Kygevvi Drug Information

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.

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 . 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 . 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 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 Abdominal pain (including abdominal pain upper) 11 Vomiting 10 Alanine aminotransferase increased (ALT) 10 Aspartate aminotransferase increased (AST) 8 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 .

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.

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 . In Trial 1, compared to adults, a higher percentage of pediatric patients experienced adverse reactions of vomiting and elevated liver transaminases . Serious adverse reactions in the pediatric population included hospitalization due to diarrhea in two patients .