FDA Approval: Uridine Triacetate for the Treatment of Patients Following

Published OnlineFirst July 11, 2016; DOI: 10.1158/1078-0432.CCR-16-0638

CCR Drug Updates Clinical Cancer Research FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs Gwynn Ison, Julia A. Beaver, W. David McGuinn Jr, Todd R. Palmby, Jeannette Dinin, Rosane Charlab, Anshu Marathe, Runyan Jin, Qi Liu, Xiao Hong Chen, Xavier Ysern, Olen Stephens, Ge Bai, Yaning Wang, Sarah E. Dorff, Joyce Cheng, Shenghui Tang, Rajeshwari Sridhara, William Pierce, Amy E. McKee, Amna Ibrahim, Geoffrey Kim, and Richard Pazdur

Abstract

On December 11, 2015, the FDA approved uridine triacetate not been established. The approval is based on data from two (VISTOGARD; Wellstat Therapeutics Corporation) for the emer- single-arm, open-label, expanded-access trials in 135 patients gency treatment of adult and pediatric patients following a receiving uridine triacetate (10 g or 6.2 g/m2 orally every 6 hours fluorouracil or capecitabine overdose regardless of the presence for 20 doses) for fluorouracil or capecitabine overdose, or who of symptoms, and of those who exhibit early-onset, severe, or life- exhibited severe or life-threatening toxicities within 96 hours threatening toxicity affecting the cardiac or central nervous sys- following the end of fluorouracil or capecitabine administration. tem, and/or early onset, unusually severe adverse reactions (e.g., Ninety-six percent of patients met the major efficacy outcome gastrointestinal toxicity and/or neutropenia) within 96 hours measure, which was survival at 30 days or survival until the following the end of fluorouracil or capecitabine administration. resumption of chemotherapy, if prior to 30 days. The most Uridine triacetate is not recommended for the nonemergent common adverse reactions were vomiting, nausea, and diarrhea. treatment of adverse reactions associated with fluorouracil or This article summarizes the FDA review of this New Drug Appli- capecitabine because it may diminish the efficacy of these drugs, cation, the data supporting approval of uridine triacetate, and and the safety and efficacy of uridine triacetate initiated more than the unique regulatory situations encountered by this approval. 96 hours following the end of administration of these drugs has Clin Cancer Res; 22(18); 1–5. 2016 AACR.

Introduction drugs and therefore manifest with early-onset, severe, or life- threatening toxicities that can result in death. One of the most Each year, hundreds of thousands of patients in the United well-described etiologies for impaired elimination of fluorouracil fl States receive treatment with either uorouracil or capecitabine and capecitabine is a partial or complete deficiency of the enzyme fl (a prodrug of uorouracil) for a variety of malignancies, dihydropyrimidine dehydrogenase (DPYD, also known as DPD), including multiple gastrointestinal malignancies and breast which is the initial rate-limiting enzyme in the catabolism of cancer (1). Fluorouracil and capecitabine are cytotoxic anti- fluoropyrimidines (8). DPD activity is subject to wide variability metabolites that interfere with nucleic acid metabolism in both due in part to genetic variation in the sequence of the DPD gene normal and cancer cells. Studies have reported an approximate (DPYD), which can result in a range of enzymatic deficiency from fl 0.5% incidence of mortality from uorouracil toxicity, and an partial (3%–5% of the population) to complete loss (0.2% of estimated 0.5% to 1% incidence of mortality from capecita- the population) of enzyme activity (9–10). Unfortunately, pre- – bine-based regimens (2 7). Although overdoses of these drugs screening of patients for "impaired" DPD activity prior to initi- fi are rare, they can result in signi cant morbidity and mortality. In ation of pyrimidine therapy is not routinely performed and is addition, certain patients have impaired elimination of these not yet possible with a high level of predictive accuracy using available genotyping and/or phenotyping tests (11). Prior to uridine triacetate, there were no approved therapies for patients Center for Drug Evaluation and Research, U.S. Food and Drug Admin- istration, White Oak, Maryland. experiencing serious or life-threatening toxicities after receiving fluorouracil or capecitabine. Note: This is a U.S. Government work. There are no restrictions on its use. Corresponding Author: Gwynn Ison, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, White Oak, MD 20993. Phone: 301-796-4057; Fax: 301- Chemistry 796-9849; E-mail: [email protected] VISTOGARD oral granules contain the active ingredient uridine doi: 10.1158/1078-0432.CCR-16-0638 triacetate, which is a pyrimidine analogue. The chemical name 0 0 0 2016 American Association for Cancer Research. for uridine triacetate is (2 ,3 ,5 -tri-O-acetyl-ß-D-ribofuranosyl)-

