BioWorld International Correspondent

AM-Pharma BV has identified a third target indication for its lead investigational drug alkaline phosphatase, following an analysis of a subgroup of sepsis patients with acute renal failure.

Data from the Phase IIa study of 36 patients with severe sepsis originally were reported last fall, and indicated a 90-day relative reduction in risk of mortality of 38.4 percent vs. placebo. An analysis of 15 of the trial participants who had acute renal failure yielded some additional unexpected results.

Plasma creatinine clearance, a marker for renal function, improved by 45 percent in acute renal failure patients who received alkaline phosphatase (n=10), whereas it deteriorated by 25 percent in acute renal failure patients who received placebo (n=5). Levels of glutathione-S-transferase-A1, a marker for kidney damage, decreased by 70 percent in patients who received the drug and increased by 200 percent in those on placebo. For each marker, the results were statistically significant (p<0.05).

"It was a bit of a surprise," AM-Pharma CEO Bart Wuurman told BioWorld International. "It was an initiative of one of the investigators to look at this subgroup specifically."

The Bunnik, Netherlands-based company has been investigating the potential of alkaline phosphatase as a drug on the basis of its dephosphorylation of lipopolysaccharide (LPS), the bacterial cell wall component that can trigger septic shock. It also is assessing its potential in ulcerative colitis, as the low-level prevalence of bacterial LPS in the large intestine is thought to contribute to ongoing inflammation in the area.

The mode of action in acute renal failure "is not entirely clear" Wuurman said, but it does appear to lower nitric oxide levels. "In acute renal failure nitric, oxide plays a significant role. Basically that causes the damage to the tubuli."

AM-Pharma now plans to conduct a follow-up Phase II clinical trial in a broader population of patients with acute renal failure. Other causes of the problem include the administration of nephrotoxic drugs, complications from certain surgical procedures and aging, Wuurman said. The indication is attractive to a company of AM-Pharma's size as the clinical endpoints - such as alleviating the need for patients to undergo dialysis - are easy to measure, he said. But it aims to out-license the product to a larger company once it has sufficient efficacy data.

The company so far has used a bovine form of the enzyme derived from intestinal animal tissue. "We are working on a recombinant version of alkaline phosphatase, which potentially should allow you to give it for a prolonged period of time," Wuurman said.

AM-Pharma raised €9 million (US$11.9 million) in its last financing round. Wuurman said it will seek additional cash later this year. (See BioWorld International, Nov. 2, 2005.)