Thymidine Kinase 2 Deficiency (MTDPS2) Clinical Trials

TK2d is caused by mutations in the TK2 gene on chromosome 16, which encodes the mitochondrial enzyme thymidine kinase 2. This enzyme has a specialized job: it phosphorylates thymidine and deoxycytidine, 2 of the building blocks (pyrimidine nucleosides) that mitochondria need to make and repair their own DNA, called mitochondrial DNA (mtDNA). When TK2 enzyme activity is reduced or absent, mitochondria run short on these building blocks, mtDNA copy number falls (a process called mtDNA depletion), and the energy-making machinery inside muscle cells progressively fails.

The most common symptoms of Thymidine Kinase 2 Deficiency include Progressive muscle weakness, especially in the arms, legs, and around the shoulders and hips (proximal weakness), Difficulty breathing as respiratory muscles weaken, and many patients eventually need ventilatory support, Eye muscle weakness causing droopy eyelids (ptosis) and limited eye movement (ophthalmoplegia), Trouble chewing and swallowing (dysphagia), which can affect nutrition and increase aspiration risk, Loss of motor milestones (sitting, standing, walking) in young children with the early-onset form, among others. Estimated worldwide prevalence is roughly 1.64 cases per 1,000,000 people, making TK2d an ultra-rare disease. Biallelic pathogenic variants in TK2 account for approximately 20% of myopathic mitochondrial DNA maintenance defects. Three age-of-onset subtypes are recognized. In a 2018 review of 92 untreated patients (Garone et al., Journal of Medical Genetics), infantile-onset disease (symptoms at or before age 1) had a median survival of about 1 year after symptoms began, childhood-onset disease (after age 1 and before 12) at least 13 years, and late-onset disease (after age 12) about 23 years. Symptoms can range from mild to severe and may vary between individuals.

Trial Friend lists all active clinical trials for Thymidine Kinase 2 Deficiency from ClinicalTrials.gov, with eligibility criteria translated into plain English. Patients can filter by trial phase and recruitment status, search by location, and use the Match Me tool to score trials against their profile. On November 3, 2025, the FDA approved Kygevvi (doxecitine and doxribtimine) as the first therapy ever specifically indicated for TK2d, covering adults and pediatric patients whose symptoms began on or before age 12. On March 23, 2026, PANTHERx Rare announced that UCB had chosen it as the only specialty pharmacy that dispenses Kygevvi in the U.S.

On November 3, 2025, the FDA approved Kygevvi (doxecitine and doxribtimine) as the first targeted therapy for thymidine kinase 2 deficiency. The on-label indication covers adults and pediatric patients whose TK2d symptoms began on or before age 12. Kygevvi is an oral powder that is mixed with water; it contains two pyrimidine nucleosides (deoxycytidine and deoxythymidine analogs) that bypass the broken TK2 enzyme step and feed the building blocks directly to muscle mitochondria. In the studies behind the label, treatment reduced the overall risk of death by approximately 86% compared with matched untreated patients. In pooled data UCB presented in March 2025, 30 of 40 treated patients whose symptoms began by age 12 (75%) regained at least one motor milestone (such as sitting, standing, or walking) they had lost, and of 31 patients on a ventilator or BiPAP, 5 cut their daily use and 5 stopped it altogether. The label warns about elevated liver enzymes and about diarrhea and vomiting. Diarrhea was the most common side effect, and the label calls for liver blood tests before starting and yearly after that. On March 23, 2026, PANTHERx Rare announced that UCB had chosen it as the only specialty pharmacy that dispenses Kygevvi in the U.S. Standard supportive care (respiratory therapy, swallowing therapy, physical therapy, nutrition, and ventilatory support when needed) continues alongside Kygevvi.