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2,4(1H,3H)-pyrimidinedione. Uridine triacetate is supplied as cannot be ruled out. There is no clinically meaningful effect of 10 g packets for oral administration containing the following gender, race, and age on uridine pharmacokinetics in adults, inactive ingredients: ethylcellulose (0.309 g), Opadry Clear (Col- and no dose adjustment is needed on the basis of these intrinsic orcon; proprietary dispersion of hydroxypropylmethylcellulose factors. Although there was a trend for increase in clearance of and Macrogol; 0.077 g), and natural orange juice flavor (0.131 g). uridine triacetate with increasing body surface area (BSA) in During the New Drug Application (NDA) review, concerns related adults, given the high survival rate and large safety margin, dose to intra- and interbatch variability in the dissolution of the adjustment was not thought to be needed on the basis of BSA in products were identified that could affect the absorption and adults. A BSA-based dose of 6.2 g/m2 orally every 6 hours was availability of the drug. However, due to the demonstrated considered reasonable for pediatric patients, as there were 6 favorable benefit:risk ratio and no known toxic dose, the vari- pediatric patients who received BSA-based dosing, and all of ability was deemed acceptable, and a postmarketing commitment them survived without major safety concerns. to confirm the dissolution studies and address these concerns was agreed upon. Clinical Trial Design The approval of uridine triacetate was based on data from two Nonclinical Pharmacology and Toxicology single-arm, open-label trials. The first trial, WELL401 (n ¼ 75), was a collection of single patient investigational new drug appli- Uridine triacetate is a pyrimidine analogue and acetylated cations performed according to clinical operations procedures prodrug of uridine. Excess circulating uridine is converted to developed to provide emergency access to uridine triacetate. The uridine triphosphate (UTP), which competes with FUTP for incor- second trial, 401.10.001 (n ¼ 60), was an expanded access poration into RNA. Uridine competitively inhibits cell damage and protocol that was requested by FDA to collect better quality cell death caused by fluorouracil. The effect of uridine triacetate efficacy and safety data. Both trials included adult patients who on the antitumor activity of fluorouracil is not currently known; had either experienced a fluorouracil overdose or presented with for this reason, the product information for uridine triacetate severe or life-threatening toxicities within 96 hours following the included a limitation of use detailing the potential of uridine end of fluorouracil administration. WELL401 also included triacetate to result in decreased fluorouracil or capecitabine patients treated with capecitabine, pediatric patients, patients efficacy. treated outside of the 96-hour window post-fluorouracil admin- Repeat-dose toxicology studies in rats demonstrated that the istration, and patients treated outside of the United States. For maximum feasible dose of 2,000 mg/kg/day was well tolerated. both trials, an overdose was defined as administration of fluoro- Uridine triacetate was not genotoxic, and there were no findings uracil at a dose, or infusion rate, greater than the maximum suggestive of tumorigenic potential in the 6-month repeat-dose tolerated dose (MTD) for the patient's intended regimen of toxicity study in rats. Reports from rodent carcinogenicity studies fluorouracil or its oral prodrug, capecitabine. Patients received were not submitted or required to support this application. uridine triacetate 10 g orally every 6 hours for 20 doses (or at a BSA Uridine triacetate did not affect fertility or reproductive perfor- adjusted dosage of 6.2 g/m2/dose for 20 doses for 4 pediatric mance in male and female rats. patients), and follow-up continued for 30 days. The primary In mice given sublethal doses of fluorouracil, uridine triacetate efficacy outcome of both trials was survival at 30 days or until decreased hematologic toxicity as a function of increasing dose, the resumption of chemotherapy if prior to 30 days. Because of although hematologic toxicity was not completely prevented. In similarities between the two trials (n ¼ 135), the results from these mice given a lethal dose of fluorouracil, uridine triacetate resulted two trials have been pooled. in 90% survival when given within 24 hours. Survival decreased with increasing intervals between fluorouracil dosing and uridine triacetate treatment. Demographics and Disease Characteristics The majority of patients enrolled in the two trials were white (72%), 9% were black/African American, 6% were Hispanic, Clinical Pharmacology 4% were Asian, and 95% had a cancer diagnosis. The median Following single-dose oral administration, the maximum uri- age was 59 years (range, 1–83). A total of 6 pediatric patients dine concentrations in plasma were achieved within 2 to 3 hours, were administered uridine triacetate. Of the 135 patients, 117 and the half-life ranged from 2 to 2.6 hours. Mean uridine were treated with uridine triacetate following an overdose of concentrations after 20 doses increased approximately 1.5 times fluorouracil (n ¼ 112) or capecitabine (n ¼ 5), and 18 were in the clinical trials. Food had no impact on the pharmacokinetics treated after exhibiting early-onset, severe, or life-threatening of uridine, and uridine triacetate can be administered without toxicities within 96 hours following the end of therapy (Fig. 1). regard to meals. When necessary, uridine triacetate can be admin- Of the 112 patients overdosed with fluorouracil, 105 (94%) istered via a nasogastric or gastrostomy tube. were overdosed by infusion rate only (range, 1.3–720 times Uridine can be excreted via the kidneys and can also be the planned infusion rate), 4 (4%) were overdosed by dose metabolized by normal pyrimidine catabolic pathways present only, and 3 (3%) were overdosed by both dose and rate. These in most tissues. In vitro enzyme data did not reveal meaningful fluorouracil overdoses occurred most frequently from incorrect effects of uridine triacetate or uridine on cytochrome P450 inhi- programing of the infusion pump (42%) or pump malfunc- bition or induction. In vitro data showed that uridine triacetate tions (23%). Of the patients who exhibited impaired elimina- was a weak substrate for P-glycoprotein (ABCB1, also known as tion, the severe or life-threatening toxicities seen involved the P-gp). Because of the potential for high concentrations of central nervous system (e.g., encephalopathy,acutemental uridine triacetate in the gut after dosing, the interaction of status change), cardiovascular system, gastrointestinal system uridine triacetate with orally administered P-gp substrate drugs (e.g., mucositis), and bone marrow (e.g., neutropenia).

