Description for Kygevvi
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 C9H13N3O4 and the molecular weight is 227.22 g/mol. The chemical structure is:
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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 C10H14N2O5 and the molecular weight is 242.23 g/mol. The chemical structure is:
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Each packet of KYGEVVI powder contains 2 grams doxecitine and 2 grams doxribtimine. The inactive ingredients are colloidal silicon dioxide and magnesium stearate.
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)]
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)
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Adverse reactions |
Treated Patients |
|
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)].
Drug Interactions for Kygevvi
No information provided.
Warnings for Kygevvi
Included as part of the PRECAUTIONS section.
Precautions for Kygevvi
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)].
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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, 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).
KYGEVVI® is a trademark of the UCB Group of Companies.
©2025, UCB, Inc., Smyrna, GA 30080
All rights reserved.
Clinical Pharmacology for Kygevvi
Mechanism Of Action
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.
Pharmacodynamics
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KYGEVVI have not been fully characterized.
Pharmacokinetics
Following oral administration of doxecitine and doxribtimine in healthy adult subjects, the baseline-adjusted maximum plasma concentration (Cmax) 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 Cmax 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 (AUC0-24hr) was 108 ng·h/mL and 191 ng·h/mL for doxecitine and doxribtimine, respectively. Inter-subject variability (geometric CV%) in Cmax and AUC0-24h 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 (Tmax) 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 Cmax and AUC0-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 (CO2). Thymine, the pyrimidine nucleobase of doxribtimine, is subsequently catabolized to dihydrothymine and ultimately to γ-amino-isobutyric acid and CO2.
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 m2) or severe (eGFR ≥ 15 and ≤ 29 mL/min/1.73 m2) 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.
Patient Information for Kygevvi
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)].
KYGEVVI manufactured for:
UCB, Inc.
Smyrna, GA 30080
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