Pyrimidine Nucleos(t)ide Therapy in Patients With Thymidine Kinase 2 Deficiency

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare, progressive, and life-threatening mitochondrial myopathy caused by pathogenic variants of the thymidine kinase 2 gene. Patients often lose the ability to walk, eat, and breathe independently. There are no approved therapies; however, preclinical studies of pyrimidine nucleos(t)ide therapy have shown promising results. We investigated the safety and efficacy of pyrimidine nucleos(t)ide therapy in patients with TK2d. Medical records of children and adults with TK2d receiving pyrimidine nucleosides or nucleotides (≤800 mg/kg/d deoxycytidine and deoxythymidine or their monophosphates) were collected retrospectively from clinical sites globally. Data included baseline characteristics, medical history, disease-related outcomes, and treatment safety. To assess survival benefit, treated patients were compared with untreated TK2d controls from the literature. Baseline demographics and clinical characteristics were comparable between treated (n = 38) and untreated (n = 69) patients. Among treated patients (55.3% male; 44.7% female), the median age of TK2d symptom onset was 2.46 years. None of the treated patients (0/38) and 58% (40/69) of untreated patients died. For time to death from TK2d symptom onset or treatment start, treated patients had a reduced risk of death compared with untreated patients (85%-93% hazard ratio 0.067-0.147 vs 75%-91% 0.091-0.251, respectively). Exact conditional logistic regression analyses confirmed a 95% reduction in risk of death (odds ratios 0.044-0.047; all p < 0.0001). Before treatment, 71.1% (27/38) of patients lost ≥1 motor milestone and 3.7% (1/27) regained a milestone; during treatment, no patients lost milestones and 65.4% (17/26) regained ≥1. Similarly, 28.6% (6/21) of treated patients showed decreased ventilatory support duration, and none (0/21) showed increased duration. Of 8 patients on feeding support when starting treatment, 3 discontinued support. Most treatment-emergent adverse events (TEAEs) were mild (63.2%) and did not lead to discontinuation. No serious TEAEs experienced by more than 1 patient were treatment-related. Findings among patients with TK2d symptom onset of ≤12 years (n = 29) were similar to those of the overall group. These results indicate that pyrimidine nucleos(t)ide therapy was generally well tolerated; had an acceptable safety profile; and may reduce risk of death, positively change disease trajectory, and stabilize or improve symptoms in patients with TK2d. ClinicalTrials.gov: NCT03701568. First submitted: September 27, 2018; first participant consented: October 30, 2018. clinicaltrials.gov/study/NCT03701568. This study provides Class III evidence for a reduction in the risk of death in patients with TK2d treated with pyrimidine nucleos(t)ides.