By Debbie Strickland
In a pilot 51-patient Phase II trial in patients with AIDS-related diarrhea, Shaman Pharmaceuticals Inc.'s oral anti-diarrheal drug, Provir, achieved statistical significance in the study's two primary endpoints.
The company, however, stopped a 166-patient Phase II dose-optimization study in patients with mild diarrhea of non-specific causes following an interim analysis.
The trial design was not producing "definitive information about dose optimization," said Lisa Conte, Shaman's president and CEO. "We've stopped that type of trial design, although not the indication that we're looking for. We're still going for traveler's [diarrhea] and other moderate-to-severe cases of acute watery diarrhea, but we're looking to get our critical information about dosing in more severely ill diarrhea patients."
Two other Phase II trials are ongoing, including one in patients with traveler's diarrhea — potentially the most commercially lucrative indication.
"We're going to do a lot of Phase II work in different patient populations," said Conte, "and learn as much as we can about the broad application of the product, so then we can go forward with two short and sweet pivotal trials which cover a very broad labeling opportunity."
Based on the Phase II results in AIDS patients, the company expects to start a Phase II/III trial early next year that will test Provir in about 100 patients, with another 100 receiving placebo.
In addition to treating more patients, the Phase II/III trial likely will treat them over a longer period.
"The data from [the Phase II] study . . . suggest that there may be additional benefit to be gained by a longer treatment," said James Pennington, Shaman's senior vice president and chief medical officer, in a prepared statement. "We intend to work with the FDA in an expedited program to design and conduct trials that test Provir for longer treatment periods with larger patient populations."
By the fourth day of treatment, the 26 Provir-treated patients had experienced a reduction of 451.3 grams in average daily stool weight, vs. 150.7 grams in the control group. The Provir group also enjoyed a drop in abnormal stool frequency — from an average of 5.2 abnormal stools in 24 hours to just 2.2 by the trial's end.
"This trial was quite powerful with regard to p-values," noted Conte. "There was a continual dramatic drop each day in the treatment, and [the patients] had not yet plateaued."
In the weight reduction endpoint, the p-value was 0.018, while the frequency endpoint achieved a value of 0.047.
AIDS-related diarrhea is Provir's lead indication, though Shaman is aiming for broader labeling covering serious diarrheas.
"The mechanism of action supports a broad-based application," Conte said.
Provir is derived from an extract of the croton plant, found in Latin America. Rather than attacking infectious microbes or inhibiting gastrointestinal activity, the drug targets the underlying cellular mechanism for the diarrhea by blocking chloride secretion. In most cases, a patient's own immune response can dispatch the bugs.
Shaman has four clinical stage products, including a diabetes drug, SP-134101, whose investigational new drug application with the FDA has just been approved.
SP-134101 lowers both glucose levels and triglyceride levels and has a beneficial effect on blood pressure in animal models of Type II diabetes. The compound is one of 15 that have served as the basis for collaborations with Lipha SA, a wholly owned subsidiary of Merck KGaA, in Darmstadt, Germany, and Ono Pharmaceuticals Inc., of Osaka, Japan.
Shaman's shares (NASDAQ:SHMN) closed Thursday at $5.875, down $0.688. *