Doxecitine And Doxribtimine

1 INDICATIONS AND USAGE KYGEVVI is indicated for the treatment of thymidine kinase 2 deficiency (TK2d) in adults and pediatric patients with an age of symptom onset on or before 12 years. KYGEVVI is a combination of doxecitine and doxribtimine, both pyrimidine nucleosides, indicated for the treatment of thymidine kinase 2 deficiency (TK2d) in adults and pediatric patients with an age of symptom onset on or before 12 years. ( 1 )

2 DOSAGE AND ADMINISTRATION Obtain baseline transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels in all patients prior to treatment initiation. ( 2.1 ) Recommended dosage ( 2.2 ): KYGEVVI Dosage Level KYGEVVI Dosage (mg/kg/day) Starting 260 mg/kg/day (consisting of 130 mg doxecitine and 130 mg doxribtimine) Intermediate 520 mg/kg/day (consisting of 260 mg doxecitine and 260 mg doxribtimine) Maintenance 800 mg/kg/day (consisting of 400 mg doxecitine and 400 mg doxribtimine) Titrate to the next dosage level based on tolerability after a minimum of 2 weeks at the current dosage level. ( 2.2 ) Administer KYGEVVI orally in 3 equally divided doses with food. ( 2.2 ) See full prescribing information for dosage and administration modifications, monitoring, and preparation and administration instructions. ( 2.4 ) Use KYGEVVI only with ZX2000 administration kit. ( 2.4 ) 2.1 Important Recommendation Prior to KYGEVVI Treatment Initiation Obtain baseline liver transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels in patients prior to treatment initiation with KYGEVVI [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage The recommended dosage of KYGEVVI is based on the patient's weight (Table 1). Titrate to the next dosage level based on tolerability after a minimum of 2 weeks at the current dosage level. Table 1: Recommended Starting, Intermediate, and Maintenance Dosage of KYGEVVI KYGEVVI Dosage Level KYGEVVI Dosage (mg/kg/day) Starting 260 mg/kg/day (consisting of 130 mg doxecitine and 130 mg doxribtimine) Intermediate 520 mg/kg/day (consisting of 260 mg doxecitine and 260 mg doxribtimine) Maintenance 800 mg/kg/day (consisting of 400 mg doxecitine and 400 mg doxribtimine) Administer KYGEVVI orally in 3 equally divided doses approximately 6 hours apart (plus or minus 2 hours) with food [see Clinical Pharmacology (12.3) ] . After calculating the daily dose, use Table 2 to determine the required number of KYGEVVI packets, volume of water needed to reconstitute the powder from the packet(s), and individual volume that is administered 3 times a day [see Dosage and Administration (2.4) ]. 2.3 Dosage and Administration Modifications and Monitoring Liver Test Abnormalities If signs or symptoms consistent with liver injury are observed, interrupt treatment with KYGEVVI until liver transaminase (ALT, AST) and total bilirubin levels have either returned to baseline or stabilized at a new baseline value. Consider re-starting KYGEVVI at the last tolerated dose and increase the dose based on tolerability [see Dosage and Administration (2.2) ] . Consider permanently discontinuing KYGEVVI if signs or symptoms consistent with liver injury persist or worsen. Monitor liver transaminases and total bilirubin levels yearly and as clinically indicated [see Warnings and Precautions (5.1) ] . Gastrointestinal Based on the severity of the diarrhea and/or vomiting, reduce the dose of KYGEVVI or interrupt treatment until diarrhea and/or vomiting improves or returns to baseline. Consider re-starting KYGEVVI at the last tolerated dose and increase the dose based on tolerability [see Dosage and Administration (2.2) ] . For persistent or recurring diarrhea and/or vomiting, consider discontinuing KYGEVVI permanently. Monitor for dehydration and treat promptly with electrolyte replacement [see Warnings and Precautions (5.2) ] . 