A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy

Keith P Van Haren; Kristen Cunanan; Avni Awani; Meng Gu; Dalia Peña; Lindsay C Chromik; Michal Považan; Nicole C Rossi; Jordan Goodman; Vandana Sundaram; Jennifer Winterbottom; Gerald V Raymond; Tina Cowan; Gregory M Enns; Emmanuelle Waubant; Lawrence Steinman; Peter B Barker; Daniel Spielman; Ali Fatemi

doi:10.1212/NXG.0000000000200061

A Phase 1 Study of Oral Vitamin D₃ in Boys and Young Men With X-Linked Adrenoleukodystrophy

Neurol Genet. 2023 Mar 31;9(2):e200061. doi: 10.1212/NXG.0000000000200061. eCollection 2023 Apr.

Affiliation

¹ Department of Neurology (K.P.V.H., A.A., D.P., L.C.C., N.C.R., J.W., L.S.), Department of Pediatrics (K.P.V.H., T.C., G.M.E., L.S.), Quantitative Sciences Unit (K.C., V.S.) and Department of Radiology (M.G., D.S.), Stanford University School of Medicine Palo Alto, CA; Russell H. Morgan Department of Radiology and Radiological Science (M.P., P.B.B.), The Johns Hopkins University School of Medicine; The Kennedy Krieger Institute (M.P., P.B.B., A.F.); Department of Genetic Medicine (G.V.R.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Pathology (T.C.), Stanford University School of Medicine, Palo Alto, CA; Department of Neurology (E.W.), University of California at San Francisco, ; and Department of Neurology (A.F.), The Johns Hopkins University School of Medicine, Baltimore, MD.

Abstract

Background and objectives: There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.

Methods: In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D₃ supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.

Results: Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months.

Discussion: Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD.

Classification of evidence: This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.