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WELL401: n = 75 401.10.001: n = 60 Total: N = 135

Overdose Early onset n = 117 n = 18 (ﬂuorouracil)

Fluorouracil Capecitabine n = 112 n = 5 (includes 3 pediatric patients) Figure 1. Distribution of study participants.

Overdose by Overdose by Overdose by infusion rate dose rate and dose n = 105 n = 4 n = 3 (includes 3 pediatric patients)

Incorrect pump programming: n = 44 Pump malfunction: n = 24 Other: n = 37

fi Ef cacy Results sources including reports from the Institute of Safe Medication Of the 135 patients treated with uridine triacetate in the two Practices, U.S. FDA Manufacturers and User Facility Device Expe- trials, 96% (n ¼ 130) survived to day 30 or resumed chemother- rience database, U.S. FDA Adverse Events Database, FDA Medical apy prior to day 30, and 4% (n ¼ 5) died. As shown in Table 1, the Product Safety Network, legal documents, and physician or hos- majority of patients who received fluorouracil or capecitabine pital reports. Of these 25 representative historical patients, 84% overdoses (97%) and the majority of patients who exhibited (n ¼ 21/25) died. In comparison, the efficacy results from patients early-onset, severe, or life-threatening toxicity following the end overdosed by fluorouracil and treated with uridine triacetate of fluorouracil or capecitabine administration (89%) survived. Of revealed that 97% survived (n ¼ 109/112; see Fig. 2). the 135 patients, 131 were treated within the protocol specified Of the 18 patients treated with uridine triacetate after exhi- 96-hour window and 98% lived. Four patients were treated biting early-onset, severe, or life-threatening toxicity following outside of the 96-hour window, and 2 of these patients died. the end of fluorouracil administration, 2 (11%) died and 16 The 5 patients treated with uridine triacetate after capecitabine (89%) survived. All cases presented with toxicities affecting the ingestion and the 6 pediatric patients treated with uridine triac- cardiac, central nervous, gastrointestinal, or hematopoietic etate all survived. system, and were severe or life-threatening on initial presen- The applicant provided case reports from 25 patients who were tation. Nine patients required intubation due to fluorouracil overdosed with fluorouracil by infusion rate (range 1.9–64 times toxicity and 7 of them recovered and survived at 30 days. One the planned infusion rate) and were treated with supportive care patient required balloon-pump cardiovascular support and alone. These historical case reports came from various literature recovered. Ten patients experienced life-threatening mental

