By Lisa Seachrist
WASHINGTON — In a 400-patient pivotal trial, Shaman Pharmaceuticals Inc.'s oral anti-diarrheal drug, Provir, demonstrated its ability to fend off AIDS-related diarrhea.
The trial tested three dose-formulations of the drug and showed that the 500 milligram dose effectively quelled intransigent diarrhea associated with AIDS. In fact, the drug proved most effective in the most serious cases.
"This was the best result for us; we were looking to have activity in the 500-milligram dose," said Lisa Conte, president and CEO of South San Francisco-based Shaman. "We are right on track for filing an NDA [new drug application] in the first quarter of 1999."
Provir has been assigned fast-track designation from FDA and will receive an expedited review once the NDA is filed.
The double-blind, randomized trial tested placebo against an older formulation of the drug and two doses of a newer formulation. Patients received four doses daily of either placebo, 500-milligram beads (the older formulation), 250-milligram tablets (a newer formulation), or 500-milligram tablets (the intended commercial formulation).
The trial called for patients to be treated for six days as in-patients and if they responded to treatment to continue to be treated for three weeks as outpatients. The primary efficacy endpoint was a reduction in total daily stool weight during the inpatient stay. The group receiving the 500-milligram tablet dose achieved this endpoint.
"We have a pre-NDA meeting scheduled for January, so we don't want to detail the results of the study," Conte said. "However, I can tell you that we saw results very similar to the Phase II results we have already reported."
In October 1997, the company reported 26 patients treated with Provir for four days had a reduction of 451.3 grams in average daily stool weight versus 150.7 grams for the control group.
The pivotal trial examined the tolerability of Provir over a long treatment period, showing no unexpected adverse events or rebound diarrhea.
"We have never been [dosing] in patients for such a long period of time," Conte said. "It's very encouraging that we had no ill effects, because [the drug is] going to be used in a chronic fashion or a chronic episodic fashion."
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 the chloride secretion. In most cases, a patient's own immune response can dispatch the bacteria or viruses.
However, in AIDS-related diarrhea, patients often have no pathogenic agent causing it. Conte noted that, three years ago, in 50 percent of AIDS patients suffering from diarrhea, physicians could culture the cryptosporidium bacteria. Now, less than 10 percent of AIDS patients with diarrhea have any associated pathogen.
"We are studying a disease that didn't exist three years ago," Conte said.
Shaman is also studying Provir as a therapy for watery diarrhea, often called traveler's diarrhea. Phase II trial results showed the drug had activity in that indication. Because traveler's diarrhea is caused by pathogens, Conte said that she could see certain instances such as cholera infection where Provir could be used in combination with antibiotics.
"The results from both the AIDS-related and watery-diarrhea studies show that Provir works regardless of the patient population," Conte said. "These studies show how broadly active Provir is, and how common the chloride ion secretion mechanism is to the disease."
Shaman has initiated an extension study of Provir in patients who had previously participated in studies of Provir in AIDS-related diarrhea.
"We are acutely aware of the human suffering this diarrhea creates in people living with AIDS," Conte said. "Provir can give normalcy back to their lives. This extension study gives us more long-term data, and is our reciprocity to the people who have been on study."
Shaman develops novel therapeutics from tropical plants with a history of medicinal use. The company is developing an oral anti-fungal drug, as well as oral drugs for Type II diabetes.
Shaman's stock (NASDAQ:SHMN) closed Tuesday at $1.75, down $0.312. *