EMA Recommends Kygevvi for Rare Thymidine Kinase 2 Deficiency Treatment

The first treatment for rare thymidine kinase 2 deficiency (TK2d), Kygevvi, a combination of doxecitine and doxribtimine, has been recommended by the European Medicines Agency (EMA) for marketing authorization. This represents a pivotal milestone in addressing a condition where there is no authorized treatment. This recommendation specifically applies to patients whose disease onset occurred at or before 12 years of age.¹ The clinical data indicate that Kygevvi improves motor function of patients that encounter symptoms in that age group.¹ To this point, clinical management for this population has been limited to supportive measures such as physiotherapy, enteral nutrition, and mechanical ventilation.

How Does the Therapeutic Mechanism Address the Underlying Genetic Pathology?

The pathology of thymidine kinase 2 deficiency, or TK2d, originates from mutations in the thymidine kinase 2 (TK2) gene, which prevent the TK2 enzyme from maintaining mitochondrial DNA. This enzymatic failure leads to progressive myopathy and significant loss of motor function. The EMA’s press release on the drug states,¹ “The way Kygevvi works in patients has not been confirmed, but studies in animal models suggest that its active substances, the pyrimidine nucleosides doxecitine and doxribtimine, are modified and incorporated into mitochondrial DNA in muscle cells, improving the production and maintenance of mitochondrial DNA.” By addressing this enzymatic shortfall, the treatment is expected to slow the progression of the disease. Common side effects observed during development include vomiting, abdominal pain, and diarrhea.

What Regulatory Pathways and Clinical Evidence Supported this Recommendation?

The EMA based its recommendation on a retrospective chart review alongside a phase 2 single arm clinical study involving 39 patients.¹ The results were significant for this small population, as 84% of patients regained at least one motor function. The authorization was recommended under exceptional circumstances because the rarity of the disease precludes the provision of full efficacy and safety data. This highlights the flexibility within the EU regulatory framework for orphan products. Consequently, the EMA has requested that the company perform a new study to further validate safety and efficacy post-authorization.

Development was further facilitated through the PRIority MEdicines scheme, which provides enhanced scientific support for medicines that address unmet needs. Having already received an orphan designation in 2017, the therapy will now be assessed by the Committee for Orphan Medicinal Products to determine if this status should be maintained.¹ Now that the Committee for Medicinal Products for Human Use has adopted this positive opinion, it moves to the European Commission for a final EU-wide decision. Subsequent steps for the manufacturer will involve member state-level negotiations regarding pricing and the medicine’s integration into individual national health systems.

How Does the Molecular Bypass Strategy Stabilize Mitochondrial Function?

The efficacy of this treatment strategy stems from its ability to bypass the genetic enzymatic defect by supplementing the deoxypyrimidine monophosphates that the body fails to produce. In a thymidine kinase 2 deficiency (TK2d) environment, the resulting imbalance in deoxynucleotide triphosphate pools leads to depleted mitochondrial DNA.² Research has demonstrated that oral supplementation effectively raises deoxythymidine triphosphate concentrations and restores mitochondrial DNA levels in various tissues. This biochemical directly ameliorates defects in mitochondrial respiratory chain enzymes, which are responsible for the severe neuromuscular manifestations associated with TK2d.

What Manufacturing and Metabolic Challenges Remain for Oral bypass Therapies?

While the treatment successfully crosses biological barriers, its longevity can be limited by metabolic catabolism. Evidence indicates that intestinal thymidine phosphorylase activity can increase over time, rapidly degrading the active substances before they reach systemic circulation.² This degradation reduces treatment efficacy, suggesting that future development may require formulation strategies to inhibit enzymatic breakdown or optimize delivery. Furthermore, the dose-related response observed in studies suggests that achieving precise, therapeutic concentrations is vital for maintaining mitochondrial DNA copy numbers.

References

1. EMA. First Treatment for Rare Thymidine Kinase 2 Deficiency. Press Release. Jan 30, 2026
2. Garone, C., Garcia‐Diaz, B., Emmanuele, V. et al. Deoxypyrimidine Monophosphate Bypass Therapy for Thymidine Kinase 2 Deficiency. EMBO Mol Med 2014 6, 1016–1027. https://doi.org/10.15252/emmm.201404092