On New Year’s Eve of 2012, the US Food and Drug Administration (FDA) announced its approval of crofelemer, marking the second time a botanical preparation — and the first time an orally administered botanical preparation — has received prescription drug approval from the Administration.¹ The first and only other drug in the United States approved under the FDA’s botanical drug review process is a topical green tea extract, Veregen®, which was approved by FDA in 2006.² While several other botanical ingredients currently are approved as over-the-counter drugs, crofelemer and Veregen meet all US pharmaceutical requirements and can be dispensed only by prescription.

Crofelemer is derived from the latex of the South American sangre de drago tree (sometimes referred to as sangre de grado; Croton lechleri, Euphorbiaceae), which is used widely in the region’s traditional medicine and known in English as dragon’s blood.² A deep red latex leaks from the tree when its bark is cut, and it is this substance that contains the novel polymolecular structure crofelemer, originally discovered, isolated, and purified by Shaman Pharmaceuticals. Napo Pharmaceuticals of San Francisco now owns the intellectual property of crofelemer, and Salix Pharmaceuticals in Raleigh, North Carolina, is licensed to develop and market it in the United States under the brand name Fulyzaq™. (For an overview of the four companies involved in the drug’s development, see Table I.) Crofelemer is the first US drug approved to treat HIV-associated diarrhea.

The Phase III Trial on which FDA based its crofelemer approval — called ADVENT and designed and initiated by Napo Pharmaceuticals — was a randomized, double-blind, multi-center study that featured a one-month placebo-controlled arm and a five-month placebo-free arm.³ Patients had experienced diarrhea for one month or longer, and efficacy was analyzed based on “the proportion of patients experiencing less than or equal to two watery bowel movements per week, during at least two of the four weeks of the placebo-controlled phase of the study.” The 125 mg delayed-release tablets, to be taken twice a day, are not intended to treat infectious diarrhea, and clinical trial evidence suggests that they do not interact with HIV medications. 

According to FDA’s press release announcing the approval, “The safety and efficacy of Fulyzaq were established in a clinical trial of 374 HIV-positive patients on stable antiretroviral therapy [ART] with a history of diarrhea lasting one month or longer….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.”¹

FDA ushered the crofelemer decision out the door on the last day of 2012 — an action typical of efforts to complete pending drug reviews before the end of each calendar year.⁴ Salix called the approval a “significant step forward in addressing the unmet medical need of people with HIV/AIDS on ART who experience non-infectious diarrhea.”³The company expects Fulyzaq to be available to patients in early 2013. A Bloomberg analysis estimates the drug will bring Salix sales of $18 million in 2013 and $26 million in 2014,⁵and the market potential has been estimated at $300 million. A portion of any income will have to be paid to Napo as milestone payments and royalties. In the days following the announcement, Salix stock shares increased by about 5 percent, while Glenmark Pharmaceuticals, Ltd., the Indian manufacturer and supplier of crofelemer for 140 “emerging market” countries, experienced a 3.4% increase in market shares.⁶

Napo’s Vice-President of Sustainable Supply and Ethnobotanical Research, Steven King, PhD, noted that the company has a commitment to share benefits with governments and indigenous South American communities that have been using sangre de drago for many years and working with Napo to sustainably harvest and replant trees. It will do this through its nonprofit Healing Forest Conservancy.

“This [agreement] was put in place during the Shaman work and adopted officially by Napo,” said Dr. King (email, January 3, 2013). “The details will take a bit of time to unfold, and we of course have to receive royalties from our partners in order to begin this process.”

The patent on crofelemer will expire in 2018, but Salix mentioned in its press release the potential for crofelemer to obtain patent term restoration,³ which extends patent life by up to five years in order to “compensate patent holders for marketing time lost while developing the product and awaiting government approval.”⁷ Most US patents last for 20 years, but because a large portion of this time frequently passes while the drug is going through the long approval process, the US government wants to ensure that drug development and innovation will still be an attractive investment to patent holders, researchers, and pharmaceutical companies.

