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FDA approves first anti-diarrheal drug for HIV/AIDS patients
 
 
  Phase 3 ADVENT Trial presented at CROI 2012

Weekly response: proportion of subjects with ≤ 2 watery stools per week.

Monthly response: proportion of subjects with ≤ 2 watery stools per week for ≥ 2 of 4 weeks.

Primary endpoint: proportion of subjects with a monthly response in the PBO-controlled phase; [1-sided analysis, significance level of 0.025]).

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FDA NEWS RELEASE

Fulyzaq is the second botanical drug approved by the agency

The U.S. Food and Drug Administration today approved Fulyzaq (crofelemer) to relieve symptoms of diarrhea in HIV/AIDS patients taking antiretroviral therapy, a combination of medicines used to treat HIV infection.

Diarrhea is experienced by many HIV/AIDS patients and is a common reason why patients discontinue or switch their antiretroviral therapies. Fulyzaq is intended to be used in HIV/AIDS patients whose diarrhea is not caused by an infection from a virus, bacteria, or parasite. Patients take Fulyzaq two times a day to manage watery diarrhea due to the secretion of electrolytes and water in the gastrointestinal tract.

Derived from the red sap of the Croton lechleri plant, Fulyzaq is the second botanical prescription drug approved by FDA. A botanical drug product is often a complex mixture derived from one or more plant materials with varying degrees of purification. In 2006, the FDA approved the first botanical prescription drug, Veregen (sinecatechins), a treatment for external genital and perianal warts.

"Currently, there are no FDA-approved therapies for HIV-associated diarrhea," said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "Fulyzaq may be helpful to HIV/AIDS patients with this troublesome condition."

Just as for other types of drugs, the safety and efficacy of a botanical drug product are established through clinical trials. In addition, manufacturers of a botanical drug product must ensure rigorous control of raw materials, and good agricultural and collection practices, together with analytical testing of the complex mixture.

The safety and efficacy of Fulyzaq were established in a clinical trial of 374 HIV-positive patients on stable antiretroviral therapy with a history of diarrhea lasting one month or longer. The median number of daily watery bowel movements was 2.5 per day. Patients who had diarrhea caused by an infection or a gastrointestinal disease were excluded from participating in the trials. Patients were randomly assigned to take Fulyzaq or a placebo twice daily.

The trial was designed to measure clinical response, defined as the number of patients who had two or fewer watery bowel movements weekly. Results showed that 17.6 percent of patients taking Fulyzaq experienced clinical response compared with 8 percent taking placebo. In some patients, a persistent anti-diarrheal effect was seen for 20 weeks. Before treating patients with Fulyzaq, health care professionals should conduct proper testing to confirm the diarrhea is not caused by an infection or a gastrointestinal disease. Common side effects reported in patients taking Fulyzaq in the clinical trial were upper respiratory tract infection, bronchitis, cough, flatulence, and increased levels of the liver enzyme bilirubin.

Fulyzaq is distributed by Salix Pharmaceuticals, based in Raleigh, N.C. under license from Napo Pharmaceuticals, Inc.

Veregen is marketed by Florham Park, N.J.-based PharmaDerm.

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According to research firm GlobalData, the global HIV-associated diarrhea therapeutics market was worth $499.1 million in 2011. Crofelemer was discovered by Napo Pharmaceuticals Inc., and was licensed to Glenmark Pharmaceuticals Ltd. of Mumbai, India in 2005 and to Salix Pharmaceuticals Inc. (SLXP) in 2008.

The FDA pointed out that makers of botanicals not only have to show the safety and efficacy of their proposed products through clinical trials, but they must also demonstrate that proper agricultural and collection practices are followed and that the raw materials meet scrupulous standards.

Salix has said the market in the U.S. for Fulyzaq is relatively small, only about $300 million. Salix licenses the drug from Napo Pharmaceuticals, which this time last year announced that it was terminating a collaboration agreement with India's Glenmark Pharmaceuticals. Glenmark was supposed to "develop and commercialize the drug crofelemer in over 140 countries" but did not "file a single application for regulatory approval" in India or any other country, Napo said at the time.

Bloomberg Sept 5 2012: The drug is made from the crimson-colored sap of the Dragon's Blood tree found in the rainforests of Peru, said G. Michael Freeman, Salix's associate vice president for investor relations, in a phone interview. Questions about the production and control of the extract have been the "primary topic" of discussions with the FDA, according to the company statement.....That ingredient is "a complex mixture that is the first botanical product to be reviewed by the agency for oral use," Salix said.......The FDA extended the original decision date for crofelemer by three months in April to allow regulators more time to review the application. The agency didn't ask for additional studies, Salix said.

