Washington Editor

With few new compelling data presented at this year's American Diabetes Association Scientific Sessions annual meeting in San Francisco, Wall Street's focus turned to the expected competition in the glucagon-like peptide-1 (GLP-1) market.

Factors driving interest in GLP-1 targeted therapies include lack of hypoglycemia and weight gain, along with hints of better cardiovascular effects, such as blood pressure-lowering effects, said analyst Seamus Fernandez, of Leerink Swann Research.

GLP-1 improves blood sugar after food intake through multiple effects that work in concert on the stomach, liver, pancreas and brain.

San Diego-based Amylin Pharmaceuticals Inc.'s Byetta (exenatide), the first and only FDA-approved incretin mimetic for the treatment of Type II diabetes, so far has dominated the market.

Amylin has partnered with Indianapolis-based Eli Lilly & Co. on Byetta, which has been on the market for more than three years.

But analysts predicted that Byetta soon could face competition from investigational GLP-1 diabetes products like Novo Nordisk AS's liraglutide, Roche AG's R1583 and Human Genome Science Inc.'s and GlaxoSmithKline plc's Syncria (albiglutide).

In what appeared to preempt GLP-1 data presented at the ADA meeting, Novo Nordisk released a statement Friday claiming that a head-to-head comparison trial showed that its experimental once-daily liraglutide controlled blood sugar and lowered weight better than Amylin's twice-daily Byetta. Novo Nordisk said the 464-patient 26-week study was the first to provide a direct comparison between the two GLP-1 analogues.

Patients with Type II diabetes were randomized to treatment with either liraglutide once daily or Byetta twice daily as add-ons to their existing treatment consisting of metformin, sulfonylurea or a combination of both.

The average hemoglobin A1c level at the beginning of the study was slightly above 8 percent and the primary endpoint was the change in HbA1c. Novo Nordisk said that patients treated with liraglutide achieved a reduction in HbA1c of more than 1.1 percentage points, compared with a reduction in HbA1c of less than 0.8 percentage points in the Byetta group, a difference which Novo Nordisk called statistically significant.

While patients on both drugs lost weight during the course of the study, there was a trend toward more weight loss in the liraglutide group, Novo Nordisk said.

But Orville Kolterman, senior vice president of research and development for Amylin, noted that Novo Nordisk's top-line findings were not presented at the ADA meeting and were from "a study that has not been through any kind of a peer review."

"It's sort of interesting that this was released as a press release at the opening of a meeting that is based upon peer-reviewed scientific data," Kolterman told BioWorld Today.

He said he would not speculate further about the Novo Nordisk comparison data until it has received appropriate peer review.

Fernandez predicted that Novo Nordisk's liraglutide, which has an FDA Prescription Drug User Fee action date of March 2009, will "cannabalize Byetta sales," at least until Amylin's long-acting release formulation of exenatide is launched, which is expected in mid-2010.

While Wall Street was not too impressed with results presented Saturday from a 30-week study that compared the efficacy of once-weekly exenatide with the marketed formulation of Byetta, the tide could change in favor of Amylin based on 52-week results released Monday night at an ADA late-breaking session, said analyst Matthew Osborne, of Lazard Capital Markets.

The 30-week results of the DURATION-1 trial released Saturday showed that patients in both treatment groups showed improvements in A1c from baseline. However, treatment with exenatide once weekly resulted in statistically significant reductions, with 77 percent of patients treated achieving an A1c of 7 percent or less vs. 61 percent for Byetta.

The 52-week data presented late Monday showed that patients who received Byetta in the control arm of the study and crossed over to exenatide once weekly had further improvements in glucose control and fasting plasma glucose levels, with hemoglobin A1c values reduced by a full 2 percentage points from baseline, Kolterman said.

Exenatide once weekly also was associated with an average loss of 9.5 lbs over 52 weeks, he added.

The treatment was well tolerated, and there were no new safety observations in the 52-week data, Kolterman noted.

