Thymidine Kinase 2 Deficiency (TK2d): European Commission approves doxecitine and doxribtimine (KYGEVVI®) as first and only treatment

 UCB (Euronext Brussels: UCB), a global biopharmaceutical company, today announced that the European Commission (EC) has granted marketing authorization under exceptional circumstances for KYGEVVI (doxecitine and doxribtimine) for the treatment of paediatric and adult patients with genetically confirmed thymidine kinase 2 deficiency (TK2d) with an age of symptom onset on or before 12 years.¹ It is the first and only approved treatment for TK2d. 

“The European Commission’s approval of KYGEVVI marks a historic milestone for the TK2d community. For the first time, people across Europe living with this ultra-rare, life-threatening mitochondrial disease have access to an approved treatment beyond supportive care,” said Donatello Crocetta, Chief Medical Officer at UCB. “KYGEVVI is designed to support mitochondrial DNA maintenance in skeletal muscle, addressing a key biological driver of TK2d. We are deeply grateful to the patients, families, advocates, investigators, and clinical trial teams whose partnership, trust, and resilience made this achievement possible.”

“TK2d has a profound impact on people living with the condition and their families and, until now, they have faced a heavy burden of unmet treatment need with incredible resilience,” said Caterina Garone, Associate Professor of Medical Genetics, University of Bologna, Italy. “The TK2d community has waited a long time for this moment which brings them new hope and marks an important step forward in how clinicians can manage this devastating disease.” 

Clinical efficacy 

Supporting data for EC approval came from pooled data from two studies* of treatment with KYGEVVI (doxecitine and doxribtimine) in patients with genetically confirmed TK2d with age of symptom onset ≤12 years. These studies investigated the impact of treatment on functional outcomes (i.e. motor milestones, ventilatory support, feeding support) as well as survival.^{1,4,9,10,11,12,13} In the studies, KYGEVVI was well tolerated with the most commonly reported adverse reactions of diarrhea (86%), vomiting (28%), abdominal pain (including abdominal pain upper) (26%).¹

• Developmental motor milestone ability: A decrease in the loss of motor milestones was observed following treatment initiation with KYGEVVI; 26/31 (84%) patients regained one or more  motor milestones (e.g. sitting upright unassisted, holding head upright unassisted).¹  
• Ventilatory support: Prior to treatment start, 18/39 (46%) participants initiated ventilatory support and no participants discontinued ventilatory support. After initiation of treatment, 5/21 (24%) participants started ventilatory support while 5/23 (22%) discontinued ventilatory support.¹
• Feeding support: Prior to treatment start, 12/39 (31%) participants had a feeding tube. After initiation of treatment, 4/28 (14%) participants started feeding support, with 2 of these participants subsequently discontinuing feeding support after initiation of treatment¹ 

About TK2d

TK2d is an ultra-rare, life-threatening, genetic mitochondrial disease characterized by progressive (worsening over time) and severe muscle weakness (myopathy).^2,3,4,5 TK2d can impact all parts of a person’s daily life and wellbeing and can become worse over time and impact the ability to walk, eat and breathe independently, often necessitating around-the-clock caregiver support.^3,4,6 It is often fatal, with those experiencing initial symptoms on or before the age of 12 years facing a high risk of premature death (often occurring within 3 years after symptom onset).⁷ It is estimated that the worldwide prevalence of TK2d is 1.64 [0.5, 3.1] cases per 1,000,000 people.⁸

About KYGEVVI^®

The primary mechanism of action of KYGEVVI (doxecitine and doxribtimine) is the incorporation of pyrimidine nucleosides deoxycytidine (dC) and deoxythymidine (dT) into skeletal muscle mitochondrial deoxyribonucleic acid (DNA) to restore mitochondrial DNA copy number and improve skeletal muscle function in patients with TK2d. Doxecitine and doxribtimine likely utilize residual TK2 activity as well as cytosolic phosphorylation pathways such as thymidine kinase 1 and deoxycytidine kinase to increase mitochondrial DNA precursors deoxycytidine triphosphate and deoxythymidine triphosphate in the mitochondria.¹ 

KYGEVVI was supported through EMA’s PRIority MEdicines (PRIME) scheme, which provides early and enhanced scientific and regulatory support to medicines that have a potential to address patients’ unmet medical needs. Marketing authorization under exceptional circumstances may be granted to medicines where the applicant is unable to provide comprehensive data on efficacy and safety under normal conditions of use, because the condition to be treated is rare or because collection of full information is not possible or is unethical.¹⁴ 

