UCB announced that Neurology has published groundbreaking results from a multicenter retrospective chart review study demonstrating the potential of pyrimidine nucleoside and/or nucleotide therapy in treating thymidine kinase 2 deficiency (TK2d). The study showed a remarkable 95% reduction in risk of death among treated patients, marking a significant milestone for this ultra-rare, life-threatening genetic mitochondrial disease.
Dramatic Survival Benefit Observed
The study revealed striking survival outcomes, with no deaths recorded among the 38 treated patients compared to a 58% mortality rate (40/69) in the untreated group. Using exact conditional logistic regression analysis, researchers calculated a 95% reduction in risk of death with treatment. Additional analyses showed estimated reductions in risk of death between 85% and 93% (HR 0.067–0.147) for time from TK2d symptom onset and between 75% and 91% (HR 0.091–0.251) for time from treatment start.
"Our study showed positive results, with pyrimidine nucleoside and/or nucleotide therapy demonstrating improvement in survival," said Cristina Domínguez-González, Neurology Specialist at University Hospital 12 de Octubre, Madrid, and lead author. "These findings highlight the potential of pyrimidine nucleoside and/or nucleotide therapy as a clinically important therapeutic option, offering hope for a new standard of care if approved by the regulatory authorities."
Functional Improvements Beyond Survival
The therapy demonstrated significant functional benefits beyond survival. Before treatment, approximately 71% (27/38) of patients had lost at least one motor milestone, with 29% (11/38) losing four or more motor milestones. Remarkably, no patients lost motor milestones during treatment, and 65% (17/26) of those who had previously lost milestones regained at least one.
Respiratory function also improved in some patients. Over 50% (19/38) of patients required ventilatory support before treatment, and among those receiving therapy, 29% (6/21) experienced a reduction in their need for ventilatory support.
Safety Profile and Regulatory Status
The safety analysis showed that most treatment-emergent adverse events (TEAEs) were mild and did not lead to discontinuation. The most common TEAEs included diarrhea (68% in patients with symptom onset ≤12 years), increased blood creatine kinase (28%), pyrexia (21%), increased alanine aminotransferase (17%), and increased aspartate aminotransferase (14%).
UCB's pyrimidine nucleoside therapy, consisting of doxecitine and doxribtimine, is currently under regulatory review by US and EU regulatory authorities. If approved, it would become the first and only treatment for TK2d in patients with symptom onset on or before 12 years of age.
Addressing an Ultra-Rare Disease with No Current Treatment
TK2d is an ultra-rare mitochondrial disease with an estimated worldwide prevalence of 1.64 [0.5, 3.1] cases per 1,000,000 people. The condition affects energy-demanding parts of the body such as muscles, heart, and brain, causing progressive and severe muscle weakness that can impact the ability to walk, eat, and breathe independently.
"TK2 deficiency is an ultra-rare, progressive mitochondrial disorder with no approved therapies or internationally recognized clinical guidelines, leaving patients and families with only supportive disease management," said Donatello Crocetta, Chief Medical Officer at UCB. "As part of our mission to address severe, underserved diseases, the publication of these findings marks an important milestone — reinforcing our commitment to advancing science into potential first-in-class medicines for this community."
Mechanism of Action and Study Limitations
The investigational therapy works by incorporating pyrimidine nucleosides, deoxycytidine and deoxythymidine, into skeletal muscle mitochondrial DNA. This action restores mitochondrial DNA copy number in TK2d mutant mice, as suggested by preclinical data.
The researchers acknowledged several study limitations, including potential selection bias due to differing eligibility criteria, large confidence intervals from no deaths in the treated group complicating result precision, low patient numbers due to the rarity of the condition, and challenges in comparing treated and untreated groups due to variability in data collection and assessment protocols.
