Crofelemer Improves Diarrhea in People with HIV

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Crofelemer (brand name Fulyzaq) was well-tolerated and significantly reduced non-infectious diarrhea among HIV positive people taking antiretroviral drugs, according to a study published in the November-December 2013 issue of HIV Clinical Trials.

Despite a dramatic reduction in opportunistic infections and the advent of better-tolerated antiretroviral agents, diarrhea remains a significant concern for people with HIV.

Rodger MacArthur from Wayne State University and colleagues conducted the ADVENT study to evaluate the safety, efficacy, and optimal dose of crofelemer, an anti-secretory agent derived from a South American plant. In this randomized Phase 3 trial, nearly 400 HIV positive participants were assigned to receive different doses of crofelemer or placebo.

Significantly more patients who received crofelemer reported a reduction in watery bowel movements compared with placebo recipients (18% vs 8%). Response rates rose with longer use, reaching 54% by week 24. "In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile," the researchers concluded.

Below is an edited excerpt from a Salix Pharmaceuticals press release describing the study and its findings in more detail.

Fulyzaq (Crofelemer) 125 mg Delayed-Release Tablets Significantly Improves Noninfectious Diarrhea in Adult Patients Living with HIV on ART Therapy

ADVENT study demonstrating the efficacy and safety of Fulyzaq featured in HIV Clinical Trials peer-reviewed journal

Raleigh, NC -- January 14, 2014 -- Salix Pharmaceuticals, Ltd. (NASDAQ:SLXP) today announced that HIV Clinical Trials, an international, peer-reviewed journal focused on human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) research, published a study that supports the efficacy and safety of Fulyzaq (crofelemer) for the treatment of noninfectious diarrhea caused by anti-retroviral therapy (ART) in adult patients with HIV. The Antidiarrhea Therapy in HIV Disease−Emerging Treatment Concepts (ADVENT) trial concluded that Fulyzaq provides significant improvement in the symptomatic relief of noninfectious diarrhea with a safety profile similar to placebo and with no negative impact on clinical immune parameters (HIV viral load and CD4+ cell count).  The study appears in the November/December issue of HIV Clinical Trials.

"Diarrhea can be an unfortunate and persistent occurrence for patients living with HIV who are on ART therapies," said Rodger MacArthur, MD, professor of medicine at Wayne State University, Division of Infectious Diseases and lead investigator. "The ADVENT trial showed that Fulyzaq (crofelemer) significantly improved diarrhea without negatively impacting ART. This is an important advancement in treatment, as Fulyzaq is the only FDA-approved option for relief of noninfectious diarrhea specifically for people living with HIV."

The ADVENT trial was a randomized, double-blind, phase 3 trial that used a two-stage design to determine optimal dose and evaluate Fulyzaq for the treatment of noninfectious diarrhea in HIV positive patients. Under the placebo-controlled method, the study evaluated 374 patients and revealed that patients achieved significant clinical response when treated with Fulyzaq 125 mg delayed-release tablets compared to the placebo (17.6% vs 8.0%, one-sided, P = .01). Additionally, Fulyzaq was minimally absorbed, well tolerated, did not negatively impact ART efficacy, and had a safety profile comparable to placebo.

"We are excited that the leading peer-reviewed journal HIV Clinical Trials highlights the ADVENT trial that demonstrates the efficacy and safety of Fulyzaq," said Bill Forbes, PharmD, Executive Vice President, Medical, Research and Development and Chief Development Officer, Salix. "It is our hope that increasing knowledge about diarrhea treatment options will enable patients living with HIV to start the dialogue with healthcare providers for managing this often under-discussed and, therefore, undertreated condition."

Fulyzaq acts as an anti-secretory, anti-diarrheal agent that works locally in the gastrointestinal (GI) lumen and exhibits minimal systemic absorption. It normalizes the flow of water in the GI tract to relieve diarrhea in people taking ART. Fulyzaq is derived on a sustainable basis from the Croton lechleri plant, native to northwestern South America. The ADVENT trial led to the Food and Drug Administration approval of Fulyzaq in December 2012. Visit www.fulyzaq.comfor more information. For more details regarding the article, visit www.hivclinicaltrials.com.

Indicationfor FULYZAQ

FULYZAQ is an antidiarrheal indicated for the symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy

Important Safety Information about FULYZAQ

FULYZAQ (crofelemer) delayed-release tablets should not be used for the treatment of infectious diarrhea. Rule out infectious etiologies of diarrhea before starting FULYZAQ. If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of noninfectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen.

Based on animal data, FULYZAQ may cause fetal harm. Safety and effectiveness of FULYZAQ have not been established in patients less than 18 years of age.

In clinical studies, the most common adverse reactions (occurring in ≥3% of patients and at a rate greater than placebo) were upper respiratory tract infection, bronchitis, cough, flatulence, and increased bilirubin.

About FULYZAQ

FULYZAQ is derived on a sustainable basis from the Croton lechleri plant, native to northwestern South America. FULYZAQ acts as an anti-secretory, anti-diarrheal agent that works locally in the GI lumen and exhibits minimal systemic absorption. At the recommended dose of one 125 mg delayed-release tablet taken orally, twice daily, FULYZAQ works to inhibit both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (C1-) channel, and the calcium-activated C1- channels (CaCC).

Inhibiting CFTR and CaCC reduces the secretion of chloride ions, along with the water that enables their transport, out of the circulatory system and into the intestinal lumen. The secretion of chloride ions has been shown to cause diarrhea, with the associated symptoms of dehydration, electrolyte imbalance, abdominal cramping, urgency and increased frequency.

Salix obtained rights to crofelemer under license from Napo Pharmaceuticals, Inc.

About HIV/AIDS-Associated Diarrhea

Diarrhea remains a common problem for patients with HIV/AIDS that may lead to discontinuation or premature switching of antiretroviral therapy (ART). Currently it is estimated that approximately 1.2 million persons are living with HIV infection in the United States. Additionally, it is estimated that approximately 135,000-270,000 persons on anti-retroviral therapy (ART) suffer from noninfectious diarrhea.

About Salix

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription products and medical devices for the prevention and treatment of gastrointestinal diseases. Salix's strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and market them through the Company's gastroenterology specialty sales and marketing team.

For more information, please visit our Website at www.salix.com or contact the Company at 919-862-1000. Follow us on Twitter (@SalixPharma) and Facebook (www.facebook.com/SalixPharma).

1/28/14

Reference

RD MacArthur, TD Hawkins, SJ Brown, et al. Efficacy and Safety of Crofelemer for Noninfectious Diarrhea in HIV-Seropositive Individuals (ADVENT Trial): A Randomized, Double-Blind, Placebo-Controlled, Two-Stage Study. HIV Clinical Trials 14(6):261-273. November-December 2013.

Other Source

Salix Pharmaceuticals. Fulyzaq (Crofelemer) 125 mg Delayed-Release Tablets Significantly Improves Noninfectious Diarrhea in Adult Patients Living with HIV on ART Therapy. Press release. January 14, 2014.