BioWorld International Correspondent

Speedel Group AG plans to move its once-daily oral endothelin A receptor antagonist SPP301 into a Phase III trial in diabetic nephropathy in the second half of this year, following favorable Phase IIb results.

The company, which had not previously disclosed the indication for which SPP301 is being developed, said 55 percent of all patients receiving the drug over a 12-week period exhibited a drop of 30 percent or more in urinary albumin excretion rate (UAER), or proteinuria, in the Phase IIb trial.

A total of 286 patients with diabetic nephropathy participated in the double-blind, randomized, placebo-controlled study. They received either 5 mg, 10 mg, 25 mg or 50 mg of drug, or placebo, in addition to standard therapy, in the form of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. All dose groups exhibited a statistically significant decrease in UAER as compared with placebo, the company said, and the decrease was highest in the two high-dose treatment arms.

In the Phase III trial, which will involve more than 2,000 patients in the U.S., Europe and Asia, the primary endpoints will be time to doubling of serum creatinine, a standard measure of kidney damage, onset of end-stage renal disease and death. The trial will take three and a half years to complete and will involve two years of treatment. SPP301 has received fast-track designation from the FDA.

"We are finalizing now the discussions on the special protocol assessment with the FDA," said Alice Huxley, CEO of Basel, Switzerland-based Speedel. The two highest doses will be repeated in the pivotal study.

Endothelin-1, a 21-amino-acid peptide that binds endothelin receptor A, is a vasoconstrictor and it modulates renal parameters such as glomerular filtration rate, sodium excretion and water balance, via mechanisms that are not fully understood. Endothelin receptor antagonists have prevented onset of renal damage in animal models of diabetes, although the duration of the Phase IIb trial was too short for any clinical effects to become apparent because the endothelin signaling system operates over a longer time frame.

Speedel has exclusive worldwide development and commercialization rights to SPP301, having purchased in 2003 an option held by F. Hoffmann-La Roche Ltd., of Basel, to license back the compound on completion of the Phase IIb study.

"This is one of four endothelin receptor antagonists that Roche developed. Every other one ended up in the hands of Actelion, either directly or indirectly," said Speedel's director of communications and investor relations, Nick Miles.

So far, Allschwil, Switzerland-based Actelion Ltd.'s biggest commercial success in the drug class has been with Tracleer (bosentan) in pulmonary arterial hypertension.

"This molecule is younger than bosentan by several years," Huxley said. The additional development time, she said, was spent on improving its liver toxicity profile.

In a recent presentation, Speedel disclosed that dosing with SPP301 resulted in liver transaminase levels more than three times above the upper limit of normal in just 0.4 percent of patients. The equivalent statistic for bosentan, the company said, is 11 percent.