Get your patient on Kygevvi (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.

• 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 )

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

None.

• 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 )

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) ]

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.

The efficacy of KYGEVVI for the treatment of patients with TK2d, with an age of symptom onset on or before 12 years of age, was established based on data from one Phase 2 clinical study (Trial 1), two retrospective chart review studies (Study 1, Study 2), and an expanded access program. The survival in treated patients was compared with survival in an untreated external control group comprised of untreated patients from published literature and Study 2.

Trial 1 (NCT03845712) is a prospective, open-label, single-arm study in 47 patients with genetically confirmed TK2d previously treated with pyrimidine nucleosides. Thirty-eight of these 47 patients have an age of TK2d symptom onset ≤12 years; none of the 38 patients discontinued treatment. The initial oral dose of KYGEVVI was matched to the patient's pyrimidine nucleoside dose of 260-800 mg/kg/day upon entering the study in patients with an age of TK2d symptom onset ≤ 12 years, and dosage was titrated, as needed, over a maximum of 4 weeks to the maintenance dose of 800 mg/kg/day.

Study 1 (NCT03701568) was a retrospective chart review study in 38 patients with genetically confirmed TK2d treated with pyrimidine nucleosides. Twenty-nine of these patients had an age of TK2d symptom onset ≤12 years; none of the 29 patients discontinued treatment. Thirty-five of these 38 patients were later enrolled in Trial 1 to receive treatment with KYGEVVI and one was later enrolled in Study 2. KYGEVVI was not administered in Study 1. Patients enrolled in Study 1 were receiving pyrimidine nucleoside treatment at doses 160-800 mg/kg/day.

Study 2 (NCT05017818) was a retrospective chart review study in 61 patients with genetically confirmed TK2d (43 untreated patients and 18 patients treated with pyrimidine nucleoside therapy). Nine of these 61 patients were also included in the expanded access program and 1 patient was included in Study 1. Twenty-seven of the 43 untreated patients had an age of TK2d symptom onset ≤12 years, and 13 of the 18 treated patients had an age of TK2d symptom onset ≤12 years. Twenty-two untreated patients were included in the untreated external control group used to evaluate survival. Of the 18 treated patients, 6 (33%) discontinued treatment due to an adverse reaction. KYGEVVI was not administered in Study 2. Patients enrolled in Study 2 were receiving pyrimidine nucleoside treatment at doses 200-1200 mg/kg/day.

Expanded Access Program

The expanded access program data included 43 patients receiving KYGEVVI; 9 patients were included in Study 2.

Efficacy Results

A total of 82 patients with genetically confirmed TK2d and the age of symptom onset ≤12 years were treated with KYGEVVI or pyrimidine nucleosides. Efficacy was assessed by comparing overall survival in the treated patients to an external control group of untreated patients matched to treated patients using age of TK2d symptom onset (≤ 2 years or >2 to ≤ 12 years). A total of 78 matched pairs were identified.

Of the 78 treated patients included in the survival analysis, 54% were male and 36% were of Hispanic or Latino ethnicity. Eighty-two percent of patients were White, 4% Black or African American, 5% Asian, 3% Other, and 1% American Indian or Alaska Native. The median age of TK2d symptom onset was 1.5 years (range: 0.01 to 12 years). The median duration of treatment was 4 years (range: 1 day to 12 years) and the median dose received was 762 mg/kg/day (range: 260 to 800 mg/kg/day).

Treatment reduced the overall risk of death from treatment start by approximately 86% (95% CI: 61%, 96%) (Table 4, Figure 1).

Note: Treated patients were matched 1:1 to untreated patients by category of age of TK2d symptom onset (≤2 years or >2 to ≤12 years). Within each category of age of symptom onset, the matching was performed as follows: treated patients were sorted in descending order, according to their age of treatment initiation; the first treated patient in the sorted list was matched with the sorted untreated patient having the highest last known age; this matched untreated patient was then no longer available for matching with any remaining treated patients; the procedure continues in order through the sorted list of treated patients. Time of treatment start in the untreated patient was set to that of the matched treated patient.

