|FDA Application No.||(NDA) 208169|
|Active Ingredient(s)||URIDINE TRIACETATE|
|Original Approval or Tentative Approval Date||September 4, 2015|
FDA APPROVAL SUMMARY
Chemotherapy induced poisoning, VISTOGARD, FDA 2015-12-11
Hereditary orotic aciduria, Xuriden, FIRST APPROVAL, 2015-09-04
Uridine triacetate is a drug used in the treatment of hereditary orotic aciduria and to treat patients following an overdose ofchemotherapy drugs 5-fluorouracil or capecitabine, or in patients exhibiting early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of 5-fluorouracil or capecitabine administration.
Uridine triacetate, formerly known as vistonuridine, is an orally active prodrug of the naturally occurring nucleoside uridine. It is used for the treatment of hereditary orotic aciduria (Xuriden), or for the emergency treatment of fluorouracil or capecitabine overdose or toxicity (Vistogard). It is provided in the prodrug form as uridine triacetate as this form delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. When used for the treatment or prevention of toxicity associated with fluorouracil and other antimetabolites, uridine triacetate is utilized for its ability to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces toxicity and cell-death associated with two cytotoxic intermediates: 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Normally, FdUMP inhibits thymidylate synthase required for thymidine synthesis and DNA replication and repair while FUTP incorporates into RNA resulting in defective strands. As a result, these metabolites are associated with various unpleasant side effects such as neutropenia, mucositis, diarrhea, and hand–foot syndrome. Like many other neoplastic agents, these side effects limit the doses of 5-FU that can be administered, which also affects the efficacy for treatment. By pre-administering with uridine (as the prodrug uridine triacetate), higher doses of 5-FU can be given allowing for improved efficacy and a reduction in toxic side effects . It can also be used as a rescue therapy if severe side effects present within 96 hours after initiation of therapy. Uridine triacetate is also used for the treatment of hereditary orotic aciduria, also known as uridine monophosphate synthase deficiency. This rare congenital autosomal recessive disorder of pyrimidine metabolism is caused by a defect in uridine monophosphate synthase (UMPS), a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway. As a result of UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, accounting for most symptoms of the disease. Additionally, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Furthermore, orotic acid crystals in the urine can cause episodes of obstructive uropathy. When administered as the prodrug uridine triacetate, uridine can be used by essentially all cells to make uridine nucleotides, which compensates for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular uridine nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced.
Marketed as the product Xuriden (FDA), uridine triacetate is indicated for the treatment of hereditary orotic aciduria. Marketed as the product Vistogard (FDA), uridine triacetate is indicated for the emergency treatment of adult and pediatric patients in the following situations: following a fluorouracil or capecitabine overdose regardless of the presence of symptoms; or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration.
Uridine Triacetate was approved by the U.S. Food and Drug Administration (FDA) on Sep 4, 2015. It was developed by Wellstat Therapeutics, then marketed as Xuriden® by Wellstat Therapeutics in US. Then it was also approved by FDA for overdose of certain types of chemotherapy on Dec 11, 2015 and marketed as Vistogard®.
Uridine Triacetate is a prodrug of the nucleoside uridine used to treat hereditary orotic aciduria. Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesize uridine, a necessary component of ribonucleic acid (RNA). Signs and symptoms of the disease include blood abnormalities (anemia, decreased white blood cell count, decreased neutrophil count), urinary tract obstruction due to the formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental delays.
Xuriden® is approved as oral granules that can be mixed with food or in milk or infant formula, and is administered once daily. The starting dosage is 60 mg/kg once daily; the dose may be increased to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy.
Mechanism Of Action
Uridine triacetate is an acetylated form of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation (Figure 1).
Figure 1: Uridine Triacetate Conversion to Uridine
URIDEN provides uridine in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis.
