Survival Analyses in Patients with Thymidine Kinase 2 Deficiency Aged ≤12 Years at Symptom Onset Who Received Pyrimidine Nucleos(t)ide Therapy

Topic:

Clinical Trials

Poster Number: P257

Author(s):

Michio Hirano, MD, Houston Merritt Neuromuscular Research Center, CUIMC, 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, Fernando Scaglia, MD, Baylor College of Medicine and Texas Children’s Hospital, TX, USA; CUHK-BCM Joint Centre, Hong Kong, 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

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare, autosomal recessive, progressive mitochondrial disease typically resulting in premature death, often from respiratory failure. Early age at symptom onset is associated with rapid disease progression. No treatments are approved; however, pyrimidine nucleoside therapy with doxecitine and doxribtimine is in development. We assessed survival 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); untreated patients were pooled from literature reviews of case series and reports (2019; updated 2021) and a retrospective chart review (NCT05017818). Survival in 50th-percentile matched-pairs of treated and untreated patients was assessed using proportional hazard and marginal Cox models and restricted mean survival time (RMST) analyses.

Survival analyses included 82 treated (median [Q1, Q3] treatment duration: 54.8 [15.2, 78.4] months) and 93 untreated patients, all aged ≤12 years at symptom onset. Three treated patients (3.7%) and 53 untreated patients (57.0%) died. Treatment reduced risk of death by 92–94% (hazard ratio=0.06–0.08; p<0.0001) and 87–95% (hazard ratio=0.05–0.13; p<0.0001) in the time from symptom onset and treatment initiation, respectively. RMST (95% confidence interval) for treated and untreated patients, respectively, was 29.2 (28.2–30.3) years and 14.4 (11.1–17.6) years over 30 years after symptom onset, and 5.8 (5.5–6.0) years and 2.8 (2.2–3.5) years over 6 years after treatment initiation. In the safety population (n=50; EAP not included), two patients (4.0%) experienced TEAEs leading to treatment discontinuation; among those with available data, diarrhea was the most common TEAE (33/39 [84.6%]). In patients with an age of TK2d symptom onset ≤12 years, pyrimidine nucleos(t)ide therapy significantly decreased mortality, increased survival time, and was well tolerated. Studies funded by UCB.