KYGEVVI

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…

5 WARNINGS AND PRECAUTIONS Elevated Liver Transaminase Levels : Obtain baseline liver transaminase (ALT, AST) and total bilirubin levels prior to treatment initiation with KYGEVVI. If signs or symptoms consistent with liver injury are observed, interrupt treatment. Consider permanently discontinuing KYGEVVI if signs/symptoms consistent with liver injury persist or worsen. Monitor patients yearly and as clinically indicated. ( 5.1 ) Gastrointestinal Adverse Reactions : Reduce KYGEVVI dosage or interrupt treatment based on severity of diarrhea and/or vomiting. If persistent severe diarrhea and/or vomiting occurs, consider discontinuing KYGEVVI permanently. ( 5.2 ) 5.1 Elevated Liver Transaminase Levels Elevated liver transaminase [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] levels were reported in patients treated with KYGEVVI [see Adverse Reactions (6.1) ] . In Study 1, two patients permanently discontinued treatment with KYGEVVI upon recurrence of elevated liver enzymes after a rechallenge at a reduced dose. Obtain baseline liver transaminase (ALT, AST) and total bilirubin levels in patients prior to treatment initiation with KYGEVVI. 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 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 Dosage and Administration (2.3) ] . 5.2 Gastrointestinal Adverse Reactions Diarrhea and vomiting leading to hospitalization, dose reduction, and permanent discontinuation were reported in patients treated with KYGEVVI [see Adverse Reactions (6.1) ] . Based on the severity of the diarrhea and/or vomiting, reduce the dosage of KYGEVVI or interrupt treatment until diarrhea and/or vomiting improves or returns to baseline. Consider restarting KYGEVVI at the last tolerated dose, and increase the dose as tolerated. For persistent or recurring diarrhea and/or vomiting, consider discontinuing KYGEVVI permanently and provide supportive care with electrolyte repletion as clinically indicated.

4 CONTRAINDICATIONS None. None. ( 4 )

8.1 Pregnancy Risk Summary There are no available data on KYGEVVI use during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Endogenous pyrimidine nucleosides are transported across the placenta. There are risks for adverse maternal and fetal outcomes during pregnancy with mitochondrial myopathies, including TK2 deficiency ( see Clinical Considerations ). In animal reproduction studies, oral administration of doxecitine and doxribtimine to pregnant rats and rabbits during organogenesis resulted in maternal and fetal toxicities in the rabbit at dose exposures 1233 and 811 times the maximum recommended human dose (MRHD) of 400 mg/kg/day doxecitine and 400 mg/kg/day doxribtimine, respectively, based on plasma exposure, but were not observed in the rat ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Mitochondrial myopathies are associated with increased adverse perinatal outcomes, including preterm birth, pre-eclampsia and gestational diabetes. Data Animal Data In an embryofetal development study in pregnant rats, once daily oral doses of 200, 600, and 2000 mg/kg/day doxecitine and doxribtimine were administered throughout organogenesis between gestation day (GD) 7 to 17. No maternal or embryofetal toxicity was observed up to 2000 mg/kg/day (1223 times and 425 times the MRHD of doxecitine and doxribtimine, respectively, based on plasma exposure). In an embryofetal development study in pregnant rabbits, once daily oral doses of 200, 600, and 2000 mg/kg/day doxecitine and doxribtimine were administered throughout organogenesis between GD 7 and GD 19. Marked maternal toxicity and fetal malformations (dilated aorta with an associated narrow pulmonary trunk) were observed at the highest dose (1233 times and 811 times the MRHD of doxecitine and doxribtimine, respectively, based on plasma exposure). The maternal and fetal no observed adverse effect level (NOAEL) in rabbits (600 mg/kg/day) was associated with maternal plasma exposures 729 times and 126 times the MRHD of 400 mg/kg/day doxecitine and 400 mg/kg/day doxribtimine, respectively.

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) ] .