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Table 1. Combined efficacy: all patients in WELL401 and 401.10.001 uridine triacetate (grade 3 nausea and vomiting). Common Overdose Early-onset Overall (grade 1–2) adverse reactions occurring in >2% of patients treated Total enrolled 117 18 135 with uridine triacetate included vomiting, nausea, and diarrhea. Survivala 114 (97%) 16 (89%) 130 (96%) Death 3 (3%) 2 (11%) 5 (4%) aSurvival includes patients who survived at 30 days or patients who resumed Discussion chemotherapy prior to 30 days. The approval of uridine triacetate was based on two open-label, single-arm trials and highlights the ability of FDA to approve a drug based on data obtained from expanded-access protocols. As status changes or encephalopathy, and 8 survived. Of the 16 described above, FDA recommended the initiation of trial surviving patients, 14 developed symptoms within 96 hours 401.10.001 to conduct a more formal expanded-access trial following administration of fluorouracil. An FDA review of the to allow for the potential of regulatory submission based on Adverse Event Reporting System was searched for postmarket- clinical data. Because of the life-threatening nature of fluorouracil ing, voluntary adverse event reports of fatalities of patients who or capecitabine overdose, and early-onset severe or life-threaten- experienced early-onset, severe, or life-threatening toxicity fol- ing toxicity, it would not have been ethical to conduct a random- lowing the end of administration of fluorouracil or capecita- ized trial; therefore, FDA viewed the nonrandomized design bine. Multiple historical cases from the last 50 years (58 cases and use of historical controls as acceptable. Despite the lack of for fluorouracil and 145 cases for capecitabine) were described; concurrent control, efficacy was clearly demonstrated with a many cases demonstrated a similar presentation of early-onset, survival benefit (96%) in 135 patients who would have otherwise severe, or life-threatening toxicity, which was treated with been expected to have substantial mortality. Furthermore, based supportive care but ultimately all resulted in death. on the trial results showing that 50% (n ¼ 2/4) of the patients treated beyond 96 hours of overdose died, as well as supportive Safety Results nonclinical results, there was a compelling rationale to specify a The primary safety population included 135 patients who 96-hour timeframe for uridine triacetate administration. As a received at least one dose of uridine triacetate. Five patients died result, a limitation of use was included in the product labeling, within 30 days of therapy, although none of the deaths were which specifies that the safety and efficacy of uridine triacetate attributed to uridine triacetate. Three of the deaths occurred in initiated more than 96 hours following the end of fluorouracil or patients who overdosed with fluorouracil and 2 deaths occurred capecitabine have not been established. in patients exhibiting early onset, severe, or life-threatening tox- Although only 6 pediatric patients were studied in one of the icity after fluorouracil administration. trials, all of the patients survived. The safety profile showed a low Although the safety review was confounded by adverse events risk to pediatric patients with only mild toxicities seen. Therefore, related to fluorouracil or capecitabine, uridine triacetate was due to the cases studied, supportive nonclinical safety informa- overall well tolerated by most patients. Only 2 patients discon- tion, adult clinical data, and a strong biologic and clinical ratio- tinued uridine triacetate due to adverse reactions (nausea, vomit- nale, the pediatric indication was included. Similarly, only 5 ing, and diarrhea) based on timing of the reaction with uridine capecitabine-treated patients were studied on the trials. However, triacetate administration. Serious adverse reactions and grade 3 all of these patients survived, and based upon the understanding adverse reactions were seen in only one patient treated with of capecitabine as a prodrug of fluorouracil, as well as additional

