Phase 2 Open-Label Study on Safety and Pharmacokinetics of Doxecitine and Doxribtimine in Thymidine Kinase 2 Deficiency Patients

The primary objective of this Phase 2 open-label study is to **characterize the safety and tolerability** of continued treatment with dC/dT, a combination of pyrimidine nucleosides administered as doxecitine and doxribtimine, in patients with **thymidine kinase 2 deficiency** who have previously been treated with dC/dT, dCMP/dTMP, or doxecitine and doxribtimine. This objective is clinically relevant as it aims to ensure the ongoing safety of the treatment regimen in a population with a rare mitochondrial disorder, potentially improving long-term management strategies for these patients.

Secondary objectives include:

• To demonstrate the continued efficacy of dC/dT administered as doxecitine and doxribtimine.
• To evaluate the pharmacokinetics (PK) of doxecitine and doxribtimine at steady state using sparse sampling methodology.

The clinical trial involves a total of **25 participants** diagnosed with **Thymidine kinase 2 deficiency**. The study population includes both male and female subjects, encompassing a broad age range from children to adults. Participants were selected based on confirmed genetic mutations in the TK2 gene and are currently undergoing treatment with nucleos(t)ides for TK2 deficiency. The trial includes a vulnerable population, indicating the presence of participants who may require additional considerations. Participants are required to maintain their current treatment and exercise regimens throughout the study. The selection criteria ensure the absence of other genetic or polygenic diseases, and female participants of childbearing potential must adhere to strict birth control measures. The trial aims to assess the safety and tolerability of continuing treatment with a combination of pyrimidine nucleosides in this specific patient group.

The clinical trial is designed to evaluate the **safety** and tolerability of continuing treatment with combination pyrimidine nucleosides, specifically **doxecitine** and **doxribtimine**, in patients with **thymidine kinase 2 deficiency**. This is a Phase 2, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial aims to assess the safety profile through adverse events, laboratory measurements, and electrocardiograms, while secondary endpoints include motor function assessments, respiratory status, feeding status, quality of life, and healthcare utilization among others. The trial is expected to run until June 2025, with recruitment having started in September 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed genetic mutation in the TK2 gene and current treatment with nucleos(t)ides for TK2 deficiency. Female participants must have a negative pregnancy test and agree to use effective birth control methods, while male participants must use condoms to prevent drug transmission. The study involves regular follow-up visits to monitor safety and efficacy, with assessments including motor function, respiratory and feeding status, and quality of life. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 72 weeks, depending on individual circumstances.

Participants may be terminated early from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The study drug is administered orally as a solution, with a maximum daily dose of 800 mg/kg. The trial is not categorized as low intervention, indicating a more intensive monitoring and data collection process. The study is conducted under the sponsorship of UCB Biosciences Inc., and the investigational product is designated as an orphan drug, highlighting its use in treating a rare disease.

The clinical trial involves the administration of the experimental medication **doxecitine and doxribtimine**, which are pyrimidine nucleosides. This medication is provided in the form of an **oral solution**. The active substances, **doxribtimine** and **doxecitine**, are of chemical origin and are manufactured by UCB Biosciences Inc. The maximum daily dose is 800 mg/kg, and the treatment period is limited to a maximum of 72 weeks. The medication is administered orally, and the dosing schedule is designed to ensure optimal therapeutic outcomes while monitoring for safety and tolerability in patients with thymidine kinase 2 deficiency.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the continuation of treatment with the combination of pyrimidine nucleosides, specifically doxecitine and doxribtimine, in patients who have previously been treated with similar compounds. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence and to evaluate the safety profile of the treatment.

Efficacy in this clinical trial will be assessed through a series of secondary endpoints designed to evaluate various aspects of patient health and treatment impact. These endpoints include assessments of motor function, respiratory status, and feeding status. Respiratory status will be evaluated using pulmonary function tests and the need for ventilatory support, while feeding status will be determined by the requirement for supplemental feeding or a feeding tube. Quality of life will be measured using the INQOL Questionnaire, and healthcare utilization will be characterized by tracking hospitalizations, surgeries, and the use of healthcare resources such as respiratory care, nursing care, and physical therapy.

Additional efficacy parameters include the occurrence of respiratory infections, growth in children under 18 years old as referenced to WHO standards, and both the Clinical Global Impression of Improvement (CGI-I) completed by the investigator and the Patient Global Impression of Improvement (PGI-I) completed by the study participant or caregiver. Biomarkers, including plasma levels potentially related to **thymidine kinase 2 deficiency** and/or drug treatment, such as creatine kinase, will also be monitored. Plasma concentrations at steady state will be evaluated to assess pharmacokinetics (PK), and palatability will be assessed using a 5-point hedonic scale. These assessments will provide a comprehensive evaluation of the treatment's efficacy in patients with thymidine kinase 2 deficiency.