Issue:
97
Page: 68-69
Update: FDA Approves Crofelemer as First Oral Botanical Drug
by Lindsay Stafford Mader
HerbalGram.
2013; American Botanical Council
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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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