Uridine triacetate is a synthetic uridine pro-drug that is converted to uridine in vivo. When used for the treatment or prevention of toxicity associated with fluorouracil and other antimetabolites, uridine triacetate is utilized for its ability to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces toxicity and cell-death associated with two cytotoxic intermediates: 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). By pre-administering with uridine (as the prodrug uridine triacetate), higher doses of 5-FU can be given allowing for improved efficacy and a reduction in toxic side effects [A18578] such as neutropenia, mucositis, diarrhea, and hand–foot syndrome. Uridine triacetate is also used for replacement therapy in the treatment of hereditary orotic aciduria, also known as uridine monophosphate synthase (UMPS) deficiency. As a result of UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, accounting for most symptoms of the disease. Additionally, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Furthermore, orotic acid crystals in the urine can cause episodes of obstructive uropathy. When administered as the prodrug uridine triacetate, uridine can be used by essentially all cells to make uridine nucleotides, which compensates for the genetic deficiency in synthesis in patients with hereditary orotic aciduria.
Production Example 1
5.6 g of uracil and 0.1 g of ammonium sulfate were dissolved in 22.4 ml of 1,1,1,3,3,3-hexamethyldisilazane and reacted at 120° C. for 2.5 hours. After the completion of the reaction, the reaction mixture was distilled to give 11.8 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine. 1H-NMR (400 MHz, in C2D6CO): δ=0.29 (s, 9H), 0.31 (s, 9H), 6.35 (d, J=5.6 Hz, 1H), 8.19 (d, J=5.5Hz, 1H)
Referential Example 11.21 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine obtained in PRODUCTION EXAMPLE 1 and 1.15 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose were dissolved in 4.8 ml of acetonitrile and cooled to 5° C. Next, 0.94 g of SnCl4 was added dropwise thereinto at the same temperature. After stirring for 10 minutes at the same temperature, the mixture was heated to 50° C. and reacted for 3 hours. The reaction mixture was analyzed by HPLC. Thus, β-uridine triacetate was obtained with a reaction yield of 83%.
0.93 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine obtained in PRODUCTION EXAMPLE 1 and 0.92 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose were dissolved in 4.7 ml of acetonitrile and cooled to 4° C. Then 0.49 g of FeCl3 was added thereto at the same temperature. After stirring for 10 minutes at the same temperature, the mixture was heated to 50° C. and reacted. The reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was added dropwise at 4° C. into a cold aqueous solution of sodium hydrogencarbonate which had been preliminarily prepared. After filtering off the catalyst residue, the filtrate was separated and the aqueous layer was extracted with 20 ml portions of ethyl acetate thrice. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After distilling off the solvent, 1.2 g (purity 80%) of the target compound was obtained as a viscous white solid.
Namely, the target compound could be obtained at a yield comparable to REFERNTIAL EXAMPLE 1 wherein SnCl4 was employed as the catalyst. 1H-NMR (400 MHz, in CDCl3): δ=2.11 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H), 4.35 (m, 3H), 5.33 (m, 2H), 5.79 (d, J=8.2 Hz, 1H), 6.04 (d, J=4.9 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H)
December 11, 2015
The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments.
“Treating cancer requires not only selecting which drug may be most effective and well tolerated, but ensuring the correct dose is given at proper intervals. While rare, unintentional overdose can occur,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents.”
Fluorouracil (taken by infusion) and capecitabine (taken orally) are similar types of chemotherapy that have been used for decades to treat several types of cancer, including breast and gastrointestinal cancers. An overdose of fluorouracil or capecitabine is rare, but when it occurs, the effects are serious and can be fatal.
Vistogard, taken orally, blocks cell damage and cell death caused by fluorouracil chemotherapy. Patients should take Vistogard as soon as possible after the overdose (whether or not they have symptoms) or early-onset (within four days) of severe or life-threatening toxicity. The patient’s health care provider will determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.
The efficacy and safety of Vistogard were studied in 135 adult and pediatric cancer patients who were treated in two separate trials and had either received an overdose of flourouracil or capecitabine, or had early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving flourouracil (not due to an overdose). The studies’ primary measure was survival at 30 days or until chemotherapy could resume if prior to 30 days. Of those who were treated with Vistogard for overdose, 97 percent were still alive at 30 days. Of those treated with Vistogard for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days.
