Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy

Abstract

Objective: Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies.

Methods: We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program.

Results: In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6-minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy.

Interpretation: This open-label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293-303.

Conflict of interest statement

Potential Conflicts of Interest

C.G., R.M., and M.H. are paid consultants to Modis Therapeutics. R.M. has equity in Modis Therapeutics. These relationships are de minimus for the United Kingdom Medical Research Council (C.G.), Vall d’Hebron Research Institute (R.M.), and Columbia University Medical Center (M.H.). Columbia University has submitted a patent, which has been licensed to Modis Therapeutics; this relationship is monitored by an unconflicted external academic researcher. The other authors declare no conflicts of interest.

© 2019 American Neurological Association.

Figures

FIGURE 1:

Kaplan–Meier survival curve of the 5 TK2-deficient patients with early onset severe myopathy (onset before 24 months and rapid progression defined by never acquiring ability to walk or loss of ability to walk, to breathe independently, or both within 1 year of onset) showed 100% survival for at least 2 years after treatment (range = 2.1–6.3 years; 3.93 ± 1.66 years, mean ± standard deviation). In contrast, the untreated historical control group with TK2-deficient early onset severe myopathy revealed that only 27.3% of patients survived at least 2 years after onset.–,–,– Shading indicates upper and lower 95% confidence interval. Comparison of treated versus untreated early onset severe myopathy patients demonstrated a significant difference in postonset survival (p = 0.0078).

FIGURE 2:

Changes from baseline in different outcome measures. (A) The graph shows individual values of distance walked in the 6-minute walk test (6MWT) at baseline and during the time on treatment, showing continuous improvements in 8 of 9 patients who were able to be evaluated by this test at any point in the treatment (note that P11 was nonambulant at baseline but regained independent gait after 12 months of treatment). (B) The group of patients with low performance (300m, mean = 27.1m, 95% CI = −32.8 to 87). (C) Individual scores in the Egen Klassifikation (EK) at baseline and after treatment show improvement in every visit compared to the previous one in the 3 early onset severe myopathy patients evaluated by EK. The mean change in the score after 6 months of treatment and after 12 to 36 months, above baseline, showed progressive improvement. (D–F) North Star Ambulatory Assessment (NSAA) scores (D) showed improvement in all the patients evaluated in the group with slower progression, with a trend to improvement in forced vital capacity (FVC; E), and maximal inspiratory pressure (MIP; F) showed mild improvement or stabilization with slight fluctuations between visits, as reflected in the individual graphics. Both FVC and MIP showed a trend to mild improvement, with stabilization of the values during the treatment. Change in score (absolute values) in EK, NSAA, FVC, and MIP were estimated by 95% CI at every period of treatment relative to baseline. There were no statistical differences in any of the outcome measures. Serum levels of growth differentiation factor 15 (GDF-15) in individual subjects (G) and aggregated in later onset and early onset groups (H).