How Supplied

KYGEVVI is supplied as follows:

Package 1 of 2

NDC 50474-350-01: Each single use packet contains 4 g of KYGEVVI as a white to off-white powder (2 g doxecitine and 2 g doxribtimine)

NDC 50474-350-30: Carton contains 30 packets

Package 2 of 2

The ZX2000 administration kit for use with KYGEVVI is supplied separately and contains the following:

• One dosing system (includes mixing bottle and dosing cup)
• Two 10 mL oral syringes
• Two spare seals

KYGEVVI (KY-JEH-vee)
(doxecitine and doxribtimine)
powder, for oral solution

Table of contents

• Instructions for use
  • Important information
• Before you start
  • Supplies for preparing and taking or giving KYGEVVI
• Important information
  • What you need to know before preparing and taking or giving KYGEVVI
  • Storing KYGEVVI packets and oral solution
• Preparing your one-day supply of KYGEVVI
  • Get supplies ready
  • Measure water and add powder from packets
  • Mix and inspect medicine
• Dosing methods
  • How to measure your individual dose
• Individual doses 50 mL or more
  • Measure and take or give your individual dose
• Individual doses less than 50 mL
  • Measure and take or give your individual dose
• Between individual doses
  • Clean up after first and second individual dose
• End-of-day clean up
  • Pour out and clean up after third individual dose
• Dosing cup maintenance
  • Replacing the seal if misplaced or damaged
• Contact information

Instructions For Use

Important information
This Instructions for Use contains information on how to prepare a one-day supply of KYGEVVI, and take or give an individual dose of KYGEVVI.

Read this Instructions for Use before taking or giving KYGEVVI and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child's medical condition or treatment.

When you are prescribed KYGEVVI for the first time, you will be provided with the carton(s) of 30 KYGEVVI packets and the ZX2000 administration kit (see Figure A ). Only use the dosing cup, mixing bottle, and oral syringes provided with your ZX2000 administration kit. Do not use a household measuring cup or measuring spoon.

Figure A

Before you start

Supplies for preparing and taking or giving KYGEVVI
Carton of 30 KYGEVVI packets

Before you start

Supplies for preparing and taking or giving KYGEVVI

Important information

What you need to know before preparing and taking or giving KYGEVVI

• You will prepare a one-day supply of KYGEVVI solution to be taken in 3 equal doses throughout the day (about 6 hours apart).
• KYGEVVI solution should be prepared on the same day as taking or giving your dose.
• KYGEVVI should be prepared and given by adults only.
• Take or give KYGEVVI exactly as prescribed by your healthcare provider.
• Do not change your dose without talking with your healthcare provider.
• Do not take or give more than the prescribed amount of KYGEVVI solution.
• Take KYGEVVI solution with food.
• Do not use KYGEVVI packets after the expiration date on the packet or carton.
• Only use the dosing cup, mixing bottle, and oral syringes provided with your ZX2000 administration kit. Do not use a household measuring cup or measuring spoon.
• Each ZX2000 administration kit comes with two oral syringes. Keep the second oral syringe as a spare.
• Rinse and dry the mixing bottle and dosing cup before first use. Do not use the dosing cup, mixing bottle, or oral syringe if it appears dirty or damaged.
• Each ZX2000 administration kit can be used for 6 months. Contact your healthcare provider when you need a replacement.
• Contact your healthcare provider or pharmacist for a replacement if your mixing bottle, dosing cup, or oral syringe is damaged or if the markings are missing or no longer readable.
• Do not use the packets if the tamper evident seal on the carton is broken.
• Mix KYGEVVI powder only with room temperature water. Do not mix KYGEVVI powder with any other liquids or foods.
• You may have KYGEVVI solution left over after taking or giving the 3 individual doses. Throw away (discard) any remaining KYGEVVI solution 16 hours after preparing or after taking or giving the 3 doses, whichever comes first.
• If powder spills out of a packet before use, do not use the packet. Throw it away and use a new KYGEVVI packet.
• If KYGEVVI solution comes in contact with your eyes or skin, rinse under cold water and contact your healthcare provider.

KYGEVVI solution is compatible with most feeding tubes. Follow the steps in this Instructions for Use booklet to prepare your one-day supply of KYGEVVI. Then follow the feeding tube manufacturer instructions on how to give KYGEVVI using a feeding tube. Draw up the prescribed individual dose using a syringe compatible with the feeding tube. Give the KYGEVVI solution right away through the feeding tube. Flush any remaining KYGEVVI solution in the syringe or feeding tube until no solution is left. Ask your healthcare provider how much water to use. Throw away (discard) any remaining KYGEVVI solution 16 hours after preparing or after taking or giving the 3 doses, whichever comes first.

Important information

Storing KYGEVVI packets and oral solution:

• Store KYGEVVI packets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store the prepared KYGEVVI solution at room temperature between 68°F to 77°F (20°C to 25°C) or in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Make sure the dosing cup is screwed on tightly to the mixing bottle when storing your KYGEVVI solution to avoid spills or leaks.
• When storing or carrying the KYGEVVI solution, keep the mixing bottle upright.
• Use the KYGEVVI solution within 16 hours of preparing. Throw away (discard) any remaining solution 16 hours after preparing or after taking or giving the 3 doses, whichever comes first.
• Keep KYGEVVI and all medicines out of the reach of children.