Thymidine kinase 2 deficiency (TK2d) is caused by mutations in the TK2 gene on chromosome 16, which makes a mitochondrial enzyme called thymidine kinase 2. This enzyme has a specialized job inside muscle mitochondria: it activates two of the building blocks (deoxycytidine and deoxythymidine) that mitochondria need to make and repair their own DNA, called mitochondrial DNA or mtDNA. When TK2 is missing or broken, mitochondria run short on these building blocks, mtDNA copy number falls in muscle cells (a process called mtDNA depletion), and the energy-making machinery in skeletal muscle progressively fails. Because muscle cells are heavy energy users, weakness shows up first in the arms and legs (proximal weakness), the eye muscles (causing droopy eyelids and limited eye movement), the swallowing muscles, and eventually the breathing muscles. The age at which symptoms first appear is the strongest predictor of how the disease behaves: infantile-onset (at or before age 1) progresses fastest, childhood-onset (after age 1 and before 12) progresses more slowly over many years, and late-onset (after age 12) can resemble adult-acquired mitochondrial myopathy.

TK2 gene sequencing is the definitive diagnostic test for thymidine kinase 2 deficiency and is required for enrollment in most clinical trials. Both copies of the TK2 gene must carry a disease-causing variant to produce TK2d, since the disease is autosomal recessive (you need a defective copy from both parents to be affected). Many different pathogenic variants have been identified, distributed across the coding region of the gene. Diagnosis is supported by elevated creatine kinase (a muscle injury marker), low mitochondrial DNA copy number on muscle biopsy, and ragged-red or COX-negative fibers on muscle biopsy stains. Cascade testing, which means testing close relatives once one family member is diagnosed, matters because each full sibling of an affected person has a 25% chance of being affected. UMDF (the United Mitochondrial Disease Foundation) maintains a TK2d patient registry called mitoSHARE that can connect affected families to research opportunities. Labs offering TK2 sequencing include GeneDx, Invitae, PreventionGenetics, Blueprint Genetics, and university metabolic disease labs.

Eligibility for Thymidine Kinase 2 Deficiency clinical trials depends on factors like age, diagnosis, treatment history, and overall health. Each trial sets its own inclusion and exclusion criteria. Trial Friend translates these requirements from medical language into plain English so patients can review them more easily. The Match Me tool can score your profile against active trials to help identify studies that may be a fit.

Participating in a Thymidine Kinase 2 Deficiency clinical trial typically involves scheduled visits, medical tests, and close monitoring by a research team. Depending on the study phase, you may receive an investigational treatment, a placebo, or the current standard of care. Trials may last from a few weeks to several years. Study participation is voluntary, and you can withdraw at any time.

Thymidine kinase 2 deficiency clinical trial activity is limited because the patient population is ultra-rare and Kygevvi is already approved. UCB's open-label continuation study (NCT03845712) completed in August 2026, the long-running Columbia University program led by Dr. Michio Hirano (NCT03639701) is no longer taking new patients, UCB still lists an expanded access program (NCT06590493) as available, and a Spain-based Phase 2 study in adults (NCT06754098) is recruiting. Patients who received the original deoxycytidine and deoxythymidine therapy through Columbia or other compassionate-use channels are typically asked to document their treatment history rather than discontinue it. Future trials of new mitochondrial therapies may exclude prior Kygevvi exposure or require a washout. Trial Friend's medication conflict checker scans each trial's exclusion criteria against Kygevvi (doxecitine and doxribtimine), the original deoxycytidine/deoxythymidine compassionate-use compounds, and supportive medications used to manage the systemic complications of TK2d. The checker flags the specific drug, the trial's exclusion language, and a confidence level so you can discuss timing with your neurologist or metabolic specialist.

Key questions to ask your neurologist or metabolic specialist about TK2d clinical trials: Has TK2 gene sequencing confirmed the diagnosis, and what age were my (or my child's) first symptoms? Does that put us in the infantile-onset, childhood-onset, or late-onset group? The Kygevvi label covers people whose symptoms began on or before age 12. Does that include us, and how would insurance approval and the specialty pharmacy work? How often will my liver enzymes (AST and ALT, the standard liver-function blood tests) be checked, and what should we do about diarrhea or vomiting, the side effects that most often led to lower doses? What is my (or my child's) current pulmonary function, such as forced vital capacity (FVC), maximum inspiratory and expiratory pressures (MIP/MEP), overnight oximetry, and how often will those be repeated, since respiratory weakness is the most life-threatening feature of TK2d? Should swallowing function be formally evaluated (a swallow study) so we can catch silent aspiration before it causes pneumonia? Should my siblings or children who have no symptoms be offered TK2 gene testing?