Survival and Functional Outcomes in Patients with Thymidine Kinase 2 Deficiency Aged >12 Years at Symptom Onset Who Received Pyrimidine Nucleos(t)ides

Topic:

Clinical Trials

Poster Number: P256

Author(s):

Fernando Scaglia, MD, Baylor College of Medicine and Texas Children’s Hospital, TX, USA; CUHK-BCM Joint Centre, Hong Kong, Michio Hirano, MD, Columbia University Irving Medical Center, New York, NY, USA, Caterina Garone, MD, PhD, University of Bologna and IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy, Richard Haas, MB, BChir, MRCP, University of California and Rady Children's Hospital, San Diego, CA, USA, Carmen Paradas, MD, Hospital Universitario Virgen del Rocío, Seville, Spain; CIBERNED, ISCIII, Madrid, Spain, Cynthia Beller, UCB, Morrisville, NC, USA, Carl Chiang, PhD, UCB, Morrisville, NC, USA, Anny-Odile Colson, PhD, UCB, Colombes, France, Susan VanMeter, MD, UCB, Cristina Domínguez-González, MD, PhD, Hospital Universitario 12 de Octubre Research Institute and CIBERER, ISCIII, Madrid, Spain

Pyrimidine nucleoside therapy with doxecitine and doxribtimine is in development for treating thymidine kinase 2 deficiency (TK2d), an ultra-rare mitochondrial disease associated with progressive proximal myopathy and premature death. Older age at symptom onset is associated with slower disease progression. We assessed survival, functional outcomes and safety in patients with an age of TK2d symptom onset >12 years who received pyrimidine nucleos(t)ides.

Patients treated with pyrimidine nucleos(t)ides were pooled from retrospective (NCT03701568, NCT05017818) and prospective (NCT03845712) sources and a company-supported expanded access program (EAP). Restricted mean survival time (RMST) analyses used 50th-percentile matched-pair data from treated and untreated patients. Treated patients’ pre- and post-treatment functional outcomes were compared.

Twenty-two patients aged >12 years at symptom onset (median age: symptom onset, 27.1 years; treatment initiation, 50.9 years) were treated for a median (Q1, Q3) duration of 27.2 (3.8, 78.0) months. Higher mortality was observed for untreated (23.8% [5/21]) versus treated (18.2% [4/22]) patients. RMST (95% confidence interval) over 30 years post-symptom onset was 27.2 (24.1–30.2) years for treated patients versus 24.8 (20.5–29.1) years for untreated patients. Among treated patients, 47.1% (8/17) lost ≥1 developmental motor milestone pre-treatment (missing/not-at-risk=5) versus 12.5% (2/16) post-treatment (missing/not-at-risk=6). Pre-treatment, no patients regained milestones; post-treatment, 33.3% (3/9) regained ≥1 milestone (missing/not-at-risk=13). Of 9 patients (40.9%) using ventilatory support at treatment initiation (missing=5), 11.1% (1/9) reduced support hours post-treatment; none discontinued support. At treatment initiation, 4 patients (18.2%) used feeding support (missing=6); 1 initiated support post-treatment. In the safety population (n=17; EAP not included), 7 patients (41.2%) experienced TEAEs leading to treatment discontinuation; among those with available data, the most common TEAE was diarrhea (10/11 [90.9%]).

In patients with an age of TK2d symptom onset >12 years, pyrimidine nucleos(t)ide therapy is well tolerated and may stabilize disease progression; further research is needed.

Studies funded by UCB.