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FDA Continues Review of Crofelemer New Drug Application beyond PDUFA Goal Date of September 5, 2012

RALEIGH, N.C.--(BUSINESS WIRE)--Sep 5, 2012 - Salix Pharmaceuticals, Ltd. today announced that the Food and Drug Administration has advised the Company that its New Drug Application (NDA) for crofelemer 125 mg tablets, for the proposed indication of symptomatic relief of non-infectious diarrhea in patients with HIV/AIDS on anti-retroviral therapy, is still under review and that a final action will not be taken by the scheduled Prescription Drug User Fee Act (PDUFA) goal date of September 5, 2012.

Bill Forbes, Pharm. D., Executive Vice President, Medical, Research and Development, and Chief Development Officer, Salix, stated, "The FDA continues to work collaboratively with Salix to progress this important product through its full review. By taking no action at this time, the FDA has allowed for the currently ongoing dialogue between Salix and the FDA to continue.

"The continuing dialogue should allow further collaboration between us and the Agency, a collaboration that has resulted in substantial progress in handling topics important to crofelemer as well as to botanical products in general. The primary topic is the production and control of the crofelemer active pharmaceutical ingredient, a complex mixture that is the first botanical product to be reviewed by the Agency for oral use. This focus is needed to ensure compliance with the manufacturing and product quality requirements of the Food, Drug & Cosmetic Act. Both Salix and the FDA are committed to a robust level of cooperation and data exchange with the goal of providing crofelemer to patients suffering from the very important unmet need of the indication for which we are seeking approval. Our efforts to date have advanced both the chemical and the regulatory science methods available to ensure the quality and clinical usefulness of crofelemer and, potentially, other botanical products.

"We look forward to this continuing collaboration, and at this time anticipate an action by the FDA on our NDA by the end of the first quarter of 2013."

About Crofelemer

Crofelemer is a first-in-class anti-diarrheal botanical drug substance. Crofelemer has minimal absorption and no effect on gut motility. Crofelemer's mechanism of action is through inhibition of both the cystic fibrosis transmembrane conductance regulator protein (CFTR) chloride ion channel and the calcium-activated chloride ion channels (CaCC). Crofelemer acts by blocking chloride ion channel secretion and accompanying high volume water loss in diarrhea, normalizing the flow of chloride ions and water in the GI tract.

About Diarrhea in HIV/AIDS Patients

Diarrhea remains a common problem for patients with HIV/AIDS that often negatively impacts their quality of life and can lead to discontinuation or premature switching of anti-retroviral therapy (ART) regimens. Approximately 1.2 million people in the United States are living with HIV/AIDS and ~40% of those patients suffer from either episodic or chronic diarrhea. This condition can not only significantly reduce quality of life, but also result in weight loss, depression, reduced social interaction, and often increase direct and indirect healthcare costs.

About Salix Pharmaceuticals

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription products 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 and market them through the Company's gastroenterology specialty sales and marketing team.

Salix markets XIFAXAN® (rifaximin) tablets 200 mg and 550 mg, MOVIPREP® (PEG 3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), OSMOPREP® (sodium phosphate monobasic monohydrate, USP and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO® (mesalamine) extended-release capsules 0.375 g, METOZOLV® ODT (metoclopramide HCl), RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection, SOLESTA®, DEFLUX®, PEPCID® (famotidine) for Oral Suspension, Oral Suspension DIURIL® (Chlorothiazide), AZASAN® (Azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC® 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT® Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg. Crofelemer, budesonide foam, RELISTOR® , Lumacan® and rifaximin for additional indications are under development.

For full prescribing information and important safety information on Salix products, including BOXED WARNINGS for OSMOPREP, AZASAN and METOZOLV, please visit www.salix.com where the Company promptly posts press releases, SEC filings and other important information or contact the Company at 919 862-1000.

Salix trades on the NASDAQ Global Select Market under the ticker symbol "SLXP".

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). Information on our web site, Twitter feed and Facebook page is not incorporated in our SEC filings.

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Napo Comments on FDA Announcing Extension of Crofelemer NDA Priority Review

SAN FRANCISCO--(BUSINESS WIRE)--May 3, 2012 - Napo Pharmaceuticals, Inc. (Napo) has been informed that the U.S. Food & Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) date for the company's first in class novel drug compound, crofelemer. The Agency's Priority Review of the New Drug Application (NDA) for crofelemer is for the indication of chronic diarrhea in people living with HIV/AIDS who are on anti retroviral therapy.

According to Salix Pharmaceuticals, Inc. (Salix), the PDUFA date, which was originally set for June 5, 2012, has been extended to September 5, 2012. The FDA apparently notified Salix that it extended the PDUFA date by three months because it needs additional time to conduct a full review of the NDA. According to Salix, the FDA has not requested additional studies.