Preparing your one-day supply of KYGEVVI

Get supplies ready

Step 1

• Wash your hands well with soap and water.
• Place the mixing bottle, dosing cup, and oral syringe (if you need one to measure your individual dose) on a clean, well-lit flat work surface. If the dosing cup is attached to the mixing bottle, unscrew it from the mixing bottle and set it down (see Figure B ).
• Make sure "KYGEVVI" appears on the carton.
• Check the expiration date printed on the bottom of the KYGEVVI carton. When opening the KYGEVVI carton for the first time, break the tamper evident seal.
• Remove the prescribed number of KYGEVVI packets needed for your one-day supply of KYGEVVI out of the carton. Your one-day supply of KYGEVVI will be divided into 3 individual doses.
• Do not open the KYGEVVI packets until Step 2.

Figure B

Preparing your one-day supply of KYGEVVI

Measure water and add powder from packets

Step 2

• On a flat surface, pour the prescribed amount of room temperature water into the mixing bottle (see Figure C ).
  • Do not pour the water into the dosing cup.
  • Important: Do not add the powder from the packets to the mixing bottle before this step.
• Check to make sure the mixing bottle is filled with water up to the marking that matches the amount prescribed by your healthcare provider. The marking should also match the number of packets needed for your one-day supply (see Figure C ).
• Check you have counted out the correct number of KYGEVVI packets for your one-day supply, as shown on your prescription.
• Tap the packet on a hard surface to settle the powder to the bottom of the packet away from the dotted line (see Figure D ).
• Carefully fold and tear or cut along the dotted line (see Figure E ). If you spill any powder, do not use it. Throw the packet away and use a new packet.
• Empty the entire packet contents into the mixing bottle containing water. Be careful not to drop the packet into the mixing bottle (see Figure F ).
• Pour only 1 packet into the mixing bottle at a time. Repeat Steps 2d to 2f , for each packet until you have poured the prescribed number of packets for your one-day supply.

Figure C	Figure D	Figure E	Figure F

Preparing your one-day supply of KYGEVVI

Mix and inspect medicine

Step 3

• Screw the dosing cup tightly onto the mixing bottle (see Figure G ).
• Place one hand at the end of the mixing bottle and the other hand at the end of the dosing cup. Gently turn the mixing bottle upside down and back at least 20 times (see Figure H ).
• Check the solution. If you see any powder, keep turning the mixing bottle upside down and back until the powder dissolves (see Figure I ).
  • The mixed solution may be cloudy and have some remaining powder at the bottom or top. This is normal.

You have now prepared your one-day supply of KYGEVVI solution for 3 individual doses . Take KYGEVVI solution with food .

Figure G	Figure H	Figure I

Dosing methods

How to measure your individual dose

There are 2 different methods to take or give KYGEVVI solution depending on your individual dose. Use the table below to identify which steps you should follow:

Individual doses 50 mL or more	Individual doses less than 50 mL (dosing cup used for dose preparation only)
Example 100 mL	Example 14 mL
Use dosing cup Follow Step 4	Use oral syringe Follow Step 5

Individual doses 50 mL or more

Measure and take or give your individual dose

Step 4: Dosing cup

• Check to make sure the dosing cup is screwed on tightly to the mixing bottle.
• Mix the already prepared solution by slowly turning the mixing bottle upside down and back at least 3 times.
• Unscrew the dosing cup from the mixing bottle and place it on a flat surface.
• Pour KYGEVVI solution from the mixing bottle into the dosing cup until it reaches the marking on the dosing cup for your prescribed individual dose (see Figure J ). Note: Your dose may be different than the dose shown in Figure J .
• Drink or give the entire solution from the dosing cup (see Figure K ).
• When it is time for the second or third individual dose , repeat Steps 4a to 4e for each individual dose.
• After the first or second individual dose , go to Step 6 for instructions on how to clean your supplies and store KYGEVVI solution. After the third individual dose , go to Step 7 for instructions on how to clean your supplies and dispose of unused KYGEVVI solution.

