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CROI 2012: Crofelemer Reduces Diarrhea in People with HIV; FDA Grants Priority Review

A plant compound known as crofelemer significantly decreased the frequency of secretory diarrhea in HIV positive patients, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last month in Seattle. The U.S. Food and Drug Administration (FDA) has given crofelemer priority review status and is expected to take action by early June.

Secretory diarrhea caused by infectious pathogens, toxins, or antiretroviral drugs is a problem for many people with HIV. Crofelemer is a proanthocyanidin compound extracted from the sap of an Amazon rainforest plant (Croton lechleri) that is used by traditional healers to treat a variety of conditions including diarrhea. It works by inhibiting 2 different mechanisms that regulate secretion of fluid from the intestines.

Rodger MacArthurfrom Wayne State University in Detroit and colleagues evaluated the safety and efficacy of crofelemer for treatment of chronic secretory diarrhea in people with HIV.

The Phase 3 ADVENT study included 376 HIV positive patients who experienced watery bowel movements on at least 5 of the 7 days prior to enrollment. Participants were on combination antiretroviral therapy (ART) with CD4 cell counts above 100 cells/mm³. They had no evidence of intestinal pathogens. About 85% were men and the average age was approximately 45 years.

Participants in the first stage of the study were randomly assigned to receive crofelemer tablets at doses of 125, 250, or 500 mg twice-daily, or else placebo, for 4 weeks. The 125 mg dose was selected and tested in more patients in the second stage. After the 4-week placebo-controlled periods, all participants received crofelemer for a 5-month extension period.

The researchers looked at weekly response, defined as the proportion of patients with 2 or fewer watery stools per week, and monthly response, defined as the proportion with 2 or fewer watery stools per week for at least 2 out of 4 weeks in a month.

Results

• In the first stage of the study, monthly response rates were 20.5% in the crofelemer 125 mg arm, 9.3% in the 250 mg arm, and 19.6% in the 500 mg arm, compared with just 2.0% in the placebo arm.
• In the second stage, 16.3% of participants receiving 125 mg crofelemer experienced monthly response, compared with 11.4% of placebo recipients.
• Combining the 2 stages, overall monthly response rates were 17.6% in the 125 mg crofelemer group versus 8.0% in the placebo group, a significant treatment difference of 9.6% (P = 0.0096).
• Placebo recipients who crossed over to crofelemer during the 5-month extension phase experienced significant benefit after 1 month (36% vs 9% response; P < 0.0001).
• In the placebo-controlled phases, crofelemer recipients had lower incidence than placebo recipients of any adverse events (27% vs 33%), serious adverse events (2% vs 3%), and treatment discontinuation due to adverse events (0% vs 3%).

Based on these findings, the researchers concluded, "Crofelemer 125 mg [twice-daily] effectively reduced secretory diarrhea in HIV positive subjects and had a safety profile similar to placebo. These results are consistent with its targeted gut action and minimal systemic absorption."

Crofelemer was discovered by San Francisco-based Napo Pharmaceuticals and was being developed by Salix Pharmaceuticals, but Napo terminated its collaboration agreement with Salix in November 2011, claiming the latter company had failed to meet its obligations to develop and commercialize the product in a timely manner.

According to a press release issued by Napo, the FDA accepted the New Drug Application (NDA) for crofelemer for HIV-related diarrhea with a Priority Review designation. The agency has set June 5, 2012, as the action date for the NDA under the Prescription Drug User Fee Act (PDUFA). The company is also studying crofelemer for irritable bowel syndrome, acute gastrointestinal infections (including cholera), and pediatric diarrhea.

4/3/2012

Reference

R MacArthur, T Hawkins, S Brown, et al.ADVENT Trial: Crofelemer for the Treatment of Secretory Diarrhea in HIV+ Individuals. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 889.

Other Source

Napo Pharmaceuticals. New Treatment Presented for Chronic Diarrhea in HIV/AIDS Patients. Press release. March 8, 2012.