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Jump to Key Points Guanabenz, an older-generation antihypertensive, was associated with a substantially lower risk of losing the ability to walk in young children with vanishing white matter disease — a rare, progressive neurologic disorder for which there is currently no disease-modifying treatment.
Results of a single-arm phase 1/2 trial showed children treated with the drug had about one third the risk of losing the ability to walk with support compared with matched untreated historical controls.
“This study highlights what could be a first disease-modifying treatment in vanishing white matter,” the investigators, led by Margo van der Knaap, MD, PhD, child neurologist and leading expert on leukodystrophies at Amsterdam UMC in Amsterdam, Netherlands, wrote.
The study was published in the September issue of The Lancet Neurology.
- Guanabenz linked to ↓ loss of supported walking in VWM; HR 0.33.
- 33 treated children vs 66 matched historical controls; 4-year follow-up.
- Benefit greatest with onset age ≥3 years; 1/18 vs 11/36 controls.
- Safety manageable; no deaths, life-threatening events, or discontinuations.
- Hallucinations common (55%); usually nocturnal, early, and self-limited.
Promising Signal for Disease Modification
Vanishing white matter is a rare, inherited, progressive leukodystrophy with no cure. The disease typically begins between ages 1 and 6 years and can lead to severe neurologic disability and early death.
The disease is caused by pathogenic variants of the genes EIF2B1-5, which reduce activity of eukaryotic initiation factor 2B and lead to chronic activation of the integrated stress response. Guanabenz, an oral alpha-2 adrenergic antihypertensive, can inhibit this maladaptive stress-response pathway and previously improved disease features in mouse models.
In the phase 1/2 trial, researchers assessed the safety, tolerability, and clinical efficacy of guanabenz in 33 children with MRI- and genetically confirmed vanishing white matter disease.
Participants had disease onset at age 6 years or younger and a disease duration of 8 years or less and retained the ability to walk at least 10 steps with no more than light support from one hand.
Guanabenz was initiated at 0.15 mg/kg/d and titrated over roughly 6 weeks toward the maximum tolerated dose, with a modeled target dose of 2 mg/kg/d. The trial lasted 4 years, with individual follow-up ranging from 1 to 4 years.
During follow-up, 7 of 33 (21%) children treated with guanabenz lost the ability to walk with support, compared with 29 of 66 (44%) matched untreated historical controls from the international Vanishing White Matter Registry.
Guanabenz was associated with a 67% lower hazard of reaching this primary efficacy endpoint (hazard ratio, 0.33).
The apparent benefit was greatest in children with disease onset at age 3 years or later. Of the 18 treated patients in this subgroup, only one lost the ability to walk with support, compared with 11 of the 36 matched controls.
Health Utility Index multiscores suggested “disease stabilization” with guanabenz in most patients, the authors reported.
“We treated patients relatively early in the disease and found that guanabenz mostly prevents further decline. Starting therapy in presymptomatic patients could have greater effects or prevent disease manifestations, whereas the effect of guanabenz in more advanced disease is expected to be less pronounced,” they wrote.
Manageable Safety Profile
The investigators characterized the safety profile as “acceptable and manageable.” There were no grade 4 or 5 adverse events, life-threatening events, or deaths, and none of the participants discontinued guanabenz because of treatment-related adverse effects.
A total of 63 serious adverse events occurred in 25 of 33 patients, and 30 events were found likely or very likely to be related to guanabenz.
Twenty-eight were classified as suspected unexpected, serious adverse reactions. Hallucinations accounted for 24 of these reactions and occurred in 18 patients (55%).
Most hallucinations appeared during the first 4 months of treatment, were predominantly nocturnal, and generally resolved within 4 months of onset. Three events were treated with low-dose risperidone, whereas most required only explanation and reassurance.
Other serious reactions included three cases of constipation severe enough to require brief hospitalization and one episode of hypotension with excessive sleepiness.
Key limitations include the small sample size and reliance on historical controls rather than concurrent randomized controls. The investigators said they considered a placebo-controlled trial ethically problematic because of the rapid, irreversible neurologic deterioration associated with early-childhood disease and the lack of effective treatment.
A First Important Step
A long-term extension study is underway to confirm the safety and durability of the observed effects. Even so, the findings mark an important first step toward a disease-modifying treatment for a condition with no approved therapies.
This is the first study to assess the safety, tolerability, and efficacy of a potential disease-modifying therapy for vanishing white matter, noted Geneviève Bernard, pediatric neurologist at McGill University and Montreal Children’s Hospital, both in Montreal, Quebec, Canada, in a linked comment.
“Larger studies with longer follow-up will be needed to confirm these findings and to determine whether the observed benefits translate into sustained disease modification,” Bernard wrote.
“Other modulators of the integrated stress response, gene therapy, and eventually combination therapy also hold promise to improve disease outcomes,” she added.
The study was funded by ZonMw, Nederlandse Hersenstichting, the European Leukodystrophy Association, and the VWM Families Foundation. Disclosures for the study authors and the comment author are available with the original publications.