"We think these robust results will likely transform the treatment going forward," he said.

Kolterman said that while data presented at the ADA meeting for other GLP-1 compounds are "intriguing," those early stage products pose no immediate threat to Byetta or exenatide once weekly, which Amylin and Lilly plan to file an application for by the end of the first half of 2009.

"We have the only GLP-1 replacement therapy or agonist therapy that has the benefit of having been through the most rigorous review process in the world, namely the full review by the FDA and granting approval for the drug on the market," he said, noting that more than 1 million patients have been exposed to Byetta.

"We are following some of these things with interest, but the lead that we have on the competition by virtue of being on the market, having an established place in the marketplace and then having truly amazing robust data . . . with the once weekly formulation allows us to feel that we are going to be a significant player in this transformation of therapy Type II diabetes going forward." Shares of Amylin (NASDAQ:AMLN) lost $3.09 Monday, to close at $26.84.

In other ADA news:

• Arisaph Pharmaceuticals Inc., of Boston, said data showed that its potent DPP-4 inhibitor, ARI-2243, produced a 29 percent reduction in glucose excursion during an oral glucose tolerance test in DPP 4 knockout mice. The company said that in multiple animal models for diabetes, ARI-2243 consistently produced dramatic efficacy results, including a 2.5 percent reduction of HbA1c in Zucker Diabetic Rats, a refractory model of diabetes. The dual mechanism of action related to ARI-2243 is expected to produce a clinically differentiated efficacy profile in the treatment of Type II diabetes, the firm said. Arisaph filed an IND for ARI-2243 during the first quarter and has initiated a first-in-man safety study in healthy volunteers.

• Elixir Pharmaceuticals Inc., of Cambridge, Mass., said data validated ghrelin, a potent, naturally occurring hormone, as a master regulator of metabolism. Mice lacking the ghrelin receptor, or the knockout mice, demonstrated a greatly improved metabolic profile compared with a matched set of normal mice, whether they were placed on a high-fat diet or low-fat diet. Specifically, the knockout mice showed significant reductions in glucose production in the liver on both diets and a significant increase in glucose uptake in muscle and fat tissue on HFD. The firm said the results were consistent with an increase in insulin sensitivity, a key goal in controlling Type II diabetes.

• Genaera Corp., of Plymouth Meeting, Pa., said preclinical data showed that treatment with trodusquemine (MSI-1436) led to significant improvements in insulin sensitivity as well as lower HbA1C levels and weight loss in animal models of diabetes.

• Hollis-Eden Pharmaceuticals Inc., of San Diego, said interim data from its ongoing Phase I/II clinical trial demonstrated that Triolex (HE3286) is safe and well tolerated to date, and that it significantly improved insulin sensitivity and significantly lowered fasting blood glucose, insulin and triglyceride levels in obese insulin-resistant subjects treated orally with the compound for 28 days compared with placebo-treated subjects. In addition, all subjects had elevated levels of MCP-1, a chemokine identified in the scientific literature to be associated with the cause of insulin resistance, before initiating Triolex therapy, and showed a significant drop in MCP-1 in serum and IL-6 in peripheral blood mononuclear cells when treated with the compound at the highest dose, compared to placebo-treated subjects.

• Halozyme Therapeutics Inc., of San Francisco, reported new Phase I data for its diabetes mellitus program showed that combining its recombinant human hyaluronidase enzyme (rHuPH20) with Humulin R (regular insulin human) or Humalog (insulin lispro) yielded pharmacokinetics and glucodynamics that better mimicked physiologic prandial (mealtime) insulin release and activity than Humulin R or Humalog alone. Key pharmacokinetic and glucodynamic improvements observed in the study included significantly faster systemic absorption of each insulin, starting with the first observation time point of three minutes after injection; significantly faster and greater glucose lowering activity early after injection; significantly greater peak insulin levels for the same dose administered; and significantly lower variability of key PK and GD variables across subjects.

