years according to Thomson Reuters Cortellis. Typical side effects that have played a role in some of the failures have been high blood pressure, weight gain and negative impacts on LDL cholesterol. But those issues seem not to have plagued Isis' drug. "We feel those are side effects tied to the small molecules, and not to antisense," Crooke told BioWorld Today. "Our approach works better, by a lot."

Isis did see some elevated liver enzyme levels in patients treated with the drug, but the company said the elevation was not associated with raised bilirubin or other indicators of liver damage and was consistent with other small-molecule inhibitors of glucagon receptor.

ISIS-GCGRRx targets the glucagon receptor, or GCGR, to reduce the effects of the hormone, which opposes the action of insulin and stimulates the liver to produce glucose in type 2 diabetes. In patients with advanced diabetes, uncontrolled glucagon action leads to a significant increase in blood glucose levels.

The drug is part of Isis' metabolic franchise, which also includes the phase II antisense candidates, ISIS-PTP1BRx, an inhibitor of protein tyrosine phosphatase-1B and ISIS-GCGRRx, a drug that targets glucocorticoid receptor. Each drug is designed to improve insulin sensitivity and/or reduce glucose production in patients with type 2 diabetes.

Isis will now work on finding an optimal dosage for ISIS-GCGRRx in a second 13-week phase II trial, likely to get under way early next year, Crooke said. "We have all the resources we need to continue development, and we're entertaining plenty of interest," he said. "At some point, we'll most likely partner the drug, but there's a lot of work to do before then."

The readout, combined with ISIS-GCGRRx's antisense mechanism, should help the company's prospects for attracting a partner despite the big cost tied to running a phase III diabetes program, JP Morgan analyst Cory Kasimov wrote in a note for investors.

Isis plans to present additional detail from the study as a late-breaking abstract program at June's American Diabetes Association 74th Scientific Sessions in San Francisco.

While shares of Carlsbad, Calif.-based Isis closed up at $25.46 Wednesday, performance is far off the company's 52-week high of $62.66. Crooke attributed that largely to a misunderstanding of positive data reported on the company's antisense drug for spinal muscular atrophy, ISIS-SMNRx, which is partnered with Biogen Idec Inc., of Cambridge, Mass. (See BioWorld Today, Feb. 24, 2014.)

As the company releases more news in the near future though, Crooke said he expects a correction.

The company said during its first quarter earnings call that it plans to initiate phase III trials for ISIS-SMNRx and ISIS-APOCIIIRx, an unpartnered candidate the company is developing for the rare genetic disorder familial chylomicronemia. (See BioWorld Today, May 2, 2014.)

Phase I studies are also in the works for the Astrazeneca-partnered ISIS-ARRx for prostate cancer, ISIS-PKKRx for hereditary angioedema, and another Biogen-partnered drug, ISIS-DMPKRx, for myotonic dystrophy type 1. "We need to get the information out and remind people about the potential for our pipeline," Crooke said.

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