Vistogard is not recommended for treating non-emergency adverse reactions associated with flourouracil or capecitabine because Vistogard may lessen the efficacy of these drugs. The safety and efficacy of Vistogard initiated more than 96 hours following the end of treatment with flourouracil or capecitabine have not been established.
The most common side effects of treatment with Vistogard were diarrhea, vomiting and nausea.
The FDA granted Vistogard orphan drug designation, which provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Vistogard was also granted priority review and fast track designations, which are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.
Vistogard is marketed by Wellstat Therapeutics Corporation based in Gaithersburg, Maryland.
With support from Almac, Wellstat delivers for a rare disease.
Proximity of API and finished drug development helps uridine triacetate to market for two indications
By Rick Mullin
“The initial contact was a cold call by Almac in 2010 or 2011,” recalls Mike Bamat, senior vice president of R&D at Wellstat Therapeutics, a small drug company in Gaithersburg, Md. “There were probably a couple of calls. It was one of those things where timing is everything.”
Almac, a Craigavon, Northern Ireland-based pharmaceutical services company, was looking to get in on Wellstat’s development of uridine triacetate, a synthetic pyrimidine analog, as an antidote for fluorouracil and capecitabine toxicity and overdose in cancer patients receiving those chemotherapies. And the calls, which Almac records indicate followed some communication between the companies, happened to come just when Wellstat was looking to change service partners as it moved toward commercial development of the drug.
Discovery: Wellstat Therapeutic’s research on the therapeutic potential of exogenous uridine leads to a determination that uridine triacetate is a safe means of delivering the agent
Applications: Treatment of hereditary orotic aciduria (HOA), an extremely rare disease in which the body does not produce uridine, causing overproduction of orotic acid; emergency treatment of toxic reaction to or overdose of the cancer treatments fluorouracil and capecitabine
Methods of action: Treating HOA, uridine triacetate restores intracellular nucleotide concentrations, normalizing orotic acid production; as a chemotherapy antidote, it increases intracellular levels of uridine to dilute fluorouracil and capecitabine
Years in development: Since 2008 for chemotherapy antidote, and 2013 for HOA
Approved: Xuriden for HOA, Sept. 4, 2015; Vistogard for chemotherapy antidote, Dec. 11, 2015
The job went to Almac, as did work that sprang up as the result of another phone call to Wellstat—this one from the U.S. Food & Drug Administration.
As Bamat explains, uridine triacetate caught FDA’s attention regarding another potential indication—an extremely rare and life-threatening disease called hereditary orotic aciduria, or HOA. A consequence of the body’s inability to produce uridine, a necessary component of ribonucleic acid, HOA can manifest in a range of symptoms including blood abnormalities, developmental delays, and urinary tract obstruction caused by overproduction of orotic acid. There have been 20 reported cases of HOA since the 1950s. Only four cases are currently known in the U.S., Bamat says, and likely fewer than 20 in the world.
Wellstat landed approvals for Xuriden, the HOA treatment, in September of last year and Vistogard, the chemotherapy antidote, in December.
The story of Xuriden centers on a raft of FDA incentives for super-rare diseases that enabled Wellstat to move forward on an expedited application for a drug that will never be made in any great volume. But bringing Xuriden and Vistogard to market may also be viewed as the story of a drug discovery firm becoming a commercial enterprise thanks to its partnership with a service provider.
As Wellstat began late-stage development of the chemotherapy antidote, its research partner at the time, QS Pharma, was acquired by the service firm WIL Research. The look and feel of the partnership changed, according to Bamat.
“We kind of lost the small, easy-to-work-with relationship we had with them,” he says. Wellstat also needed support on development and manufacturing of a finished drug product composed of granules delivered in packets or sachets. The drug is administered orally, usually sprinkled on food such as applesauce or yogurt.
Almac was deemed a good fit because of its experience with developing drugs in granule form for “sachet presentation,” a packaging method more common in Europe than in the U.S. The Northern Ireland firm’s ability to develop and manufacture the active pharmaceutical ingredient (API) and the drug product in one location—at its headquarters—would also prove to be a significant advantage.