• InteKrin Therapeutics Inc., of Los Altos, Calif., said data from a Phase IIa study showed that administration of INT131 demonstrated a significant improvement in fasting plasma glucose compared with baseline and placebo at doses of 1 mg and 10 mg daily in patients with Type II diabetes on no drug therapy. The changes in FPG were accompanied by significant improvements in insulin resistance and an increase in adiponectin, a key biomarker of PPAR-gamma mediated efficacy, the firm said. The study showed that INT131 was safe and well tolerated, without evidence of the recognized side effects of the full agonist TZDs at a dose that provides glycemic improvement as good as or better than the highest approved doses of Actos and Avandia.

• KineMed Inc.., of Emeryville, Calif., and Daiichi Sankyo Inc., of Parsippany, N.J., said researchers have discovered a key difference in bile acid metabolism in people with Type II diabetes, which may suggest a newly identified underlying disorder. Study results showed that cholic acid had a significantly higher synthesis rate in people with Type II diabetes than in patients with normal glucose levels. Researchers also learned that the rate at which deoxycholic acid was recycled back into the liver was almost twice as great in those with Type II diabetes as in the healthy subjects. In addition, the total amount of bile acid synthesized by the liver was elevated, although not statistically significantly, in people who have Type II diabetes.

• Miami VA Medical Center and the University of Miami Miller School of Medicine reported that study results from the VA Diabetes Trial, which investigated whether intense control of blood glucose in Type II diabetes would reduce the risk of cardiovascular disease in 1,791 U.S. veterans at 20 Veterans' Affairs medical centers, found a reduction in cardiovascular events, but it was not statistically significant. Participants in both groups were at or below targets for lipids and blood pressure within the first two years, and maintained them for the six years of their participation. While the average A1C was 9.5 percent on entry into the trial, the standard group reached 8.4 percent and the intensive group reached 6.9 percent within six months. VA Diabetes Trial specifically included only patients who already had failed what he called simple therapy.

• Nastech Pharmaceutical Co. Inc., of Bothell, Wash., said data from a 29-patient Phase II clinical trial demonstrated that its ultra rapid acting intranasal insulin was both superior to usual therapy and noninferior to insulin aspart. The data also demonstrated a statistically significant reduction in the incidence of hypoglycemia compared with insulin aspart in the four hours following the meal.

• Orexigen Therapeutics Inc., of San Diego, said a review of data from a Phase IIb trial showed that patients assigned to Contrave dosage groups demonstrated a 50 percent reduction in the prevalence of metabolic syndrome, a group of risk factors associated with obesity that may increase the risk of developing diabetes or cardiovascular disease. A retrospective evaluation on the baseline prevalence of metabolic syndrome revealed that among Contrave patients who completed 24 weeks of treatment, the percentage of subjects with metabolic syndrome decreased from 31 percent to 15 percent. Among patients on placebo, the prevalence of metabolic syndrome decreased by a smaller percentage, from 38 percent to 30 percent.

• Sangamo BioSciences Inc., of Richmond, Calif., said Phase Ib data showed there was a clinically relevant magnitude of improvements observed in measurements of nerve health and function in subjects with mild to moderate diabetic neuropathy after a single administration of SB-509. The data demonstrated that SB-509 may have a neuroprotective and a neuroregenerative effect. Subjects received a single treatment in both legs of either placebo or SB-509. All of the subjects completed six-month follow-up testing. SB-509 was well tolerated and no drug-related severe adverse events were observed.

• XOMA Ltd., of Berkeley, Calif., said an animal study showed that XOMA 052 preserved insulin production, reduced fasting glucose and cholesterol levels and preserved beta-cell function in mice with a diet-induced obesity model of Type II diabetes. In the 14-week study, mice were fed either a normal diet or a high-fat, high-sucrose diet. Subsets were then treated with either twice weekly injections of 1 mg/kg Xoma 052 or a negative control antibody.