Neurology Publication Demonstrates 95% Reduction in Mortality Risk with Pyrimidine Nucleos(t)ide Therapy in Patients with Thymidine Kinase 2 Deficiency (TK2d)
UCB, a global biopharmaceutical company focused on the discovery and development of innovative treatments for serious diseases, today announced the publication of pivotal results in Neurology from a multicenter retrospective chart review study evaluating investigational pyrimidine nucleoside and/or nucleotide therapy in individuals living with thymidine kinase 2 deficiency (TK2d).
The study’s findings provide compelling evidence that pyrimidine nucleos(t)ide therapy significantly reduces the risk of death and improves motor and functional outcomes in patients with TK2d—an ultra-rare, life-threatening mitochondrial disorder for which no approved treatments currently exist.
Study Overview and Key Findings
The Neurology publication reported outcomes from a global multicenter retrospective chart review involving both treated and untreated patients with TK2d. The analysis demonstrated that pyrimidine nucleos(t)ide therapy was associated with remarkable survival benefits and functional improvements across multiple clinical parameters.
Among the 38 treated patients, no deaths were reported, whereas 58% (40 of 69) of untreated patients died during the observation period. Statistical analyses estimated a reduction in the risk of death ranging from 85% to 93% when measured from the time of symptom onset (hazard ratio [HR]: 0.067–0.147) and between 75% and 91% when measured from treatment initiation (HR: 0.091–0.251). Further, using exact conditional logistic regression, the therapy was associated with a 95% reduction in mortality risk—a dramatic outcome highlighting the therapy’s potential to alter the natural course of the disease.
Before beginning treatment, 71% (27 of 38) of patients had lost at least one motor milestone, and 29% (11 of 38) had lost four or more. Following initiation of pyrimidine nucleos(t)ide therapy, no additional motor milestones were lost, and among those who had previously lost them, 65% (17 of 26) regained at least one. This recovery of motor function represents a major advancement for a condition previously considered relentlessly progressive.
Additionally, over 50% (19 of 38) of patients required ventilatory support prior to treatment. Of those who received pyrimidine nucleos(t)ide therapy, 29% (6 of 21) demonstrated a reduction in their need for ventilatory assistance, further supporting the potential functional benefits of this treatment.
Safety Profile and Tolerability
Pyrimidine nucleos(t)ide therapy was generally well tolerated in the study population. Most treatment-emergent adverse events (TEAEs) were mild and transient, with no discontinuations attributed to safety concerns.
The most frequently reported TEAEs included:
- Diarrhea: 68% overall (26/38); among those with age of symptom onset ≤12 years: 62% (18/29)
- Increased blood creatine kinase (CK): 23% overall (9/38); ≤12 years: 28% (8/29)
- Pyrexia (fever): 16% overall (6/38); ≤12 years: 21% (6/29)
- Increased alanine aminotransferase (ALT): 16% overall (6/38); ≤12 years: 17% (5/29)
- Increased aspartate aminotransferase (AST): 13% overall (5/38); ≤12 years: 14% (4/29)
These results suggest that the therapy’s safety profile is consistent with previous observations and manageable within standard clinical monitoring frameworks.
Study Limitations
The authors acknowledged several limitations typical of rare disease studies. These included potential selection bias arising from heterogeneous inclusion criteria (mitigated partly through patient matching algorithms), wide confidence intervals due to the absence of deaths in the treated group, and limited sample size owing to the rarity of TK2d. In addition, variability in data collection methods, missing patient metrics, and differences in assessment standards across sites posed challenges to cross-group comparisons. Despite these constraints, the magnitude and consistency of survival benefit strongly support the therapy’s clinical potential.
Expert Perspectives
“The publication of these results in Neurology, a leading medical journal, underscores the importance of these findings for the global TK2d community,” said Dr. Cristina Domínguez-González, Neurology Specialist at University Hospital 12 de Octubre in Madrid and lead author of the study. “Our analysis revealed a dramatic survival benefit, with pyrimidine nucleoside and/or nucleotide therapy demonstrating clear improvements in survival and motor outcomes. These data highlight the promise of this treatment as a potentially transformative therapeutic option, offering hope where none previously existed.”
Adding to this, Dr. Donatello Crocetta, Chief Medical Officer at UCB, emphasized the company’s ongoing commitment to rare disease research:
“Thymidine kinase 2 deficiency is an ultra-rare, progressive mitochondrial disorder with no approved therapies or standardized care pathways. The publication of these pivotal data represents a major milestone for UCB and the TK2d community. It reinforces our mission to translate cutting-edge science into meaningful, first-in-class treatments that can address the profound unmet needs of patients and families worldwide.”