The distance between Gaithersburg and Craigavon, however, was a concern, according to Bamat. “We debated it. Especially those of us who knew we would be going there,” he says. “We couldn’t just jump in a car and go. But we looked at a variety of things, including cost and value, and it was all very positive at Almac.”
According to David Downey, vice president of commercial operations at Almac, bringing Wellstat’s work on uridine triacetate to commercial production posed several challenges, the first being to secure supply of uridine starting material, which is extracted from sugar beets by Euticals, an Italian firm. Next was developing a method to control particle size in both the API and the finished product. Almac also had to validate process equipment as it scaled up production.
“Uridine triacetate is Wellstat’s first commercial product,” Downey says. “So we were provided with a process more fit for development than for commercial production.”
The basic formulation of a granule drug product is simple, according to Downey: The API and excipient are mixed in a dry blender. The challenge is developing an analytical regimen to assure the granules are blended uniformly. Meeting the challenge required a high level of coordination between API and drug product process development.
“Wellstat needed a partner that could support them from the API to the drug product,” Downey says. The physical proximity between the Almac facilities in Craigavon conducting API and drug product work was a key advantage, he claims.
“If you listen to our business development people, you’ll hear them use the term, ‘crossing car parks as opposed to crossing oceans,’ ” Downey says, explaining that many competitors who offer API and finished drug services run these operations thousands of kilometers apart from each other, sometimes on different continents.
Before it signed on with Almac, Wellstat had been working with uridine triacetate for about 10 years. Its focus on developing the antidote drug started in 2008. Branching into the HOA treatment, however, upped the stakes.
Clinical study development for an HOA therapy was expedited via a full house of regulatory incentives from FDA, according to Bamat. “We had orphan drug designation, rare pediatric designation, breakthrough therapy designation, and priority review,” he says. “So they really went all out in helping us develop this.”
Although Wellstat was interested in developing a life saving drug for children, it was concerned about paying for it, given the tiny market. “At that time, the rare pediatric disease priority review voucher program was just on the radar,” Bamat says. “FDA said, ‘Consider this new program. Maybe it’s a way that at some risk you could recoup some of your costs.’ We looked at it and were willing to take the risk.”
It paid off. Wellstat was able to sell its priority review voucher—which entitles a company that brings a rare pediatric drug to market to receive expedited review of a subsequent drug—to AstraZeneca last year for an undisclosed amount. Other vouchers sold in 2015 brought high sums, including $350 million for one that AbbVie bought from United Therapeutics in August.
Bamat says Wellstat is not likely to change focus after its success with uridine triacetate. It continues to investigate new indications for the compound and will likely work with Almac on anything going into commercial development.
He emphasizes the importance of maintaining an effective working relationship with an outsourcing partner. “My main consideration is that these are people we can really work with on a day-to-day, week-to-week basis,” Bamat says. “Will the communication be good? Will they be honest and transparent with us, and will we be the same for them? That was a key factor, and we felt it was a plus with Almac.”
|Trade names||Vistogard, Xuriden|
|Metabolism||Pyrimidine catabolic pathway|
|Onset of action||Tmax = 2-3 hours|
|Biological half-life||2-2.5 hours|
|Molar mass||370.31 g·mol−1|
- HIGHLIGHTS OF PRESCRIBING INFORMATION OF XURIDEN
- BTG Announces FDA Approval of VISTOGARD® (Uridine Triacetate) as Antidote to Overdose and Early Onset, Severe, or Life-Threatening Toxicities from Chemotherapy Drugs 5-Fluorouracil (5-FU) or Capecitabine
- “FDA Approved Drugs:Uridine Triacetate”. FDA. 2015-12-11. Retrieved 2016-04-29.
- “Uridine triacetate”. DrugBank.
- 1. J. Am. Chem. Soc. 1953, 75, 2017-2019.2. Angew. Chem. internat. Edit. 1971, 10, 75.
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