FDA Approves Doxecitine and Doxribtimine Combination Therapy as First Treatment for Thymidine Kinase 2 Deficiency

In major news, the FDA has approved UCB’s doxecitine (dC) and doxribtine (dT), a fixed-dose combination therapy, as the first treatment for patients with thymidine kinase 2 deficiency (TK2d), an ultra-rare neuromuscular disorder that causes issues with myopathy, difficulty walking, and breathing, among others. Marketed as Kygevvi, this combination treatment targets the root cause of TK2d, giving patients and families newfound hope for treating the disease.¹

This new therapy, a 1:1 mixture of dC and dT, is designed to support mitochondrial DNA replication by bypassing the deficient TK2 enzyme and leveraging cytosolic kinases. TK2d, a disorder with a worldwide prevalence of about 1.64 cases per million, is primarily induced by mitochondrial depletion, resulting in progressive muscle weakness, respiratory failure, developmental regression, and premature death.

Kygevvi is still under review by the Europeans Medicines Agency, with other global submissions to come in the near future. The therapy, which previously received orphan drug, breakthrough, and priority review designations by the FDA, is expected to commercially available in the first quarter of 2026.

"The approval of doxecitine and doxribtimine represents a pivotal moment for the TK2d community who previously had no FDA-approved treatment options for this rare genetic mitochondrial disease beyond supportive [palliative] care," Donatello Crocetta, chief medical officer at UCB, said in a statement.¹ "We extend heartfelt thanks to the patients, families and friends, advocates, healthcare providers and dedicated clinical trial teams who have partnered with us on this important journey."

For Kygevvi, the approved label notes important safety information, including for the potential of elevated liver transaminase levels as well as gastrointestinal adverse reactions. Clinicians are recommended to obtain baseline liver transaminase and total bilirubin levels in patients prior to treatment initiation with the combination treatment.

"I've been studying mitochondrial diseases for more than three decades and have witnessed firsthand the impact TK2d has on patients and their families," Michio Hirano, MD, professor of neurology and chief of the division of neuromuscular medicine at Columbia University Irving Medical Center, said in a statement.¹ "We have been waiting for an approved treatment for many years, and this approval marks a significant milestone in how we can support and manage this debilitating condition."

UCB’s application, submitted at the end of 2024, was granted priority review, breakthrough therapy designation, and rare pediatric disease designation by the FDA. Its clinical program is comprised of one phase 2 study (NCT03845712), 2 retrospective chart review studies, and an expanded access use program.

A total of 82 unique patients treated with Kygevvi or pyrimidine nucleosides were assessed across the studies and compared with an external control group of untreated, matched patients. After pairing, results revealed an 86% (95% CI, 61%-96%) reduced overall risk of death over a median treatment duration of 4 years (range, 1 day to 12 years).¹

Findings from the phase 2 trial presented earlier this year at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16-19 in Dallas, Texas featured pooled data of patients with TK2d less than 12 years of age treated with dC and dT. Overall, treatment with the nucleoside and/or nucleotide therapy resulted in reduced risk of death by 92-94% (HR, 0.06-0.08; P <.0001) and 87-95% (HR, 0.05-0.13; P <.0001) in the time from symptom onset and starting treatment, respectively. Importantly, the combination therapy was generally well tolerated, with diarrhea (range from 84.6%-90.9%) was the most reported treatment-emergent adverse event (TEAE).

On functional outcomes, 75.0% (30 of 40) of treated patients with TK2d regained at least 1 of their previously lost motor milestone, with 22.5% (9 of 40) regaining 4 or more motor milestones. Over time, ventilatory support dependency decreased, with 16.1% (5 of 31) of patients reducing usage time and 16.1% (5 of 31) discontinuing ventilatory support altogether after treatment.

Prior to Kygevvi, there were no approved pharmacological treatments for TK2d. Many patients will often turn to feeding support approaches, respiratory interventions, rehabilitative therapies, as well as mobility aids to help manage their symptoms. In addition, there has been an increase in genetic counseling for families and caregivers, as well as more geared management of specific complications, like hearing loss or seizures.

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In 2024, investigators published data on the pharmacokinetics, effect of food, and tolerability of 2 study drug formulations of dC and dT, evaluated in 2 phase 1 studies (Study MT-1621-103 and Study MT-1621-105). In both studies (n = 14 healthy adults each), a sequential, ascending 1:1 dose ratio of 86.6, 173.4, and 266.6 mg/kg was administered after a 28-day (MT-1621-103) or 35-day (MT-1621-105) screening. Doses were given following an overnight fast, with 48-hour PK assessments and washouts between. After another 48 hours, participants received 266.6 mg/kg post–high-fat meal.³

In the phase 1 studies, Plasma concentrations of dC and dT increased rapidly and dose-dependently, with a median T_max of 1 to 2 hours under fasting conditions and 2 to 4 hours when administered with food. Levels returned to near baseline within 8 to 12 hours, indicating rapid elimination. Exposure was less than dose-proportional for dC and greater than dose-proportional for dT, with moderate-to-high pharmacokinetic variability (>30%).

A significant food effect was observed, with dC C_max and area under the curve (AUC) increasing by approximately 79–96% and 137–250%, respectively, and dT C_max and AUC increasing by 27–29% and 74–89%. Renal clearance contributed minimally to elimination (Fe < 0.3%). The study drug was generally well tolerated, with the most common treatment-related AEs being diarrhea (14%) and dizziness (10%), both mostly mild to moderate in severity.

Earlier this year, several clinician authors published a case study in Molecular Genetics and Metabolism highlighting the use of dC and dT treatment in a 26-year-old female with childhood-onset TK2d. Prior to initiating treatment, she was described as experiencing myopathy, fatigue, weight loss, atrophy, bone fractures, dysphagia, neuropathy, and respiratory failure. After almost 3 years of deoxynucleoside therapy and multiple therapy modalities (physical, occupational, and speech), the patient’s rate of decline slowed, and she began to show steady improvement. In addition, she saw enhanced respiratory status with BiPAP transitioning from continuous to only during sleep.⁴

REFERENCES
1. U.S. FDA approves KYGEVVI® (doxecitine and doxribtimine), the first and only treatment for adults and children living with thymidine kinase 2 deficiency (TK2d). News release. UCB. November 3, 2025. Accessed November 3, 2025. https://www.prnewswire.com/news-releases/us-fda-approves-kygevvi-doxecitine-and-doxribtimine-the-first-and-only-treatment-for-adults-and-children-living-with-thymidine-kinase-2-deficiency-tk2d-302603083.html
2. New data on investigational therapy for thymidine kinase 2 deficiency presented at Muscular Dystrophy Association (MDA) 2025 Conference. News release. March 19, 2025. Accessed August 13, 2025. https://www.ucb.com/newsroom/press-releases/article/new-data-on-investigational-therapy-for-thymidine-kinase-2-deficiency-presented-at-muscular-dystrophy-association-mda-2025-conference
3. Mittur A, VanMeter SA, Orujov E, Glidden P. Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults. Clin Ther. 2024;46(7):576-587. doi:10.1016/j.clinthera.2024.06.006
4. Chow E, Miller L, Clearman A, Arnold P, Koenig MK, Russo SN. Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency. Mol Genet Metab. 2025;145(4):109159. doi:10.1016/j.ymgme.2025.109159