Novel Drug Approvals for 2015

1.Name       - XURIDEN

2. Active Ingredient-     Uridine triacetate

3. Indication-      To treat patients with heriditary orotic aciduria

Date         Sept 4th 2015

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use XURIDEN safely and effectively. See full prescribing information for XURIDEN. XURIDENTM (uridine triacetate) oral granules

Initial U.S. Approval: 2015

------------------INDICATIONS AND USAGE---------------­ XURIDEN is a pyrimidine analog for uridine replacement indicated for the treatment of hereditary orotic aciduria. (1) --------

---- DOSAGE AND ADMINISTRATION-----------­ Recommended Dosage (2.1): • The starting dosage is 60 mg/kg once daily; the dose may be increased to120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy.

• See the full prescribing information for 60 mg/kg and 120 mg/kg weight-based dosing tables. Preparation and Administration

(2.2) • Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered. • Administer the dose with food (applesauce, pudding or yogurt) or in milk or infant formula. See full prescribing information for preparation and administration instructions.

-----------DOSAGE FORMS AND STRENGTHS--------­ Oral granules: 2 gram packets. (3) -

-----------------CONTRAINDICATIONS------------------­ None (4) -------------WARNINGS AND PRECAUTIONS----------­ None (5)

-----------------ADVERSE REACTIONS-------------------­ No adverse reactions were reported with XURIDEN in patients with hereditary orotic aciduria (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Wellstat Therapeutics Corporation at (1-800-914-0071) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling Revised: 09/ 2015 FULL

ADVERSE REACTIONS-

­ No adverse reactions were reported with XURIDEN in patients with hereditary orotic aciduria

-----------------CONTRAINDICATIONS------------------­ None (4) -------------WARNINGS AND PRECAUTIONS----------­ None (5)

--DOSAGE FORMS AND STRENGTHS--------­ Oral granules: 2 gram packets. (3) --------------

----CONTRAINDICATIONS------------------­ None (4)

-------------WARNINGS AND PRECAUTIONS----------­ None (5)

-----------------ADVERSE REACTIONS-------------------­ No adverse reactions were reported with XURIDEN in patients with hereditary orotic aciduria (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Wellstat Therapeutics Corporation at (1-800-914-0071) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

-----------DOSAGE FORMS AND STRENGTHS--------­ Oral granules: 2 gram packets. (3) -

PATIENT COUNSELING INFORMATION-

Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use) Administration Advise the patient or caregiver:

• To measure the prescribed dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered

• To discard the unused portion of granules in a packet after measuring out the dose. • That XURIDEN can be taken mixed in food (applesauce, pudding or yogurt) or mixed in milk or infant formula.

• That the XURIDEN granules should not be chewed.

Manufactured and distributed by:Wellstat Therapeutics Corporation Gaithersburg, MD 20878 XURIDENTM is a trademark of Wellstat Therapeutics Corporation. The Wellstat logo is a registered trademark of Wellstat Therapeutics Corporation

CLINICAL PHARMACOLOGY-

12.1 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).

7 Reference ID: 3821044 Figure 1: Uridine Triacetate Conversion to Uridine XURIDEN 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.

12.2 Pharmacodynamics-                                                                                                     Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in uridine monophosphate synthase (UMPS).

The UMPS gene encodes uridine 5'monophosphate synthase, a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway in mammalian cells. The defect in UMP synthase in hereditary orotic aciduria has two primary biochemical consequences.

First, the blockade of de novo UMP synthesis results in a systemic deficiency of pyrimidine nucleotides, accounting for most clinical consequences of the disease.

Second, 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. Orotic acid crystals in the urine can cause episodes of obstructive uropathy. XURIDEN delivers uridine into the circulation, where it can be used by essentially all cells to make uridine nucleotides, compensating 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

12.3 Pharmacokinetics Absorption XURIDEN delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. Maximum concentrations of uridine in plasma following oral XURIDEN are generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours.