The EC approval follows the recent approval of KYGEVVI by the U.S. Food and Drug Administration (FDA) for the treatment of adults and pediatric patients living with thymidine kinase 2 deficiency (TK2d), with an age of symptom onset on or before 12 years.¹⁵

*These two studies comprise 39 participants with an age of TK2d symptom onset ≤12 years – the median age of TK2d symptom onset was 1.89 years (Q1, Q3 = 1.2, 2.7) and the median duration of treatment was 91.4 months (Q1, Q3 = 80.2, 117.8; all treated > 5 years). Survival was compared to an external control group, after matching on Age of Symptom Onset Category. Information on functional outcomes in the treated patients (motor milestones, ventilatory support, and feeding support) was collected during the pre- and post-treatment period and analyzed.¹

For more information about the trials visit: https://clinicaltrials.gov/study/NCT03845712 (TK0102/NCT03845712) and https://clinicaltrials.gov/study/NCT03701568 (MT-1621-101/NCT03701568).

Increase in Liver Transaminases
Elevated liver enzymes and liver dysfunction/failure have been observed as a clinical manifestation of TK2d. In clinical studies elevations in alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] have occurred in patients with TK2d following treatment with KYGEVVI. Transaminase levels should be checked prior to initiation of treatment, and changes in liver function monitored periodically during treatment with KYGEVVI and according to routine patient management.

Gastrointestinal disturbances
Gastrointestinal disturbances such as diarrhoea, vomiting, and abdominal pain (including abdominal pain upper) are very commonly reported adverse reactions with doxecitine and doxribtimine treatment. In the pooled safety population 37 out of 50 participants (74%) experienced diarrhoea early after treatment initiation (<3 months). The majority of events of diarrhoea were mild to moderate in severity and were generally self-limiting or improved with temporary dose reduction. Of 133 events of diarrhoea, 12% (16/133) required dose reduction with a median duration of 80 days (Q1, Q3=33.0, 201.5). None of the 50 participants discontinued due to gastrointestinal disturbances, including diarrhoea.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

References:

1. KYGEVVI^® (doxecitine and doxribtimine) EU Summary of Product Characteristics
2. Berardo A, et al. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies. J Neuromuscul Dis. 2022;9(2):225-235.
3. Wang J, et al. eds. GeneReviews^®. [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.
4. Domínguez-González C, Chiang C, Colson AO, et al. Pyrimidine Nucleos(t)ide Therapy in Patients With Thymidine Kinase 2 Deficiency: A Multicenter Retrospective Chart Review Study. Neurology. 2025;105(6):e213908. doi:10.1212/WNL.0000000000213908.
5. National Institute of Health. TK2-related mitochondrial DNA depletion syndrome, myopathic form. https://medlineplus.gov/genetics/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form/#genes. Accessed February 2026.
6. Thymidine kinase 2 deficiency. National Organization for Rare Disorders. Updated September 14, 2022. https://rarediseases.org/rare-diseases/thymidine-kinase-2-deficiency/. Accessed February 2026.
7. Hirano M, et al. The Disease Course of Untreated Patients with Thymidine Kinase 2 Deficiency (TK2d) Aged ≤12 Years at TK2d Symptom Onset: Findings from the Largest International TK2d Dataset. 2025 AAN.
8. Ma Y. 2023 ISPOR Europe. EPH140.
9. ClinicalTrials.gov. NCT03701568. https://clinicaltrials.gov/study/NCT03701568. Accessed February 2026. 
10. ClinicalTrials.gov. NCT03845712. https://clinicaltrials.gov/study/NCT03845712. Accessed February 2026.
11. ClinicalTrials.gov. NCT05017818. https://clinicaltrials.gov/study/NCT05017818. Accessed February 2026.
12. ClinicalTrials.gov. NCT06590493. https://clinicaltrials.gov/study/NCT06590493. Accessed February 2026.
13. Lopez-Gomez C, et al. Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency. Ann Neurol. 2017;81(5):641-652.
14. Committee for Medicinal Products for Human Use (CHMP). Summary of opinion (initial authorization. Kygevvi. 
15. KYGEVVI™ U.S. Prescribing Information.