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Pyrimidine Nucleos(t)ide Therapy in Patients With Thymidine Kinase 2 Deficiency: A Multicenter Retrospective Chart
Cristina Domínguez-González1,2,3, Carl Chiang4, Anny-Odile Colson5
1Neuromuscular Diseases Unit, Neurology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
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.
Insights
Pyrimidine nucleos(t)ide therapy shows significant survival benefits for patients with thymidine kinase 2 deficiency (TK2d), a severe mitochondrial myopathy. This treatment may reduce mortality risk and improve motor function and respiratory support in affected individuals.
Area of Science:
- Mitochondrial Medicine
- Rare Genetic Disorders
- Clinical Pharmacology
Background:
- Thymidine kinase 2 deficiency (TK2d) is a life-threatening, ultra-rare mitochondrial myopathy.
- Current therapeutic options for TK2d are limited, with no approved treatments.
- Preclinical data suggest pyrimidine nucleos(t)ide therapy holds promise for TK2d.
Purpose of the Study:
- To evaluate the safety and efficacy of pyrimidine nucleos(t)ide therapy in patients with TK2d.
- To assess the impact of this therapy on survival rates and disease progression in TK2d patients.
Main Methods:
- Retrospective collection of medical data from global clinical sites for TK2d patients receiving pyrimidine nucleos(t)ide therapy.
- Comparison of survival outcomes between treated TK2d patients and untreated controls from existing literature.
- Analysis of disease-related outcomes including motor milestones, ventilatory support, and feeding support.
Main Results:
- Pyrimidine nucleos(t)ide therapy demonstrated a significant reduction in the risk of death (95% reduction) compared to untreated TK2d patients.
- Treated patients showed stabilization or improvement in motor milestones, with no loss of milestones during treatment.
- The therapy was generally well-tolerated, with most treatment-emergent adverse events being mild and not leading to discontinuation.
Conclusions:
- Pyrimidine nucleos(t)ide therapy is a generally well-tolerated and safe treatment option for TK2d.
- The therapy shows potential to reduce mortality, alter disease trajectory, and stabilize or improve symptoms in TK2d.
- Class III evidence supports the use of pyrimidine nucleos(t)ides in reducing mortality risk for thymidine kinase 2 deficiency.
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