FDA approves first treatment for thymidine kinase 2 deficiency

The US Food and Drug Administration (FDA) has approved Kygevvi (doxecitine and doxribtimine) powder for the treatment of thymidine kinase 2 deficiency (TK2d) in adults and pediatric patients who develop symptoms at or before 12 years of age. The therapy received Breakthrough Therapy Designation for this indication.

A rare mitochondrial disorder

TK2d is an inherited genetic disorder that disrupts the body’s ability to produce and repair mitochondrial DNA (mtDNA). Low mtDNA levels can lead to mitochondrial depletion syndromes, which are characterized by progressive muscle weakness and respiratory failure. TK2d is considered ultra-rare, with approximately 120 patients described in medical literature, though it is likely underdiagnosed.

Efficacy supported by survival data

The FDA based its approval on data from one phase 2 clinical trial, two retrospective chart review studies, and an expanded access program. Survival outcomes in treated patients were compared with an untreated external control group drawn from published data and one of the retrospective studies.

Among 78 matched pairs of treated and untreated patients, 3 deaths (4%) occurred in the Kygevvi group compared with 28 deaths (36%) in the control group. The mean survival time at 10 years was 9.6 years for treated patients versus 5.7 years for those in the control group.

Pharmacokinetics and formulation studies

The pharmacokinetics, food effect, and tolerability of Kygevvi were further evaluated in Study MT-1621-103 and Study MT-1621-105, which included 14 healthy adult volunteers per study. Participants received sequential doses of 86.6, 173.4, and 266.6 mg/kg of the study drug with a 48-hour pharmacokinetic assessment and washout between doses, followed by administration with a high-fat meal.²

Plasma levels of deoxycytidine (dC) and deoxythymidine (dT) rose rapidly and dose-dependently above baseline, with a median Tmax of 1 to 2 hours under fasting conditions and near-baseline return by 8 to 12 hours, suggesting rapid elimination. Administration with food delayed Tmax to 2 to 4 hours and substantially increased plasma exposure, with dC Cmax and AUC increasing by up to 96% and 250%, respectively, and dT Cmax and AUC increasing by up to 29% and 89%, respectively.²

The findings indicate a significant food effect and support a 3-times-daily dosing regimen with food. Renal clearance was minimal (Fe < 0.3%). The study drug was generally well tolerated, with the most frequent adverse events being diarrhea (14%) and dizziness (10%), primarily mild to moderate in severity.²

Safety profile

The most common adverse effects of Kygevvi in patients with TK2d were diarrhea, vomiting, elevated liver enzymes, and abdominal pain.

References:

1. FDA Approves 1st Drug for Thymidine Kinase 2 Deficiency, a Very Rare Mitochondrial Disease. FDA. Press release. November 3, 2025. Accessed November 3, 2025.
2. Mittur A, VanMeter SA, Orujov E, Glidden P. Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults. Clin Ther. 2024;46(7):576-587. doi:10.1016/j.clinthera.2024.06.006