Four months after reporting positive results from a Phase IIb trial of its endothelin A receptor antagonist, SPP301, in diabetic nephropathy, Speedel Group AG initiated a pivotal Phase III study in Type II diabetes patients.

The ASCENT (Avosentan on Doubling of Serum Creatinine, End Stage Renal Disease and Death in Diabetic Nephropathy) study is a placebo-controlled morbidity and mortality trial designed to evaluate more than 2,000 patients at 260 sites with a composite event-driven endpoint assessed by the time it takes for a patient's serum creatinine to double, the advent of end-stage renal disease or death. Patients will be randomized to receive either 25 mg or 50 mg of SPP301 once daily plus standard therapy, or standard therapy alone.

"We're looking for enough events to occur to demonstrate statistically significant efficacy," said Nick Miles, director of communications and investor relations for Basel, Switzerland-based Speedel. "At the moment, we think it will take about three and a half years."

Specific secondary endpoints were not disclosed, though Miles said those would be cardiovascular and metabolic related.

Speedel received a special protocol assessment from the FDA for the trial. That, along with a fast-track designation for SPP301, could allow an expedited review process.

"All being well, we should get results in the first half of 2009," Miles told BioWorld Today, "and then get it reviewed and get it launched in the U.S. in late 2009."

Diabetic nephropathy, which refers to any harmful effect on kidney structure or function due to diabetes mellitus that ultimately can progress to end-stage renal disease, would be a new indication for an endothelin A receptor antagonist, which several other companies have used to develop treatments for pulmonary arterial hypertension (PAH). Tracleer, a dual antagonist from Actelion Ltd., of Allschwil, Switzerland, was approved in 2001. Houston-based Encysive Pharmaceuticals Inc. awaits FDA approval for its PAH drug, Thelin (sitaxsentan), while Myogen Inc., of Denver, has ongoing Phase III trials for ambrisentan.

But the PAH field "is a very different market from us," Miles said. He added that the company has not disclosed what, if any, additional indications it might pursue with SPP301.

Speedel is funding the Phase III study itself, and the cost is estimated at more than CHF 100 million (US$76.9 million) spread over four years. Miles said the investment largely was prompted by promising Phase II data reported in March. Those results showed that all four dose groups (5 mg, 10 mg, 25 mg and 50 mg) demonstrated statistically significant decreases, as determined by assessing patients' urinary albumin excretion rates, compared to placebo.

The company believes SPP301 will be "a very strategic asset to us, which will increase the value of our pipeline," Miles said. "And the response from the FDA and EMEA was so positive that we felt encouraged to take [the product] into Phase III ourselves."

Speedel originally licensed SPP301 from F. Hoffmann-La Roche Ltd., of Basel, Switzerland, to test in several indications. After selecting diabetic nephropathy, Speedel bought out Roche's rights to the product in 2003.

"We own the full commercialization rights to it," Miles said, adding that, over the next couple of years, Speedel will be looking at different marketing options, such as co-promotion and distribution agreements.

"Or we could do something on our own, such as build a sales force in the U.S.," he added. "We would need about 65 to 100 people. Then maybe we could do a co-promotion agreement here in Europe."

Existing therapies for diabetic nephropathy primarily consist of angiotensin converting enzyme (ACE) inhibitors, and Miles said those products generated about $1 billion in 2003 for a patient population estimated at about 8 million across seven countries, including the U.S., Japan and five European nations.

"Given that we've got a new mode of action, and that a number of other competitors are looking to get into the market with novel patented therapies," Miles said, "we're looking at a market potential of $3 billion to $4 billion."

Possible competitors include New York-based Keryx Biopharmaceuticals Inc., which began a Phase III/IV program late last month for its KRX-101 (sulodexide) gelcaps, as well as South San Francisco-based Fibrogen Inc., in early clinical trials with FG-3019, a fully human monoclonal antibody.

SPP301 is the first product that Speedel has moved into late-stage studies by itself. The company licensed SPP100 (aliskiren), an oral renin inhibitor from Novartis Pharma AG, of Basel, Switzerland, which it advanced through early clinical trials in hypertension before licensing it back to Novartis for Phase III development.

Speedel licensed SPP200 (pegmusirudin), a recombinant protein designed as a long-acting direct thrombin inhibitor, from Abbott Laboratories, of Abbott Park, Ill. That product is in a Phase IIb study for vascular graft occlusion in patients undergoing chronic hemodialysis for end-stage renal disease. Miles said Abbott retains a call-back option at the end of that trial, and "we expect results and a decision from [Abbott] in the second half of 2006."

The company has two renin inhibitors, SPP630 and SPP635, in early Phase I studies in hypertension and end-organ protection, and has several ongoing preclinical programs.