Pyrimidine Nucleos(t)ide Therapy in Patients With Thymidine Kinase 2 Deficiency: A Multicenter Retrospective Chart Review Study

Abstract

Background and objectives: 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.

Methods: 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.

Results: 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.

Discussion: 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.

Trial registration information: ClinicalTrials.gov: NCT03701568. First submitted: September 27, 2018; first participant consented: October 30, 2018. clinicaltrials.gov/study/NCT03701568.

Classification of evidence: This study provides Class III evidence for a reduction in the risk of death in patients with TK2d treated with pyrimidine nucleos(t)ides.

Figure 1. Matched-Pairs Cox Proportional Hazard Plots of Survival Hazard Ratios After Pyrimidine Nucleos(t)ide Treatment in the (A) Overall Population and (B) Population With Age of TK2d Symptom Onset of ≤12 Years

The Cox PH models reported here include matched pairs as strata variable. Analyses were performed with or without age of TK2d symptom onset as covariate. Treatment was a time-independent covariate in the model. HR = hazard ratio; NE = not estimable; PH = proportional hazard; TK2d = thymidine kinase 2 deficiency.

Figure 2. Summary of Lost (A and B) and Regained (C and D) Motor Milestones Stratified by Treatment Period in Overall Treated Patients

Data are from treated patients identified in the retrospective chart review study MT-1621-101. ^aSpecific number of motor milestones initially achieved are mutually exclusive. ^bNo initially achieved milestones before treatment. ^cNo milestones initially achieved and not lost before treatment/achieved after treatment. ^dInitially achieved ≥1 milestone before treatment. ^eAchieved ≥1 milestone and not lost before treatment/regained before treatment/initially achieved after treatment. ^fA patient may be counted in more than 1 motor milestone item, but only once within each milestone category; percentages are based on the number of patients “at risk” of losing or regaining the specific developmental motor milestone. ^gSpecific number of motor milestones initially achieved are mutually exclusive. ^hNo lost milestones before treatment. ⁱNo milestones lost and not regained before treatment/lost after treatment. ^jLost ≥1 milestone before treatment. ^kLost ≥1 milestone and not regained before treatment/lost after treatment.

Figure 3. Summary of Lost (A and B) and Regained (C and D) Motor Milestones Stratified by Treatment Period in Treated Patients With Age of TK2d Symptom Onset of ≤12 Years

Data are from treated patients identified in the retrospective chart review study MT-1621-101. ^aSpecific number of motor milestones initially achieved are mutually exclusive. ^bNo initially achieved milestones before treatment. ^cNo milestones initially achieved and not lost before treatment/achieved after treatment. ^dInitially achieved ≥1 milestone before treatment. ^eAchieved ≥1 milestone and not lost before treatment/regained before treatment/initially achieved after treatment. ^fA patient may be counted in more than 1 motor milestone item, but only once within each milestone category; percentages are based on the number of patients “at risk” of losing or regaining the specific developmental motor milestone. ^gSpecific number of motor milestones initially achieved are mutually exclusive. ^hNo lost milestones before treatment. ⁱNo milestones lost and not regained before treatment/lost after treatment. ^jLost ≥1 milestone before treatment. ^kLost ≥1 milestone and not regained before treatment/lost after treatment. TK2d = thymidine kinase 2 deficiency.