UCB has announced promising results from studies of its investigational pyrimidine nucleoside therapy for thymidine kinase 2 deficiency (TK2d), a rare and life-threatening genetic mitochondrial disease. The data, presented at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Dallas, Texas, demonstrated significant survival benefits and functional improvements in patients treated with doxecitine (dC) and doxribtimine (dT).
The clinical findings show remarkable efficacy in patients who developed symptoms before age 12, with treatment reducing mortality risk by 92-94% compared to untreated individuals. The therapy also demonstrated substantial functional improvements across all age groups, offering hope for patients with this debilitating condition that currently has no approved treatments.
Significant Survival Benefits Demonstrated
Among individuals with TK2d who developed symptoms at age 12 or younger, treatment with the nucleoside therapy reduced the risk of death by 92-94% (hazard ratio=0.06-0.08; p<0.0001) when measured from symptom onset. When measured from treatment initiation, the risk reduction remained impressive at 87-95% (hazard ratio=0.05-0.13; p<0.0001).
"There are no approved therapies or international clinical guidelines for the management of TK2d, therefore we are very excited to share this data with the medical community at MDA," said Donatello Crocetta, Chief Medical Officer at UCB. "The data highlight the positive impact this investigational treatment could have on the lives of people living with this debilitating and life-threatening condition."
Functional Improvements Across Multiple Domains
The therapy demonstrated substantial functional benefits beyond survival. Among patients who developed symptoms before age 12, 75% (30/40) regained at least one previously lost motor milestone following treatment, with 22.5% (9/40) regaining four or more motor milestones.
Ventilatory support requirements also improved significantly. Of patients requiring breathing assistance, 16.1% (5/31) were able to reduce usage time, while another 16.1% (5/31) discontinued ventilatory support entirely after treatment.
Safety Profile and Tolerability
Across all study populations, the pyrimidine nucleoside therapy was generally well tolerated. Diarrhea was the most commonly reported treatment-emergent adverse event, occurring in 84.6-90.9% of patients. Despite this side effect, the overall safety profile appears manageable, particularly when weighed against the potential benefits for this life-threatening condition.
Understanding TK2d: A Devastating Rare Disease
Thymidine kinase 2 deficiency is characterized by progressive and severe muscle weakness (myopathy) that can profoundly impact basic functions like walking, eating, and breathing independently. The worldwide prevalence is estimated at just 1.64 cases per million people, making it an ultra-rare condition.
The disease manifests differently based on age of onset, with patients categorized as having symptom onset at age 12 or younger, or after age 12. TK2d profoundly affects multiple aspects of health and quality of life, as children struggle to achieve developmental milestones or lose them, while adults experience loss of functional independence with challenges in breathing, eating, and walking.
Patient experience data presented at the conference highlighted the severe physical and psychological impact of living with TK2d. Many individuals reported the "extreme" impact the condition has on quality of life, particularly regarding mobility, breathing, and eating/swallowing difficulties. Caregivers also reported significant emotional and physical burdens, with constant caregiving demands leading to persistent stress and emotional burnout.
Mechanism of Action
Doxecitine and doxribtimine is a nucleoside therapy that supports mitochondrial DNA replication, resulting in increased or stabilized mitochondrial function in patients with TK2d. Pre-clinical data suggest the primary mechanism involves incorporating nucleosides deoxycytidine (dC) and deoxythymidine (dT) into skeletal muscle mitochondrial DNA, potentially restoring mitochondrial DNA copy number and improving skeletal muscle function.
Regulatory Status
The therapy is currently under review by both US and European regulatory authorities. In the United States, the application has received priority review status, Breakthrough Therapy Designation, and Rare Pediatric Disease Designation, highlighting the significant unmet need for effective treatments for this condition.
The data presented at MDA were pooled from multiple sources, including retrospective and prospective clinical studies and a company-supported expanded access program. Untreated participant data were gathered from literature reviews of case series and reports, as well as a retrospective chart review study.
As the regulatory review process continues, these promising results offer new hope for patients and families affected by this devastating rare disease. If approved, doxecitine and doxribtimine would represent the first authorized treatment specifically for TK2d, potentially transforming the management of this life-threatening condition.