Historic control cases Uridine triacetate– (supportive care only) treated cases n = 25 n = 112 3%

16%

Figure 2. Outcome of ﬂuorouracil overdose historical control cases versus uridine triacetate–treated cases. 84% 97%

Survived Died

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capecitabine patient cases submitted in the 120-day safety report presence of symptoms, or of patients who exhibit early-onset, demonstrating definitive uridine triacetate benefit, the indication severe, or life-threatening toxicity affecting the cardiac or cen- included capecitabine. tral nervous system, and/or early-onset, unusually severe The patients with early-onset, severe, or life-threatening adverse reactions (e.g., gastrointestinal toxicity and/or neutro- toxicity from fluorouracil were closely examined, as a potential penia) within 96 hours following the end of fluorouracil or risk exists that using uridine triacetate in a nonemergent setting capecitabine administration. In addition, there were supportive for patients who experience usual toxicities of fluorouracil or nonclinical data and a safety profile that was acceptable and capecitabine might result in decreased efficacy of fluorouracil or low risk. Despite small numbers in certain subgroups such capecitabine. To address this concern, the timing of early-onset as early-onset toxicity, capecitabine-treated patients, and pedi- toxicities (within 96 hours) and a detailed description of the atric patients, the overall benefit:risk profile was favorable to expected affected organ systems with potential severe or life- support approval. The approval demonstrates FDA's commit- threatening toxicities were described in the indication state- ment to regulatory flexibility through use of available clinical ment. In addition, a limitation of use was added to further trial data from expanded-access protocols to advance the treat- highlight this potential risk. ment of life-threatening conditions. The subset of patients studied with early-onset, severe, or life- threatening toxicity from fluorouracil was further examined in Disclosure of Potential Conflicts of Interest relation to DPD deficiency. Although 19 patients in the two No potential conflicts of interest were disclosed. trials were tested for DPD deficiency (9 patients had variants in DPYD, with four having genotypes often associated with com- Authors' Contributions plete or partial DPD deficiency), the available genetic testing Conception and design: G. Ison, J.A. Beaver, S. Tang, R. Pazdur results could not definitively account for the early-onset, severe, Development of methodology: G. Ison, J.A. Beaver, R. Pazdur or life-threatening toxicities from fluorouracil or capecitabine Analysis and interpretation of data (e.g., statistical analysis, biostatistics, administration. This may be in part due to the inconsistencies computational analysis): G. Ison, J.A. Beaver, W.D. McGuinn, R. Charlab, R. Jin, Q. Liu, Y. Wang, S.E. Dorff, J. Cheng, S. Tang, R. Sridhara, W. Pierce, G. Kim introduced by the use of different tests with differing methods Writing, review, and/or revision of the manuscript: G. Ison, J.A. Beaver, and alleles assayed, as well as the unclear functional impact of W.D. McGuinn, T.R. Palmby, J. Dinin, R. Charlab, A. Marathe, R. Jin, Q. Liu, some of the variants identified. In addition, there were cases of X.H. Chen, O. Stephens, G. Bai, Y. Wang, S.E. Dorff, S. Tang, R. Sridhara, early-onset toxicity that did not have a DPYD variant identified W. Pierce, A.E. McKee, A. Ibrahim, G. Kim, R. Pazdur and cases for which no testing was performed. For these Administrative, technical, or material support (i.e., reporting or organizing reasons, no specificdescriptionofDPDdeficiency was included data, constructing databases): J.A. Beaver, J. Dinin, R. Jin, R. Sridhara, G. Kim, R. Pazdur in the label. Other (CMC): X. Ysern In conclusion, uridine triacetate demonstrated efficacy for the emergency treatment of adult and pediatric patients fol- Received March 9, 2016; revised May 2, 2016; accepted May 10, 2016; lowing a fluorouracil or capecitabine overdose regardless of the published online September 15, 2016.

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FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs

Gwynn Ison, Julia A. Beaver, W. David McGuinn, Jr, et al.

Clin Cancer Res Published OnlineFirst July 11, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-16-0638

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