Although Salix filed the NDA with the FDA for CRO-HIV, Napo discovered and developed crofelemer and owns all the IP related to the drug. On November 4, 2011, Napo terminated its Collaboration Agreement, dated December 9, 2008, with Salix because Salix breached the agreement. In May 2011, prior to terminating the Collaboration Agreement, Napo filed suit against Salix because of Salix's alleged failure to satisfy its contractual obligations to commercialize crofelemer in a timely manner. Crofelemer has received fast-track designation by the FDA to treat diarrhea in people living with HIV/AIDS.

Despite the announcement of crofelemer's highly statistically significant Phase 3 ADVENT trial results for CRO-HIV on November 4, 2010, Salix did not file the NDA with the FDA for this indication until December 2011 after Napo filed suit against Salix and served Salix with its notice of termination of the Collaboration Agreement.

"Our company is committed to the advancement of crofelemer," says Lisa A. Conte, CEO of Napo. "We are optimistic about our ability to bring it to the HIV community and the global marketplace as quickly as possible." Napo has already invested tens of millions of dollars in the development of crofelemer.

According to the Center for Disease Control, there are 1.2 million people living with HIV/AIDS in the United States, of which approximately 338,000 suffer from chronic diarrhea.

Napo Pharmaceuticals, Inc.

Napo focuses on the development and commercialization of proprietary pharmaceuticals for the global marketplace. The company's business model merges traditional high-value markets in the West with the higher volume business models of emerging and developing economies. Napo's discovery process is based on the knowledge of traditional healers, or shamans, working in rain forest areas and provides benefit sharing to the communities with which it works. Visit Napo at www.napopharma.com.

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Salix Pharmaceuticals Announces Extension of Crofelemer NDA Priority Review

RALEIGH, N.C.--(BUSINESS WIRE)--Apr 30, 2012 - Salix Pharmaceuticals, Ltd. today announced that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) goal date for the Agency's Priority Review of the New Drug Application (NDA) for Crofelemer 125 mg tablets for the proposed indication for the control and symptomatic relief of diarrhea in patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) on anti-retroviral therapy (ART). The FDA has notified Salix that it requires additional time for a full review of the submission and has extended the June 5, 2012 goal date by three months. The extended user fee goal date is September 5, 2012. The FDA did not request additional studies.

About Crofelemer

Crofelemer is a first-in-class, gastrointestinal agent of botanical origin. Crofelemer is a gut-targeted, orally administered, anti-secretory, anti-diarrheal agent that has minimal absorption. Crofelemer is a locally-acting product that is believed to possess dual novel mechanisms of action that might be effective in treating both acute infectious diarrhea and chronic diarrhea. Investigational studies support the use of crofelemer as an anti-secretory anti-diarrheal agent that may provide relief to patients through the inhibition of chloride secretion by both gut CFTR (Cystic Fibrosis Transmembrane Conductance Regulator Protein) as well as gut CaCC (calcium-activated chloride channel). Inhibiting CFTR and CaCC prevents the secretion of chloride and other ions, along with the water that passively follows chloride, out of the body into the intestinal lumen. This secretion leads to diarrhea, with the associated symptoms of dehydration, electrolyte imbalance, abdominal cramping, urgency and increased frequency. Additionally, crofelemer, unlike other anti-diarrheal agents, does not affect gut motility. In trials to date, crofelemer is well tolerated, and demonstrates a safety profile comparable to placebo. Crofelemer, if approved, would be a first-in-class CFTR inhibitor as well as a first-in-class CaCC inhibitor that would work as an anti-secretory anti-diarrheal drug.

About HIV/AIDS-Associated Diarrhea

Approximately 50% of the 1 million people in the United States living with HIV/AIDS are currently taking an anti-retroviral therapy (ART), and approximately 30% of HIV/AIDS patients on ART (approximately 150,000 patients) experience episodic or chronic diarrhea. Diarrhea in this patient population can result in weight loss, reduced quality of life, poor compliance with ART and increased healthcare costs.

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Salix Pharmaceuticals Announces FDA Granting of Priority Review Designation for the Crofelemer NDA for Treatment of Diarrhea in Patients with HIV/AIDS on Anti-Retroviral Therapy

RALEIGH, N.C.--(BUSINESS WIRE)--Feb 7, 2012 - Salix Pharmaceuticals, Ltd. (NASDAQ:SLXP) today announced that the U.S. Food and Drug Administration (FDA) has granted Priority Review designation for the Company's New Drug Application (NDA) for crofelemer 125 mg tablets for the proposed indication for the control and symptomatic relief of diarrhea in patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) on anti-retroviral therapy (ART).

