Doxecitine and Doxribtimine

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 )

Powder for oral solution: 2 g doxecitine and 2 g doxribtimine as white to off-white powder in a single use packet. Powder for oral solution: 2 g doxecitine and 2 g doxribtimine. ( 3 )

None. None. ( 4 )

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.

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) ] .

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.

8.2 Lactation Risk Summary There are no data on the presence of doxecitine and doxribtimine or its metabolites in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Data from published literature reports the presence of nucleosides and nucleotides in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KYGEVVI and any potential adverse effects on the breastfed infant from KYGEVVI or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of KYGEVVI for the treatment of thymidine kinase 2 deficiency (TK2d) have been established in pediatric patients with an age of symptom onset on or before 12 years. Use of KYGEVVI for this indication in this population is supported by evidence from two retrospective studies (Study 1, Study 2), one open-label study (Trial 1), and an expanded access program in which a total of 68 patients 0.7 years of age to less than 17 years of age were treated [see Clinical Studies (14) ] . In Trial 1, compared to adults, a higher percentage of pediatric patients experienced adverse reactions of vomiting and elevated liver transaminases [see Adverse Reactions (6.1) ] . Serious adverse reactions in the pediatric population included hospitalization due to diarrhea in two patients [see Warnings and Precautions (5.2) ] .

8.5 Geriatric Use Clinical studies of KYGEVVI did not include sufficient number of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment Plasma concentrations of doxecitine and doxribtimine increased in patients with moderate or severe renal impairment. The pharmacokinetics (PK) of doxecitine and doxribtimine have not been evaluated in patients with mild renal impairment. An appropriate dosage adjustment of KYGEVVI in patients with renal impairment could not be determined because renal impairment had distinct effects on the PK of doxecitine and PK of doxribtimine, and it is not feasible to separately adjust the dosage for doxecitine or doxribtimine contained in KYGEVVI [see Clinical Pharmacology (12.3) ] .

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.

The safety and effectiveness of KYGEVVI for the treatment of thymidine kinase 2 deficiency (TK2d) have been established in pediatric patients with an age of symptom onset on or before 12 years. Use of KYGEVVI for this indication in this population is supported by evidence from two retrospective studies (Study 1, Study 2), one open-label study (Trial 1), and an expanded access program in which a total of 68 patients 0.7 years of age to less than 17 years of age were treated [see Clinical Studies (14) ] . In Trial 1, compared to adults, a higher percentage of pediatric patients experienced adverse reactions of vomiting and elevated liver transaminases [see Adverse Reactions (6.1) ] . Serious adverse reactions in the pediatric population included hospitalization due to diarrhea in two patients [see Warnings and Precautions (5.2) ] .

Clinical studies of KYGEVVI did not include sufficient number of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

KYGEVVI is a combination of doxecitine and doxribtimine, both of which are pyrimidine nucleosides. KYGEVVI is a powder for oral solution. Both doxecitine and doxribtimine are white to off-white powders and soluble in water. Doxecitine The chemical name of doxecitine is 4-Amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one. The molecular formula is C 9 H 13 N 3 O 4 and the molecular weight is 227.22 g/mol. The chemical structure is: Doxribtimine The chemical name of doxribtimine is 1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione. The molecular formula is C 10 H 14 N 2 O 5 and the molecular weight is 242.23 g/mol. The chemical structure is: Each packet of KYGEVVI powder contains 2 grams doxecitine and 2 grams doxribtimine. The inactive ingredients are colloidal silicon dioxide and magnesium stearate. Chemical Structure Chemical Structure

Administration of KYGEVVI is intended to incorporate the pyrimidine nucleosides, deoxycytidine and deoxythymidine, into skeletal muscle mitochondrial deoxyribonucleic acid (DNA). This action restores mitochondrial DNA copy number in TK2d mutant mice.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KYGEVVI have not been fully characterized.

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.

, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to evaluate the carcinogenic potential of doxecitine and doxribtimine have not been conducted. Mutagenesis Doxecitine and doxribtimine were not mutagenic or clastogenic in an in vitro bacterial reverse mutation (Ames) and an in vivo rat micronucleus assay. Doxecitine and doxribtimine induced chromosomal aberrations in the absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. One compound (alpha-hydroxythymidine) originating from a doxribtimine starting material and present in the final drug product was positive for mutagenesis in the Ames assay and positive for clastogenesis in human peripheral lymphocytes when tested alone. Impairment of Fertility Doxecitine and doxribtimine had no effect on male or female fertility or early embryonic development at doses up to 2000 mg/kg/day in rats (1131 times and 1223 times the MRHD in males and females respectively for 400 mg/kg/day doxecitine and 1056 times and 425 times the MRHD in males and females respectively for 400 mg/kg/day doxribtimine, based on plasma exposure).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Preparation and Administration Instructions of KYGEVVI Solution Advise the patient to use the ZX2000 administration kit provided by the pharmacy to prepare and administer KYGEVVI solution. Inform the patient to prepare a one-day supply of the KYGEVVI solution each morning and take each individual dose with food [see Dosage and Administration (2.4) ]. Elevated Liver Transaminase Levels Inform the patient that KYGEVVI may cause liver enzyme elevations. Instruct the patient to promptly report loss of appetite, abdominal pain, dark urine, or jaundice to his/her healthcare provider [see Warnings and Precautions (5.1) ]. Gastrointestinal Adverse Reactions Inform the patient that KYGEVVI may cause diarrhea and vomiting. Advise the patient to promptly report to his/her healthcare provider diarrhea and vomiting that lasts longer than a few days while taking KYGEVVI [see Warnings and Precautions (5.2) ].

Store KYGEVVI packets at 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store reconstituted KYGEVVI solution at controlled room temperature or in the refrigerator. Discard KYGEVVI solution 16 hours after reconstitution or after taking or giving the 3 doses, whichever comes first [see Dosage and Administration (2.5) ].