Following the breaking news of crofelemer’s approval, some herbalists voiced concerns over how it might affect their ability to use sangre de drago — generally more common for herbalist practices in Latin America — as well as consumers’ ability to access it as a dietary supplement. Because prescription crofelemer is an isolated and purified chemical from the tree’s latex, its approval has no impact on the access of the tree’s latex for use as a traditional medicine or dietary supplement; herbalists and consumers will continue to be able to access whole plant-based sangre de drago and any sangre de drago dietary supplements as long as these products do not make inappropriate health claims. FDA confirms this in its 2004 Guidance for Industry on Botanical Drugs, noting that as long as the dietary supplement has been on the market before the drug approval, it is not in jeopardy.⁸

“The latex is not crofelemer,” said Dr. King. “It’s nothing close to crofelemer. So the sale and use of latex anywhere in the world should be unaffected by the approval of this drug.”

The drug’s approval marks an important event in the decades-long history of crofelemer. The original Investigational New Drug application was submitted by Shaman in the early 1990s. In 2001, Shaman went bankrupt and later that year CEO Lisa Conte reorganized into Napo Pharmaceuticals, retaining Shaman’s original intellectual property.² Napo continued to work toward crofelemer’s NDA submission, conducting two Phase III trials. In 2008, Salix obtained a license from Napo in order to complete the ADVENT clinical trial started by Napo, and to complete crofelemer’s development to treat HIV-associated diarrhea.

Salix filed the NDA for crofelemer in December 2011. Due to the serious nature of the medical condition crofelemer treats, FDA assigned the NDA “priority review” status, which indicates that the Administration would aim to approve or reject the application in approximately six months.² Although FDA accepted the NDA for filing in February 2012, it delayed its decision twice, including the most recent delay in September 2012, which added to Napo’s concerns regarding the length of time it was taking Salix to move the product forward and adequately prepare for possible commercialization. In May 2011, Napo filed a legal complaint for breach of contract against Salix, claiming that Salix was “unnecessarily stalling the advancement of this compound.” Salix has maintained that it proceeded with the NDA expeditiously. The lawsuit, currently before the New York Supreme Court, is still pending and a ruling is yet to be determined.

—Lindsay Stafford Mader

References

1. FDA approves first anti-diarrheal drug for HIV/AIDS patients [press release]. Silver Spring, MD: US Food and Drug Administration; December 31, 2012. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333701.htm?source=govdelivery. Accessed January 2, 2013.
2. Mader L. FDA delays decision on crofelemer for second time. HerbalEGram: Volume 9, Number 11, November 2012. Available at: http://cms.herbalgram.org/heg/volume9/11November/Crofelemer_2ndFDAdelay.html. Accessed January 15, 2013.
3. FDA approves Fulyzaq™ (crofelemer) 125 mg delayed-release tablets for the symptomatic relief of diarrhea in patients with HIV/AIDS on anti-retroviral therapy (ART) [press release]. Raleigh, NC: Salix Pharmaceuticals, Inc.; January 2, 2013. Accessed January 2, 2013.
4. Carroll J, McBride R. Last-minute drive at FDA added 6 new drug approvals. FierceBiotech. January 2, 2012. Available at: www.fiercebiotech.com/story/last-minute-drive-fda-added-6-new-drug-approvals/2013-01-02. Accessed January 2, 2013.
5. Edney A, Bostick R. Salix wins FDA approval of dragon’s blood drug for diarrhea. Bloomberg. December 31, 2012. Available at: www.bloomberg.com/news/2012-12-31/salix-wins-fda-approval-of-dragon-s-blood-drug-for-diarrhea-1-.html. Accessed January 2, 2013.
6. Shah A. Glenmark shares rise on Salix drug approval. Livemint. January 1, 2013. Available at: www.livemint.com/Companies/dl82yNxYg3goZoAmigTHhP/Glenmark-shares-rise-on-Salix-drug-approval.html. Accessed January 2, 2013.
7. Small business assistance: frequently asked questions on the patent term restoration program. US Food and Drug Administration website. Available at: www.fda.gov/drugs/developmentapprovalprocess/smallbusinessassistance/ucm069959.htm. Accessed January 7, 2013.
8. Guidance for Industry on Botanical Drugs Products. US Department of Health and Human Services. US Food and Drug Administration, Center for Drug Evaluation and Research. June 2004. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf. Accessed January 7, 2013.