Thymidine Kinase 2 Deficiency (TK2d) Treatments

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.

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

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

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.

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

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

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.

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

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.

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:

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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

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

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

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

You have now prepared your one-day supply of KYGEVVI solution for

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:

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

NDC 50474-350-30

kygevvi

(doxecitine and doxribtimine)

2 g/2 g per packet

Only use the dosing cup, mixing bottle, and oral syringes

See enclosed Instructions for Use for important preparation

30 packets

Each 4 g packet contains 2 g doxecitine and 2 g doxribtimine.