The FDA grants a Priority Review designation to drugs offering major advances in treatment, or providing a treatment where no adequate therapy exists. Based on this review classification, the FDA has issued an action date for the NDA of June 5, 2012 under the Prescription Drug User Fee Act (PDUFA).

"We are pleased with the FDA's acceptance of the NDA for crofelemer and their decision to grant Priority Review for our application," stated Bill Forbes, Pharm.D., Executive Vice President, Medical, Research and Development, and Chief Development Officer, Salix. "This review classification signals that the FDA believes that crofelemer has the potential to provide a significant advance in the treatment of HIV/AIDS-associated diarrhea for patients on ART. We believe the availability of crofelemer has the potential to change the treatment paradigm for HIV/AIDS patients suffering from diarrhea."

About Crofelemer

Crofelemer is a first-in-class, gastrointestinal agent of botanical origin. Crofelemer is a gut-targeted, orally administered, anti-secretory, anti-diarrheal agent that has minimal absorption. Crofelemer is a locally-acting product that is believed to possess dual novel mechanisms of action that might be effective in treating both acute infectious diarrhea and chronic diarrhea. Investigational studies support the use of crofelemer as an anti-secretory anti-diarrheal agent that may provide relief to patients through the inhibition of chloride secretion by both gut CFTR (Cystic Fibrosis Transmembrane Conductance Regulator Protein) as well as gut CaCC (calcium-activated chloride channel). Inhibiting CFTR and CaCC prevents the secretion of chloride and other ions, along with the water that passively follows chloride, out of the body into the intestinal lumen. This secretion leads to diarrhea, with the associated symptoms of dehydration, electrolyte imbalance, abdominal cramping, urgency and increased frequency. Additionally, crofelemer, unlike other anti-diarrheal agents, does not affect gut motility. In trials to date, crofelemer is well tolerated, and demonstrates a safety profile comparable to placebo. Crofelemer, if approved, would be a first-in-class CFTR inhibitor as well as a first-in-class CaCC inhibitor that would work as an anti-secretory anti-diarrheal drug.

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NDA Submitted for Crofelemer

Salix Pharmaceuticals Announces NDA Submission for Crofelemer for the Treatment of HIV-Associated Diarrhea


RALEIGH, N.C.--(BUSINESS WIRE)--Dec 14, 2011 - Salix Pharmaceuticals, Ltd. today announced that the Company has submitted to the U.S. Food and Drug Administration (FDA) a New Drug Application (NDA) for Crofelemer for the proposed treatment of HIV-associated diarrhea. By regulation, the FDA has 60 days from the date of submission to conduct a filing review to determine if the application is sufficiently complete to permit a substantive review.

Salix has an exclusive license to the HIV-associated diarrhea indication for Crofelemer and the additional indications of pediatric diarrhea and acute infectious diarrhea in North America, Europe (excluding Iceland, Liechtenstein, Norway and Switzerland) and Japan. Salix also has a worldwide license to all other possible human indications, including irritable bowel syndrome, for Crofelemer. Napo has purported to terminate the license due to Salix's alleged failure to develop Crofelemer and other alleged breaches of the parties' Collaboration Agreement. As Salix has previously explained, Napo's purported termination of the license is groundless and without merit.

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

FDA To Rush Review Of SP-303/Provir As Anti-Diarrheal For AIDS Patients

South San Francisco, CA -- May 7, 1998 -- The United States Food and Drug Administration has granted Shaman Pharmaceuticals, Inc.'s anti-diarrheal compound SP-303/Provir(TM), currently in Phase III clinical trials, a Fast Track Product designation for the treatment of diarrhea in patients with AIDS.

With this designation, the FDA is expected to take such actions as are appropriate to expedite the development and review of an application for marketing approval of the product.

Chronic diarrhea is a devastating syndrome that afflicts 20 to 60 percent of patients with AIDS. The syndrome not only compromises their quality of life, it can dramatically impact their health and significantly increase the cost of their care. Despite the treatment breakthroughs of protease inhibitors and highly active antiretroviral therapy, diarrhea is a persistent problem among patients with AIDS. Furthermore, symptomatic therapies for diarrhea have proven limited in efficacy and frequently resulted in undesirable side effects.

SP-303/Provir(TM) is currently being evaluated in a Phase III human clinical trial which began in late March. This double-blind, placebo-controlled study is planned to include approximately 300 patients at more than 20 sites throughout the U.S. The study includes both an in-patient and an out-patient phase for a total of four weeks of treatment.

In October, 1997, Shaman reported results of an earlier Phase II study, also evaluating the efficacy of SP-303/Provir(TM) in patients with AIDS suffering from diarrhea. The study showed that treatment with SP-303/Provir(TM) was effective in reducing stool weight and abnormal frequency in patients with AIDS and that the study drug was well tolerated.

 
 
 
 
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