Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders

We evaluated the safety and efficacy of enteral deoxycytidine/deoxythymidine combination therapy in treatment of POLG-related disorders, genetic mitochondrial diseases characterized by progressive neurological degeneration. A single-centre open-label phase II trial was conducted. Inclusion criteria included: age 3 months to 60 years, clinical diagnosis of POLG-related disorder, and biallelic pathogenic POLG variants. Participants received deoxycytidine/deoxythymidine initially at 100 mg/kg/day (50 mg/kg deoxycytidine and 50 mg/kg deoxythymidine), titrated to 400 mg/kg/day over three weeks. The current protocol is a 60-month treatment period with primary outcomes the Newcastle Mitochondrial Disease Scale sections I-III and serum growth differentiation factor 15. Secondary outcomes include quality of life questionnaires, seizure diary, EEG, and blood and urine laboratory tests assessing end organ function. Outcomes were assessed at baseline, 1-month, 2-month, 3-month, and 6-month timepoints, then every 6 months thereafter. Twenty-five individuals (14 male, 11 female; mean age 12.3 years) started deoxycytidine/deoxythymidine. Five died during the trial and five withdrew. The most common treatment-related adverse event was diarrhea. Newcastle Mitochondrial Disease Scale sections I-III score decreased (improved) from baseline at all timepoints from 1 month to 24 months (p < 0.05). Serum growth differentiation factor 15 significantly decreased (improved) from baseline at 1-month, 2-month, and 3-month timepoints (p < 0.05). Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p < 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized.