Napo Pharmaceuticals, Inc. Announces That Crofelemer Demonstrates Highly Statistically Significant Results in the Treatment of Chronic Diarrhea in People Living With HIV/AIDS

Update: Fulyzaq (crofelemer) Now FDA Approved - December 31, 2012

Pivotal Phase 3 Trial Provides Clarity on Efficacy and Dose

SAN FRANCISCO--(BUSINESS WIRE)--Nov 4, 2010 - Napo Pharmaceuticals, Inc. (“Napo”) is pleased to announce the completion of top-line analysis of the primary efficacy endpoint from the phase 3 ADVENT trial, a randomized, double-blind, parallel-group, placebo-controlled, two-stage, adaptive design phase 3 study designed to evaluate the safety and efficacy of crofelemer in the treatment of chronic diarrhea in people living with HIV/AIDS on anti-retroviral therapy (“ARV”). Crofelemer at a daily dose of 125 mg twice daily demonstrated a highly statistically significant improvement in the primary responder analysis, defined as patients having two or less watery stools in two of the four week placebo-controlled phase. Crofelemer was well tolerated in this study and its adverse event profile was not different from that of the placebo-treated group.

The ADVENT trial is being conducted under a “fast track” status and has been a part of a “special protocol assessment” (“SPA”) agreement. Due to the adaptive nature of the trial design, the pre-specified p-value for the treatment difference was 0.025. The p-value achieved in the ADVENT trial was 0.0096. The aforementioned results achieve the efficacy targets set forth in the SPA agreement.

Up to 40 percent of the one million people living with HIV in the United States manage diarrhea on a chronic basis, which can affect adherence to life-saving anti-retroviral regimens. Crofelemer is a first-in-class, anti-secretory, anti-diarrheal agent that acts locally in the gastrointestinal tract, without significant absorption and locally regulating the fluid balance in the gut.

The ADVENT trial is a two-stage adaptive randomized, double-blind, placebo-controlled study that evaluated the effects of crofelemer in HIV-associated diarrhea. Stage I of ADVENT evaluated the effects of 125 mg twice daily (BID), 250 mg BID and 500 mg BID crofelemer against a placebo-controlled group following 28 days of treatment as a balanced randomization. Following the completion of 4 weeks of dosing in approximately 200 patients, with about 50 patients in each group, a crofelemer dose of 125 mg BID was selected by an independent committee for the second stage of the ADVENT trial. The crofelemer dose of 125 mg BID performed very similarly to the 500 mg BID dose of crofelemer. The trial continued with the randomization of an additional approximately 180 patients to either placebo or 125 mg BID dose of crofelemer.

All patients that participated in the ADVENT trial were rolled into a 5-month placebo-free extension phase of the trial, in a blinded fashion, wherein all patients were randomized to receive either the 125 mg BID, 250 mg BID or 500 mg BID dose of crofelemer.

“Napo is gratified to receive these important and powerful results in a study of crofelemer in the treatment of HIV-associated diarrhea. This is a complex study population that is managing many medications. These results represent the beginning of the final steps to bring crofelemer to FDA regulatory approval, and the potential cascade of global regulatory approvals both coincident and subsequent to this,” said Napo CEO Lisa Conte. “With these results and an anticipated pre-NDA meeting with the FDA in mid Q1 2011 we look forward to the commercial launch of crofelemer in 2012 in the U.S. and globally. Crofelemer has previously shown benefit in patients with mild to severe acute watery diarrhea, including cholera. The potential benefit to populations around the world suffering from lack of access to clean water and the attendant devastating diarrheal diseases is enormous, and generating sustainable product access to such populations is central to Napo's mission.”

“To our knowledge, this is the first time that a two-stage adaptive trial has been executed as a pivotal phase 3 study to evaluate the safety and efficacy of a new drug in a patient population,” said Dr. Pravin Chaturvedi, Chief Scientific Officer of Napo. “Crofelemer is a novel, first-in-class anti-diarrheal agent that has a physiological and different mechanism of action from traditional anti-diarrheal agents. We are very pleased with the efficient nature of the adaptive design of ADVENT that allowed us to conduct the dose assessment and dose confirmation in a single trial in people living with HIV/AIDS and provided significant clinical benefit.”

Dr. Jerome Ernst, M.D., Napo's Clinical Advisor said, “People infected with HIV who have access to ARVs are achieving undetectable HIV viral loads in ever increasing numbers, allowing them, in many cases, to live healthier lives and also to slow disease transmission. Key to a successful ARV regimen is adhering to a daily dosing regimen and the effective management of side effects such as watery diarrhea. Having a drug like crofelemer that controls diarrhea with no drug-drug interactions, no systemic adsorption and, unlike current anti-diarrheals, no serious side effects, and that can be used chronically, is a significant and welcome advance.”

