Lancet Neurol. 2026 Sep;25(9):818-829. doi: 10.1016/S1474-4422(26)00241-3.
ABSTRACT
BACKGROUND: Vanishing white matter is a neurodegenerative disease with onset mostly in children aged 1-6 years that causes early death and has no effective therapy. The disease is caused by a genetic defect affecting eukaryotic initiation factor 2B, a key regulator of the integrated stress response. The α2-adrenergic antihypertensive drug guanabenz inhibits this stress response and has shown benefit in a mouse model of the disease. We aimed to assess the safety, tolerability, and efficacy of guanabenz in young children with vanishing white matter.
METHODS: This single-arm, phase 1/2 trial was conducted at the Amsterdam University Medical Center, Amsterdam, Netherlands, with international recruitment. Eligible patients had a diagnosis of vanishing white matter, confirmed by MRI and genetic testing; were aged 6 years or younger at disease onset; had a disease duration of 8 years or less; and were still able to walk at least ten steps with, at most, the light support of one hand. Oral guanabenz was started at a dose of 0·15 mg/kg per day and titrated over approximately 6 weeks to the maximum tolerated dose, with an optimum (target) dose of 2 mg/kg per day. Trial duration was 4 years with minimum follow-up of 1 year. The primary safety objective was to evaluate the safety and tolerability of guanabenz in the intention-to-treat population, defined as all patients for whom informed consent was provided and who received at least their first dose of guanabenz. The primary efficacy outcome was the time to loss of walking with support. Patients were matched (1:2, without replacement) to untreated historical controls from the Vanishing White Matter Registry, on the basis of a similar age of onset and similar disability at the same disease duration as the patient. Groups were compared using Kaplan-Meier curves, log-rank tests, and hazard ratios (HRs) estimated using Cox proportional hazards models with treatment group and year of onset as covariates. The study was registered with the EU Clinical Trials Register (2017-001438-25) and the EU Clinical Trials Information System (2023-503320-89-00).
FINDINGS: Between May 31, 2021 and May 31, 2024, 33 patients were screened, found eligible, and enrolled, of whom 31 completed the trial. The median age of patients was 5·4 years (IQR 3·6-7·9), the median age of disease onset was 3·1 years (IQR 2·1-4·5), and the median treatment duration was 3·1 years (IQR 2·4-3·6). 63 serious adverse events were reported in 25 (76%) of 33 patients. 30 (48%) of these 63 events were judged likely or very likely to be related to guanabenz, of which 28 were classified as suspected unexpected serious adverse reactions. 24 of these reactions were hallucinations, occurring in 18 (55%) of 33 patients; these occurred intermittently, occurred mostly within the first 4 months of treatment, and mostly resolved within 4 months after the first event. The remaining four reactions-three of constipation of unexpected severity and one of transient hypotension with sedation-each required brief hospital admission and resolved. After the initial 4-6 months, guanabenz was well tolerated and no patients discontinued the study because of side-effects. After titration, four small dose reductions were applied, but there were no dose interruptions. No life-threatening events or deaths occurred. The 33 patients treated with guanabenz had a significantly lower risk of losing the ability to walk with support than the 66 historical controls (HR 0·33 [95% CI 0·16-0·69]; log-rank p=0·0061).
INTERPRETATION: Guanabenz treatment had an acceptable and manageable safety profile and, after the initial phase, was well tolerated in children with vanishing white matter. Treated patients with disease onset at age 6 years or younger, who were still ambulant at baseline, had a significantly lower risk of losing the ability to walk with support than did matched historical controls, although this was a non-randomised comparison. The disease-modifying effect of guanabenz should be confirmed in a long-term extension study.
FUNDING: ZonMw, Nederlandse Hersenstichting, European Leukodystrophy Association, and the VWM Families Foundation.
PMID:42586097 | DOI:10.1016/S1474-4422(26)00241-3