2.4 Preparation and Administration Instructions Use Table 2 for preparation and administration information. Table 2: Recommended Dosage - Preparation and Dosing by Daily-Dose Range Total Daily Dose (mg/day) Volume of Solution (mL) (administered 3 times per day) Total mL of Water for Reconstitution Total Number of KYGEVVI Packets for Reconstitution 750 – 824 2.5 40 1 825 – 974 3 975 – 1,124 3.5 1,125 – 1,299 4 1,300 – 1,449 4.5 1,450 – 1,649 5 1,650 – 1,949 6 1,950 – 2,249 7 2,250 – 2,549 8 2,550 – 2,849 9 2,850 – 3,149 10 3,150 – 3,449 11 3,450 – 3,749 12 3,750 – 4,049 13 4,050 – 4,349 14 80 2 4,350 – 4,649 15 4,650 – 4,949 16 4,950 – 5,249 17 5,250 – 5,549 18 5,550 – 5,849 19 5,850 – 6,149 20 6,150 – 6,449 21 6,450 – 6,749 22 6,750 – 7,049 23 7,050 – 7,349 24 7,350 – 7,649 25 7,650 – 7,949 26 7,950 – 8,249 27 The volume of each individual dose, when multiplied by 3, may not match the corresponding water volume used in the preparation of the oral solution as the final volume of the reconstituted oral solution will increase after the powder from the packets is added to the water volume. 8,250 – 8,549 28 120 3 8,550 – 8,849 29 8,850 – 9,749 30 9,750 – 11,249 35 11,250 – 12,749 40 12,750 – 14,249 45 160 4 14,250 – 15,749 50 15,750 – 17,249 55 17,250 – 18,749 60 200 5 18,750 – 20,249 65 20,250 – 21,749 70 21,750 – 23,249 75 240 6 23,250 – 24,749 80 24,750 – 26,249 85 280 7 26,250 – 27,749 90 27,750 – 29,249 95 29,250 – 30,749 100 320 8 30,750 – 32,249 105 32,250 – 33,749 110 33,750 – 35,249 115 360 9 35,250 – 36,749 120 36,750 – 38,249 125 38,250 – 39,749 130 400 10 39,750 – 41,249 135 41,250 – 42,749 140 42,750 – 44,249 145 440 11 44,250 – 45,749 150 45,750 – 47,249 155 47,250 – 48,749 160 480 12 48,750 – 50,249 165 50,250 – 51,749 170 51,750 – 53,249 175 520 13 53,250 – 54,749 180 54,750 – 56,249 185 560 14 56,250 – 57,749 190 57,750 – 59,249 195 59,250 – 60,749 200 600 15 60,750 – 62,249 205 62,250 – 63,749 210 63,750 – 65,249 215 640 16 65,250 – 66,749 220 66,750 – 68,249 225 Use the ZX2000 administration kit provided separately to prepare and administer the prescribed dose [see How Supplied/Storage and Handling (16) ] . Refer to the Instructions for Use for full preparation and administration information on use of KYGEVVI with the ZX2000 administration kit. Household devices such as measuring cups or spoons are not adequate measuring devices. KYGEVVI should be prepared and administered by adults only. Preparation Instructions Preparation of KYGEVVI with a liquid other than water has not been studied clinically and is not recommended. Obtain the required number of KYGEVVI packets to prepare a one-day supply of solution each morning. Use 40 mL of water per packet. Pour the prescribed volume of room temperature water (between 20°C - 25°C or 68°F - 77°F) into the mixing bottle. Add the powder from the required number of KYGEVVI packets into the mixing bottle. Screw the dosing cup tightly onto the mixing bottle and gently invert the mixing bottle back and forth at least 20 times. If powder remains, repeat until the powder dissolves. The mixed solution may appear cloudy and have some residual powder (inactive ingredients) remaining at the bottom or top. Administration Instructions Oral Administration Before each administration, gently invert the tightly closed mixing bottle slowly back and forth at least 3 times. Use 1 of 2 methods (dosing cup or oral syringe) to administer KYGEVVI solution. Choose the method based on the volume of solution to be administered per dose. Take KYGEVVI solution in 3 equally divided doses approximately 6 hours apart (plus or minus 2 hours) with food. Do not administer another dose if the dose is spit out or if a complete dose is not taken. Take the next dose at the next scheduled time. Discard any remaining KYGEVVI solution 16 hours after reconstitution or after taking or giving the 3 doses, whichever comes first. Feeding Tube Administration KYGEVVI is compatible with most commonly available feeding tubes. KYGEVVI is compatible with feeding tubes made with polyvinylchloride (PVC) free from DEHP (Phthalates), polyurethane (PUR), and silicone (SIL) material. Follow the instructions of the feeding tube manufacturer to administer KYGEVVI. Draw up the KYGEVVI solution using a syringe compatible with the feeding tube. Administer the solution immediately through the feeding tube. Flush any residual solution in the syringe or feeding tube until no solution is left. To flush the tube, a single flushing step with a volume of water equivalent to the tube's priming volume is sufficient. Discard any remaining KYGEVVI solution 16 hours after reconstitution or after taking or giving the 3 doses, whichever comes first. 