Napo's licensee, Salix Pharmaceuticals, Inc., has licensed the commercial and development rights to crofelemer for all indications in North America, Europe (excluding certain smaller countries), and Japan, and, for certain other indications including irritable bowel syndrome, worldwide. Salix estimates that the HIV-associated diarrhea market opportunity alone in the U.S. may be $300 million annually. All product commercialized by Salix (and any sub-licensees) shall reference Napo as the licensor, include Napo's logo, and to the extent legally permitted, indicate that the product is sustainably harvested.

Crofelemer has also been licensed to Glenmark Pharmaceuticals, Ltd. in India plus 140 emerging countries (rest of world, or “ROW” territories) for indications related to HIV, use in acute adult infectious diarrhea, and use in pediatric diarrhea. Glenmark anticipates approval of crofelemer in India in 2012. Glenmark and Salix have entered into a commercial supply agreement for crofelemer active pharmaceutical ingredient (API).

Luye Pharmaceuticals has licensed rights to crofelemer in China (including Hong Kong and Macau) for various indications including HIV-associated diarrhea, infectious diseases and pediatric diarrhea.

CROFELEMER'S PEDIATRIC APPLICATIONS

Napo has organized a program to accelerate the development of crofelemer for pediatric watery and infectious diarrheal diseases. Dehydration from watery diarrhea causes death in approximately two million children under age two each year, and measurable morbidity in hundreds of millions more. The company estimates that pediatric diarrhea is the largest market opportunity in ROW territories.

Napo has financed certain pediatric development efforts through an innovative royalty-based funding vehicle called the Crofelemer Access Program (“Cap Global”). With its stakeholders, the company is pursuing long-term sustainable solutions to health issues among pediatric populations in resource-constrained regions. For example, one key investor has assigned his ongoing royalty return from Cap Global to the Angkor Hospital for Children in Siem Reap, Cambodia.

Napo has established a global advisory board to ensure that the development guidelines for a pediatric product incorporate World Health Organization (“WHO”) Essential Medicines guidelines for oral rehydration solution (“ORS”), zinc, etc., and to generate a formulation that is practical and safe for resource-constrained regions with limited health personnel. Napo has formed alliances with Direct Relief International and others to make crofelemer accessible to every childhood population in need, and this program is recognized as a Clinton Global Initiative.

Napo is also in the planning stages for clinical development of crofelemer for severe cholera in pediatric populations, after a second study of crofelemer in treating severe cholera in adults, at the International Centre for Diarrheal Disease Research in Bangladesh (ICDDR, B).

About Crofelemer

Napo's proprietary patented gastrointestinal compound, crofelemer, is a first-in-class anti-secretory agent extracted from Croton lechleri, a medicinal plant sustainably harvested under fair-trade working conditions from several countries in South America. Crofelemer is in various stages of clinical development for four distinct indications:

 

  • Crofelemer for HIV-related diarrhea (CRO-HIV), Phase 3 (under Special Protocol Assessment)
  • Crofelemer for diarrhea irritable bowel syndrome (CRO-IBS), Phase 2
  • Crofelemer for acute infectious diarrhea (including cholera), Phase 2 (CRO-ID)
  • Crofelemer for pediatric diarrhea (CRO-PED), Phase 1

The FDA has granted fast track status to crofelemer development for IBS- and HIV-related indications.

About Napo Pharmaceuticals, Inc.

Napo Pharmaceuticals, Inc. focuses on the development and commercialization of proprietary pharmaceuticals for the global marketplace in collaboration with local partners. The company seeks partners in both traditional high-value markets and in the higher volume business models of emerging and developing economies. Napo was founded in November 2001 and is based in San Francisco, California, with a subsidiary in Mumbai, India.

In addition to crofelemer, Napo holds the exclusive worldwide rights to novel small-molecule potential second-generation anti-secretory agents, which have been licensed to Napo from the Regents of the University of California, and are the subject of NIAID funding. Napo is developing an early clinical stage/ready for Phase 2 product, NP-500, for the treatment of insulin-resistant diseases of Type II diabetes and metabolic syndrome (Syndrome X; pre-diabetic syndrome). Napo has a library of approximately 2,300 medicinal plants.

Napo's discovery process leverages the knowledge of traditional healers, or shamans, working in rain forest areas. Napo provides benefit sharing to the cultures with which it works through a non-profit established by the company called the Healing Forest Conservancy, which is devoted to recognizing the intellectual contributions of indigenous knowledge, the conservation of biological diversity, indigenous cultures, and basic human rights of those communities.

Please note: The materials provided herein contain projections and other forward-looking statements regarding future events. Such statements are just predictions and are subject to risks and uncertainties that could cause the actual events or results to differ materially. These risks and uncertainties include, among others: the cost and unpredictability of the duration and results of clinical trials and FDA approval; the possible impairment of, or inability to obtain, intellectual property rights and the costs of obtaining such rights from third parties; market acceptance for approved products; ability to secure the product; and generic and other competition and the need to acquire new products.

Contact: Napo Pharmaceuticals, Inc.
Lisa A. Conte, CEO, +1 415-371-8302
www.napopharma.com

 

 

Posted: November 2010

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