FDA Approves UCB’s Kygevi for TK2 Deficiency Based on Multi-Study Clinical Program Demonstrating Significant Survival and Motor Gains

The FDA has approved UCB’s Kygevi (doxecitine and doxribtimine) for the treatment of thymidine kinase 2 deficiency (TK2d), becoming the first and only therapy for adults and children living with the genetic mitochondrial disease.¹

The approval is based on data from a clinical program comprised of a Phase II trial (NCT03845712), two retrospective chart review studies (NCT03701568, NCT05017818), and an expanded access use program (NCT06590493).

Phase II results highlight efficacy across clinical program

In the Phase II study, from which UCB shared results in March at this year’s Muscular Dystrophy Association Clinical and Scientific Conference, doxecitine and doxribtimine demonstrated survival benefits and improvement in functional motor outcomes.²

Detailed findings from the trial highlighted:

• Survival benefit: In patients with symptom onset at age ≤12 years, nucleoside/nucleotide therapy reduced the risk of death by 92-94% from symptom onset and by 87-95% from treatment initiation (p<0.0001).
• Motor function recovery: 75% of treated patients regained at least one lost motor milestone, and 22.5% regained four or more.
• Ventilatory improvement: Among patients requiring respiratory support, 16.1% reduced use and 16.1% discontinued ventilatory support after therapy.
• Safety profile: Therapy was generally well tolerated, with diarrhea (85-91%) being the most frequent treatment-emergent adverse event.
• Quality of life: Patient and caregiver reports highlight significant physical and emotional burdens of TK2d, including mobility, breathing, and feeding difficulties, and high caregiver stress due to limited support.

In a press release, Donatello Crocetta, chief medical Officer at UCB, said: "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. 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."

Study design and endpoints

The Phase II trial evaluating Kygevi was a prospective, open-label study evaluating doxecitine and doxribtimine in TK2d participants who previously took part in the retrospective study MT-1621-101 (NCT03701568) or were on nucleos(t)ide therapy.³

• Population: Single-arm study enrolling participants who received up to 800 mg/kg/day orally, divided into three doses given 6-8 hours apart with food.
• Primary endpoints: Safety assessed by adverse events, laboratory parameters, and ECG changes over ~3 years.
• Secondary endpoints: Efficacy outcomes included motor milestone recovery, pulmonary function, growth and nutrition metrics, and need for feeding support, along with pharmacokinetics and biomarker analyses.
• Patient-reported outcomes: Quality of life measured using the INQoL questionnaire, Clinical and Patient Global Impressions of Improvement, and overall health-care utilization over the 3-year study period.

Outcomes from across the Kygevi clinical program

As mentioned earlier, Kygevi’s approval is based on data from a group of studies. The clinical program included a total of 82 unique patients treated with Kygevi or pyrimidine nucleosides with an age of TK2d symptom onset ≤12 years.

Efficacy was evaluated by comparing overall survival between pediatric and adult patients with TK2 deficiency who received nucleos(t)ide therapy and an external control group of untreated, age-matched patients (≤2 years or >2 to ≤12 years at symptom onset).

Results from the program in its entirety showed:

• A total of 78 matched pairs were included in the survival analysis.
• Treatment with nucleos(t)ide therapy reduced the risk of death by approximately 86% (95% CI: 61%–96%) from the start of treatment.
• Among treated patients, the median age at symptom onset was 1.5 years (range: 0.01–12 years).
• The median duration of treatment was four years (range: 1 day-12 years), and the median dose received was 762 mg/kg/day (range: 260-800 mg/kg/day).

While Kygevi is not yet approved anywhere outside of the US, it is currently being reviewed by the EMA. UCB expects the treatment to be commercially available in the US early next year.

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 5, 2025. https://www.ucb.com/newsroom/press-releases/article/us-fda-approves-kygevvir-doxecitine-and-doxribtimine-the-first-and-only-treatment-for-adults-and-children-living-with-thymidine-kinase-2-deficiency-tk2d

2. New data on investigational therapy for thymidine kinase 2 deficiency presented at Muscular Dystrophy Association (MDA) 2025 Conference. News release. UCB. March 19, 2025. Accessed November 5, 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. An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (Continuation). ClinicalTrials.gov. Updated May 18, 2025. Accessed November 5, 2025. https://www.clinicaltrials.gov/study/NCT03845712