Doxecitine/doxribtimine cuts mortality risk in early-onset TK2d, new data show

Two newly published manuscripts in Brain Communications provide additional evidence on the clinical course of thymidine kinase 2 deficiency (TK2d) and the treatment effects of doxecitine and doxribtimine (KYGEVVI, UCB) in patients with early-onset disease. For pediatric neurologists and neuromuscular specialists managing this ultra-rare mitochondrial myopathy, the findings offer the first substantive efficacy and safety dataset for an approved pharmacologic intervention in a condition previously limited to supportive care.^1-3

"TK2d can have a devastating impact on patients and families if left untreated, which the data compiled and published in Brain Communications confirm," said Caterina Garone, MD, an associate professor of medical genetics at the University of Bologna, Italy, and co-author of both studies. The publications coincide with the agent's recent regulatory approvals in both the United States and Europe.¹

Integrated efficacy and safety findings

The first manuscript reports findings from an Integrated Summary of Efficacy and Safety (ISE/ISS) incorporating data from 104 treated and 114 untreated patients with TK2d.² The analysis focused primarily on a subgroup of patients whose symptom onset occurred at or before 12 years of age—the population aligned with the current approved indication.

In that subgroup, treatment with doxecitine and doxribtimine was associated with a 92% to 94% reduction in risk of death from the time of symptom onset compared with untreated patients, according to the study authors. Treated patients in this cohort lived an average of 29.2 years over a 30-year observation period, compared with 14.4 years for untreated counterparts. Functional recovery was also documented: 75% of treated patients regained at least 1 motor milestone after treatment initiation, and 22.5% regained 4 or more.²

On the safety side, diarrhea was the most frequently reported treatment-emergent adverse event (TEAE), occurring in 86% of patients; however, it was generally mild to moderate and resolved with dose reduction. Overall, 13.4% of patients discontinued treatment due to a TEAE, and 23.9% required dose reduction. Elevated liver transaminases were also reported and are included in the prescribing information as a monitored safety signal requiring baseline and periodic assessment.⁴

Natural history data underscore disease severity

The second manuscript draws on a dataset of 257 untreated patients with TK2d—among the largest such cohorts published to date—to characterize the natural disease course.³ Among patients with symptom onset at or before 12 years of age, 56.4% died, with a median age at death of 1.9 years (Q1, Q3: 1.0, 3.5). The mortality burden was most pronounced in the youngest patients: Approximately two-thirds of those with onset at or before age 2 years died, compared with 22.2% of those with onset between ages 2 and 12 years.

Loss of motor milestones was nearly universal in this population, with 81.3% losing at least 1 milestone and 37.3% losing 4 or more; spontaneous recovery was rare. Ventilatory and nutritional support were commonly required regardless of age at symptom onset, underscoring the multisystem burden of the disease.³

Disease background and unmet need

TK2d is caused by mutations in the TK2 gene, which encodes a mitochondrial matrix enzyme responsible for the phosphorylation of pyrimidine deoxyribonucleosides. Loss of TK2 function impairs mitochondrial DNA (mtDNA) replication, leading to mtDNA depletion and consequent myopathy.^2,3 The condition is ultra-rare, with an estimated worldwide prevalence of 1.64 cases per 1,000,000 people (95% CI: 0.5–3.1).⁵ Diagnostic delays are common, as TK2d may be misattributed to other neuromuscular conditions.

Regulatory status

KYGEVVI received FDA approval in November 2025 and European Medicines Agency (EMA) approval in March 2026 for the treatment of TK2d in adults and pediatric patients with symptom onset at or before 12 years of age.^2,3 It is the first and only approved pharmacologic treatment for this indication. The agent is formulated as a powder for oral solution and supplies exogenous pyrimidine nucleoside substrates—doxecitine (deoxycytidine) and doxribtimine (deoxythymidine)—to bypass the enzymatic defect and support mtDNA synthesis.

Interpretive considerations

Clinicians should interpret these findings with appropriate caution. The ISE/ISS analysis was not a prospectively randomized controlled trial; comparisons between treated and untreated cohorts are subject to selection bias and confounding inherent to natural history controls. The magnitude of the reported mortality reduction, while striking, should be contextualized within these design limitations. Longer-term follow-up data and broader registry experience will be essential for characterizing durability of response and late-emerging safety signals, particularly regarding hepatotoxicity.

References

1. UCB announces publication of data in Brain Communications demonstrating positive impact of KYGEVVI® (doxecitine and doxribtimine) in patients with Thymidine Kinase 2 Deficiency (TK2d). News release. UCB. June 17, 2026. Accessed June 16, 2026. https://www.prnewswire.com/news-releases/ucb-announces-publication-of-data-in-brain-communications-demonstrating-positive-impact-of-kygevvi-doxecitine-and-doxribtimine-in-patients-with-thymidine-kinase-2-deficiency-tk2d-302802242.html
2. Hirano M, Garone C, Haas R, et al. Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency. Brain Commun. 2026.
3. Domínguez-González C, Garone C, Nascimento A, et al. Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset. Brain Commun. 2026.
4. KYGEVVI (doxecitine and doxribtimine) U.S. Prescribing Information. Smyrna, GA: UCB, Inc.
5. Ma Y, Hines L, Agne M, Chinn C. EPH140 prevalence estimation of thymidine kinase 2 deficiency: an ultra-rare autosomal recessive mitochondrial disease. Value Health. 2023;26(12):S229. doi:10.1016/j.jval.2023.09.1182