A study in patients with hereditary orotic aciduria included an assessment of plasma uridine pharmacokinetics in 4 patients. Three of the patients were previously treated with oral uridine. On 8 Reference ID: 3821044 Day 0 (baseline), these three patients received their usual daily dose of oral uridine as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral XURIDEN treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to uridine replacement therapy.

The dose of XURIDEN was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and4) and plasma uridine concentrations were assessed on Day 160 (44 days after the dose increase). Plasma uridine levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3.

Mean exposure to plasma uridine as assessed by Cmax and AUC was greater after oral XURIDEN than after oral uridine (approximately 4-fold on an equiweight basis, and 6-fold on an equimolar basis), although individual differences in relative bioavailability were noted. Plasma concentrations of the uridine catabolite uracil were generally below the limit of quantitation in all patients. Table 3: Pharmacokinetic Parameters for Plasma Uridine Pharmacokinetic Parameters (Plasma Uridine) Day 0 (Baseline) (Oral Uridine, 150 to 200 mg/kg once daily) N = 3 a Day 1 (Oral XURIDEN, 60 mg/kg once daily) N = 4 Day 28 (Oral XURIDEN, 60 mg/kg once daily) N = 4 Day 160 (Oral XURIDEN, 120 mg/kg once daily) N = 2 b Cmax (µM) mean ± SD 56.0 ± 16.6 91.3 ± 32.2 88.7 ± 43.2 80.9 ± 20.0 Tmax (hours) median (rangec ) 2.0 (1.0, 4.0) 2.0 (1.2, 2.1) 1.3 (1.0, 2.5) 3.0 (2.0, 4.0) t1/2 (hours) mean ± SD 1.6 ± 0.7 1.6 ± 0.6 2.3 ± 1.6 8.2 ± 6.8 AUC(0-8) (µM•hr) mean ± SD 238.0 ± 163.2 311.2 ± 153.3 278.7 ± 148.5 465.6 ± 95.3 a Data shown are from patients previously treated with oral uridine b The dose of XURIDEN was increased on Day 116 to 120 mg/kg per day.

Serial plasma samples were taken on Day 160 (44 days after the dose increase) for plasma uridine levels. c Tmax range is expressed as the minimum and maximum values obtained 9 Reference ID: 3821044 Figure 2 Plasma Uridine Following Oral Administration of Uridine (Day 0) or XURIDEN (Days 1, 28 and 160) in Patients with

Hereditary Orotic Aciduria Food Effect on Uridine PK: A study in healthy adult subjects receiving a slightly different formulation of uridine triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of uridine exposure.

Distribution Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier. 10 Reference ID: 3821044

Excretion Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues.

Drug Interaction Studies In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of uridine triacetate or uridine on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1

. In vitro enzyme induction data did not reveal an inducing effect of uridine triacetate or uridine on CYP1A2, CYP2B6, or CYP3A4. In vitro data showed that uridine triacetate was a weak substrate for P-glycoprotein.

Uridine triacetate inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 µM. Due to the potential for high local (gut) concentrations of the drug after dosing, the interaction of XURIDEN with orally administered P-gp substrate drugs cannot be ruled out. In vivo data in humans are not available.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary There are no available data on XURIDEN use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, uridine triacetate at doses similar to the maximum recommended human dose (MRHD) of 120 mg/kg per day was not teratogenic and did not produce adverse effects on embryo-fetal development [see Data].

The background risk of major birth defects and miscarriage for the indicated population are unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of uridine triacetate in human milk, the effect on the breastfed infant or the effect on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for XURIDEN and any potential adverse effects on the breastfed infant from XURIDEN or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of XURIDEN have been established in pediatric patients. Use of XURIDEN is supported by a single open-label clinical trial of uridine triacetate in 4 patients and a retrospective review of the clinical course of 18 patients with hereditary orotic aciduria who were treated with uridine beginning at ages 2 months to 12 yea

There are no apparent differences in clinical response between adults and pediatric patients with hereditary orotic aciduria treated with uridine, however, data are limited. [see Clinical Studies (14)]

ne. The molecular weight is 370.3 and it has an empirical formula of C15H18N2O9