Doxecitine–Doxribtimine Becomes First Approved Treatment for Rare Genetic Disorder

The FDA approved doxecitine and doxribtimine powder (Kygevvi) for the treatment of adults and pediatric patients with thymidine kinase 2 deficiency (TK2d) who begin to develop symptoms at or before the age of 12, according to a news release from the agency. It is the first treatment approved for the mitochondrial disorder.^1,2

What Clinical Data Backs Doxecitine–Doxribtimine’s Approval?

A phase 2 clinical study, 2 retrospective chart review studies, and an expanded access program supported the efficacy and safety of doxecitine–doxribtimine powder for these patients. In the program, patient survival in those treated with doxecitine–doxribtimine powder was compared with survival in an untreated external control group featuring untreated patients.¹

According to the survival analysis for 78 matched pairs of treated and untreated patients, there were only 3 deaths (4%) in the patients receiving doxecitine–doxribtimine powder compared with 28 deaths (36%) in the external control group. Furthermore, the mean survival time of 10 years was 9.6 years for treated patients, compared with 5.7 years in the control group.¹

Are There Safety Considerations for Patients and Pharmacists?

Safety indications in this evaluation were mostly positive. Common adverse effects of doxecitine–doxribtimine included diarrhea, vomiting, increased liver enzymes, and abdominal pain. In the package insert for doxecitine–doxribtimine, there are warnings and precautions listed for elevated liver enzyme levels and gastrointestinal adverse reactions. Positively, there were no contraindications listed for its use.¹

A pharmacist or an appropriate health care provider should obtain and monitor baseline transaminase levels in all patients prior to treatment initiation given the risk of liver enzyme increases. Accordingly, pharmacists should pay close attention to the dosage and administration information for doxecitine–doxribtimine. The FDA lists the starting dose as 260 mg/kg/day, the intermediate dose as 520 mg/kg/day, and the maintenance dose as 800 mg/kg/day. For each dose, there is exactly half doxecitine and half doxribitimine.^1,3

Based on patient tolerability, the dosage of doxecitine–doxribtimine should be titrated after a minimum of 2 weeks at the starting dosage level. The powder is to be administered orally with food in 3 equally divided doses. If adverse reactions—such as elevated liver enzymes or gastrointestinal events—do occur, the dosage of doxecitine–doxribtimine should be reduced, interrupted, or permanently discontinued, based on the severity of the reaction.³

What is Thymidine Kinase 2 Deficiency?

TK2d is an extremely rare mitochondrial depletion and deletion syndrome characterized by mutations in the nuclear TK2 gene, which is responsible for encoding the mitochondrial thymidine kinase 2 enzyme. The role of TK2 is to phosphorylate the nucleosides deoxycytidine and deoxythymidine required for mitochondrial DNA (mtDNA) replication. In children, the condition presents as mtDNA depletion, respiratory difficulty, and progressive muscle weakness.⁴

Reports of this disorder in medical literature are limited due to its rare incidence, but the available reports indicate its severity. One case report of a patient with TK2d, a 26-year-old female with childhood-onset disease, was characterized by progressive myopathy, fatigue, weight loss, bone fractures, dysphagia, neuropathy, and respiratory failure.

Before this approval, treatment options focused on a multi-faceted approach using multiple therapeutic modalities. Now, patients with the rare disorder have a new option for treatment and prevention.⁴

REFERENCES

1. FDA approves 1st drug for thymidine kinase 2 deficiency, a very rare mitochondrial disease. News Release. FDA. Released November 3, 2025. Accessed November 3, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-1st-drug-thymidine-kinase-2-deficiency-very-rare-mitochondrial-disease?utm_medium=email&utm_source=govdelivery

2. Ebert M. FDA approves first treatment for thymidine kinase 2 deficiency. Contemporary Pediatrics. Published November 3, 2025. Accessed November 3, 2025. https://www.contemporarypediatrics.com/view/fda-approves-first-treatment-for-thymidine-kinase-2-deficiency

3. FDA. Package insert: Kygevvi (doxecitine and doxribtimine) powder, for oral solution. Released November 3, 2025. Accessed online November 3, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219792s000lbl.pdf?utm_medium=email&utm_source=govdelivery

4. Chow E, Miller L, Clearman A, Arnold P, Koenig MK, Russo SN. Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency. Mol Genet Metab. 2025;145(4):109159. doi:10.1016/j.ymgme.2025.109159