2.5 Storage Instructions for Prepared KYGEVVI Solution Store reconstituted KYGEVVI solution at controlled room temperature between 20°C to 25°C (68°F to 77°F) or in the refrigerator between 2°C to 8°C (36°F to 46°F). Discard KYGEVVI solution 16 hours after reconstitution or after taking or giving the 3 doses, whichever comes first. 2.6 Missed Dose If a dose is missed, take the missed dose as soon as possible but do not take within 2 hours of the next scheduled dose. In that case, skip the missed dose and resume the regular schedule. A double dose should not be taken to make up for the missed dose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Elevated Liver Transaminase Levels [see Warnings and Precautions (5.1) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥5%) are diarrhea, abdominal pain (including abdominal pain upper), vomiting, alanine aminotransferase increased (ALT), and aspartate aminotransferase increased (AST). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of KYGEVVI was evaluated in a prospective, open-label, single-arm study in pediatric and adult patients with genetically confirmed TK2d previously treated with pyrimidine nucleosides (Trial 1). Additional safety information was derived from retrospective chart review studies (Study 1, Study 2) and from an expanded access program [see Clinical Studies (14) ] . Permanent discontinuation of KYGEVVI due to an adverse reaction occurred in 9% of patients (Trial 1, Study 1, and Study 2). The adverse reactions which resulted in permanent discontinuation of KYGEVVI in >2% of patients were diarrhea (3%) and elevated liver enzymes (3%). In the expanded access program, diarrhea resulted in permanent discontinuation in 2 patients. Dose reductions of KYGEVVI due to an adverse reaction occurred in 22% of patients (Trial 1, Study 1, and Study 2). Adverse reactions which required dose reduction in >2% of patients included diarrhea (21%) and abdominal pain (3%). Diarrhea resulted in hospitalization in 2 pediatric patients (Study 1 and expanded access program). Adverse Reactions from Trial 1 A total of 47 patients, between the ages of 0.7 and 74 years of age at enrollment, received KYGEVVI or pyrimidine nucleosides dosages up to 800 mg/kg/day [see Clinical Studies (14) ] . KYGEVVI is not approved for use in patients with an age of TK2d symptom onset > 12 years. The mean (SD) KYGEVVI or pyrimidine nucleosides exposure during Trial 1 was 6.6 (2) years. Table 3 summarizes the adverse reactions reported in ≥ 5% patients treated with KYGEVVI or pyrimidine nucleosides. Table 3: Adverse Reactions That Occurred in ≥5% Adult and Pediatric Patients with TK2d Treated with KYGEVVI or Pyrimidine Nucleosides (Trial 1) Adverse reactions Treated Patients (N=47) n (%) Diarrhea 34 (72) Abdominal pain (including abdominal pain upper) 11 (23) Vomiting 10 (21) Alanine aminotransferase increased (ALT) 10 (21) Aspartate aminotransferase increased (AST) 8 (17) Adverse reactions, vomiting and elevated liver transaminases, were observed in a higher percentage of pediatric patients than in adult patients. In Trial 1, vomiting occurred in 28% (9/32) of pediatric patients compared to 7% (1/15) of adult patients. Elevated liver transaminases occurred in 25% (8/32) for ALT and 22% (7/32) for AST of pediatric patients compared to 13% (2/15) for ALT and 7% (1/15) for AST of adult patients. Laboratory Adverse Reaction Elevated liver enzymes have been observed as a clinical manifestation of TK2d. In Trial 1 and Study 1, elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) occurred in 28% (14/50) and 22% (11/50) of patients respectively. In Trial 1, of all the patients who started treatment with elevated AST/ALT at baseline, 5% had last post-baseline ALT values that were higher severity than the baseline severity while continuing treatment [see Warnings and Precautions (5.1) ] .

