Editor

About half of the estimated 18 million diabetics in the U.S. either have or will develop nephropathy, a potentially catastrophic condition that is the most common cause of chronic kidney failure and end-stage renal disease.

With only partial or insufficient therapies available, nephropathy makes for a tempting drug target. No wonder the condition and its would-be therapies gained media limelight last week through data offered at the 38th annual meeting of the American Society of Nephrology in Philadelphia.

Coming on strong is Keryx Pharmaceuticals Inc.'s KRX-101 (sulodexide), the first-in-class, oral heparinoid undergoing testing in a Phase III study to treat Type II diabetic nephropathy patients with persistent microalbuminaria. Keryx detailed final Phase II results at the ASN meeting, showing that 200 mg of the compound as a gel cap demonstrated statistically significant advantages over placebo. The primary endpoint for the Phase III trial is the percentage of patients at the end of the trial who achieve either a 50 percent reduction in albumin to creatinine (ACR) ratio or normalization of ACR, with a least a 25 percent reduction in that score.

Ronald Renaud, an analyst with JPMorgan, wrote in a research note that the most important information was the finding of statistically significant improvement in the 200-mg treatment, when analysis was conducted on a per-protocol basis. The outcome was "a very positive surprise to both the company and the sulodexide investigators and should be well received by investors." Secondary endpoints "also continued on a positive trend," Renaud wrote.

"I won't say I am surprised," Michael Weiss, Keryx's chairman and CEO, told BioWorld Financial Watch. "I was certainly pleased. This is a drug that has been extensively studied in Europe, and the primary objective [of the Phase II study] was to see if we would see a trend in the data that gives us a reality check' before moving into Phase III. We don't need to see [more] statistically significant activity - we have study after study showing the drug works." Researchers wanted one more set of data before going forward.

Now they have it. Renaud pointed out that the intent-to-treat analysis missed statistical significance by just one patient in the 200-mg sulodexide group, even though the study was underpowered to show a significant result.

"All secondary endpoints remained on a positive trend for the 200-mg sulodexide group," he wrote.

Weiss said researchers also have seen activity with the compound against peripheral vascular disease, where it has improved mean walking distance over placebo. In patients who have suffered heart attacks, the drug has proved to reduce the risk of a second attack. Results in both areas came from "Phase IV-type" studies in Italy and Europe, where sulodexide already was on the market.

Diabetic nephropathy, though, is where the eyes of most investors have been drawn toward. Keryx's compound has taken the lead, with the Swiss firm Speedel AG also moving along. Speedel offered final Phase IIb results with endothelin-A receptor antagonist, SPP301, at the ASN meeting. Data show the compound reduced proteinuria when administered on top of standard therapy for the treatment of diabetic nephropathy, confirming top-line results reported earlier this year.

At all doses, SPP301 decreased the rate of proteinuria excretion compared to placebo, with the two highest doses of 25 mg and 50 mg recording the greatest drop. The drug also cut total cholesterol over placebo. A total of 286 patients were enrolled in the 12-week study, and Speedel reported top-line results in March. The once daily, oral SPP301 is licensed from F. Hoffmann-La Roche Ltd. Speedel holds exclusive worldwide development and commercialization rights.

The Phase III trial with SPP301, which began in July, is expected to take at least three and one-half years to finish.

"It's not a race, because we're so far ahead [of Speedel]," Weiss said. "Based on our clinical trial plan, we should be on the market anywhere from two years to four years before they'd be able to make it." Keryx expects to launch at the end of 2007 or in the first half of 2008.

Renaud said the distinctive product profile of the Keryx drug probably is what led the Collaborative Study Group - the world's largest renal clinical trial group, made up of academic and tertiary nephrology care centers - to choose to work with Keryx's Phase III program.

While the precise mechanisms of action for sulodexide remain somewhat uncertain, the drug apparently prevents and corrects the thickening of the glomerular basement membrane (GBM). It also blocks and fixes the loss of negative charge in the GBM, while offering anti-transforming growth factor-beta effects and suppressing albumin leakage into the kidney, Renaud wrote.

Another drug in the space is Eli Lilly and Co.'s Arxxant (ruboxistaurin mesylate), an oral inhibitor of protein kinase C-beta, which has failed Phase III trials in neuropathy, diabetic retinopathy and macular edema. Early this year, a one-year pilot study in neuropathy "looked good," Renaud said, but the company did not provide enough details to draw solid conclusions.

During the summer, Lilly said it no longer would seek FDA approval for Arxxant in diabetic neuropathy, but Renaud would not rule out future trials in that indication. "While not yet a direct competitor with sulodexide in the diabetic nephropathy landscape, it is widely expected that Lilly will move the drug into late-stage trials in the nephropathy arena," he wrote. Word on the status of the Arxxant program is expected by the end of this year.

"I don't think it's a competitive marketplace anyway"" Weiss said. "People will be treated with multiple agents [at once]."

Patients now are given angiotensin converting enzyme inhibitors or angiotensin receptor blockers, "ideally at the highest approved doses," he said. "We know that those patients will still progress to end-stage renal disease, but you can delay the progression. The paradigm will be: treat the patients with ACEs or ARBs, monitor them every six months to 12 months and then [add] the next compound. It will be a cocktail approach, layered in over time."