Figure J

Figure K

Individual doses less than 50 mL

Measure and take or give your individual dose

Step 5: Oral syringe

• Check to make sure the dosing cup is screwed on tightly to the mixing bottle.
• Mix the already prepared solution by slowly turning the mixing bottle upside down and back at least 3 times.
• Unscrew the dosing cup from the mixing bottle and place on a flat surface.
• Pour slightly more than the amount of KYGEVVI solution needed for your prescribed individual dose into the dosing cup (see Figure L ).
• Push the plunger of the oral syringe all the way down to make sure there is no air in the oral syringe when measuring the dose (see Figure M ).
• Place the tip of the oral syringe into the dosing cup with the oral solution. Fill the oral syringe by pulling the plunger back until it reaches the marking on the oral syringe that matches your prescribed individual dose (see Figure N ).
  Note: If your individual dose is more than 10 mL, you will need to use the same oral syringe more than 1 time. Follow your healthcare provider's instructions on how to measure your dose.

  Figure L
  Figure M	Figure N

• Place the tip of the oral syringe into the mouth and point the tip towards the inside of either cheek (see Figure O ).
  • If you are giving KYGEVVI to a young child, the child must be seated and held in place to prevent the oral solution from going down the wrong way or choking.
• Slowly push the plunger all the way down until the oral syringe is empty (see Figure O ).

  Figure O

• If your prescribed individual dose is more than 10 mL, repeat Steps 5d to 5h until you take or give the full individual dose.
• Pour back any remaining solution from the dosing cup into the mixing bottle.
• When it is time for the second or third individual dose , repeat Steps 5a to 5j for each individual dose.
• After the first or second individual dose , go to Step 6 for instructions on how to clean your supplies and store KYGEVVI solution. After the third individual dose , go to Step 7 for instructions on how to clean your supplies and dispose of unused KYGEVVI solution.

Between individual doses
Clean up after first and second individual dose

Step 6
After you complete the first or second individual dose:

• Rinse the dosing cup with cold water after each use (see Figure P ).
• Dry the dosing cup with a clean, dry towel.
• After the dosing cup is dry, screw the dosing cup tightly onto the mixing bottle (see Figure Q ) and store it at room temperature or in the refrigerator until it is time for the next individual dose.
• If you used the oral syringe, clean it with cold water:
  • Rinse the oral syringe with cold water by filling the oral syringe with water and pushing it back out (see Figure R ). Then remove the plunger from the barrel and rinse the plunger and barrel under running tap water until it is clean (see Figure R ).
  • Let the oral syringe barrel and plunger dry in the open air. After the oral syringe barrel and plunger are dry, put the plunger back into the barrel.
• Do not wash the dosing cup or oral syringe in the dishwasher.

Figure P	Figure Q
Figure R

End-of-day clean up

Pour out and clean up after third individual dose

Step 7
After you take or give the third individual dose, throw away any remaining KYGEVVI solution in the sink.
Do not save KYGEVVI solution for another day.

• Remove the seal from the dosing cup to thoroughly clean it (see Figure S ).
• Clean the mixing bottle, dosing cup and seal by hand with soap and warm water. Use a brush to remove any residue left in the mixing bottle or dosing cup (see Figure T ).
• Dry the mixing bottle, dosing cup and seal with a clean towel. Put the dry seal back into the dosing cup, with the thin side of the seal facing the groove.
• If you used the oral syringe, clean it with cold water:
  • Rinse the oral syringe with cold water by filling the oral syringe with water and pushing it back out (see Figure U ). Then remove the plunger from the barrel and rinse the plunger and barrel under running tap water until it is clean (see Figure U ).
  • Let the oral syringe barrel and plunger dry in the open air. After the oral syringe barrel and plunger are dry, put the plunger back into the barrel.
• Do not wash the mixing bottle, dosing cup, seal, or oral syringe in the dishwasher.
• Store all supplies in a clean, dry area out of the reach of children for the next day's use.

Figure S	Figure T
Figure U

Dosing cup maintenance

Replacing the seal if misplaced or damaged

Changing the dosing cup seal

If you misplace the dosing cup seal or you notice leakage when the dosing cup is screwed on tightly to the mixing bottle, change the seal using one of the two spare seals provided in the ZX2000 administration kit. Follow these steps to replace the seal:

• Remove the seal in the dosing cup (see Figure V ). Skip this step if you misplaced the seal.
• Wash the dosing cup groove with warm water (see Figure W ).
• Get a new seal from the spare seal box (see Figure X ).
• Insert the seal into the groove of the dosing cup with the thin side of the seal facing the groove (see Figure Y ).

Figure V	Figure W
Figure X	Figure Y

Contact Information

Contact your healthcare provider or pharmacist if you have any questions about this Instructions for Use. You may also contact UCBCares at 1-844-599-CARE (2273) for assistance.

KYGEVVI manufactured for: UCB, Inc., Smyrna, GA 30080
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Approved: 11/2025

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.