12.3 Pharmacokinetics Following oral administration of doxecitine and doxribtimine in healthy adult subjects, the baseline-adjusted maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) increased in a less than dose proportional manner for doxecitine at doses ranging from 43 mg/kg to 133 mg/kg and more than dose proportional manner for doxribtimine at doses ranging from 43 mg/kg to 133 mg/kg. There is minimal or no accumulation of doxecitine and doxribtimine following multiple dose administrations. Following oral administration of doxecitine and doxribtimine at the recommended maintenance dosage of 800 mg/kg/day under fed conditions in 18 TK2d pediatric and adult subjects, the estimated baseline-unadjusted geometric mean C max at steady state was 12 ng/mL and 19 ng/mL for doxecitine and doxribtimine, respectively, and the geometric mean AUC from time 0 to 24 hours (AUC 0-24hr ) was 108 ng∙h/mL and 191 ng∙h/mL for doxecitine and doxribtimine, respectively. Inter-subject variability (geometric CV%) in C max and AUC 0-24h values of doxecitine and doxribtimine were greater than 70%. Absorption The absolute bioavailability of doxecitine and doxribtimine following oral administration has not been determined. The median time to peak plasma concentration (T max ) was approximately 2 hours for doxecitine and 4 hours for doxribtimine. Effect of Food Following an oral administration of 133 mg/kg doxecitine and 133 mg/kg doxribtimine with a high-fat, high-calorie meal in healthy adult subjects, baseline-adjusted plasma C max and AUC 0-t increased by 79% and 137%, respectively, for doxecitine; and increased by 27% and 74%, respectively, for doxribtimine, compared to fasted conditions [see Dosage and Administration (2.2) ] . Distribution In vitro plasma protein binding of doxecitine and doxribtimine was less than 10% over the concentration range between 0.23 mcg/mL and 23 mcg/mL. Elimination The mean half-life was approximately 1 hour for doxecitine and 5 hours for doxribtimine following a single oral administration of 133 mg/kg doxecitine and 133 mg/kg doxribtimine under fed conditions in healthy adult subjects. Metabolism Doxecitine and doxribtimine are primarily degraded (catabolized) by cytidine deaminase and thymidine phosphorylase, respectively, to their nucleobases and the 2-deoxy-α-D-ribose 1-phosphate moiety. Intermediate products of doxecitine catabolism are deoxyuridine, uracil, and dihydrouracil with the end products β-alanine, ammonia, and carbon dioxide (CO 2 ). Thymine, the pyrimidine nucleobase of doxribtimine, is subsequently catabolized to dihydrothymine and ultimately to γ-amino-isobutyric acid and CO 2 . Doxecitine and doxribtimine are not known to be metabolized by cytochrome P450 (CYP) isoforms. Excretion Urinary excretion of intact doxecitine and doxribtimine was <1% of the dose in healthy subjects following an oral administration of doxecitine and doxribtimine. Specific Populations Male and Female Patients The pharmacokinetics of doxecitine and doxribtimine were not significantly different between male and female subjects. Patients with Renal Impairment The pharmacokinetics of doxecitine and doxribtimine in subjects with moderate (estimated glomerular filtration rate [eGFR] ≥ 30 and ≤ 59 mL/min/1.73 m 2 ) or severe (eGFR ≥ 15 and ≤ 29 mL/min/1.73 m 2 ) renal impairment were compared with healthy subjects with normal renal function following a single oral administration of 133 mg/kg doxecitine and 133 mg/kg doxribtimine. Baseline-adjusted plasma doxecitine AUC was 122% and 66% higher in subjects with moderate and severe renal impairment, respectively, compared with matched control subjects with normal renal function. Baseline adjusted plasma doxribtimine AUC was 447% and 148% higher in subjects with moderate and severe renal impairment, respectively, compared with matched control subjects with normal renal function [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of doxecitine and doxribtimine. Drug Interaction Studies In Vitro Studies CYP enzymes : Doxecitine and doxribtimine are not inducers, inhibitors, or substrates of CYP isozymes at clinically relevant concentrations. Transporter systems : Doxecitine and doxribtimine do not inhibit P-glycoprotein (P-gp), BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K at clinically relevant concentrations. Doxribtimine may be a substrate of BCRP, but its clinical significance is unknown.