Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy

a Phase II Pilot Study

Carlos Casasnovas, Montserrat Ruiz, Agatha Schlüter, Alba Naudí, Stéphane Fourcade, Misericordia Veciana, Sara Castañer, Antonia Albertí, Nuria Bargalló, Maria Johnson, Gerald Raymond, Ali Fatemi, Ann B. Moser, Francesc Villarroya, Manuel Portero-Otín, Rafael Artuch, Reinald Pamplona, Aurora Pujol

Research output: Contribution to journalArticle

Abstract

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.

Original languageEnglish (US)
JournalNeurotherapeutics
DOIs
StatePublished - Jan 1 2019

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Adrenoleukodystrophy
Antioxidants
Biomarkers
Safety
Oxidation-Reduction
Spastic Paraparesis
Thioctic Acid
Tocopherols
Environmental Monitoring
Acetylcysteine
Therapeutics
Disease Progression
Oxidative Stress
Homeostasis
Fatty Acids
Placebos
Clinical Trials
Inflammation
Mutation

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Cite this

Casasnovas, Carlos ; Ruiz, Montserrat ; Schlüter, Agatha ; Naudí, Alba ; Fourcade, Stéphane ; Veciana, Misericordia ; Castañer, Sara ; Albertí, Antonia ; Bargalló, Nuria ; Johnson, Maria ; Raymond, Gerald ; Fatemi, Ali ; Moser, Ann B. ; Villarroya, Francesc ; Portero-Otín, Manuel ; Artuch, Rafael ; Pamplona, Reinald ; Pujol, Aurora. / Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy : a Phase II Pilot Study. In: Neurotherapeutics. 2019.
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abstract = "X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.",
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Casasnovas, C, Ruiz, M, Schlüter, A, Naudí, A, Fourcade, S, Veciana, M, Castañer, S, Albertí, A, Bargalló, N, Johnson, M, Raymond, G, Fatemi, A, Moser, AB, Villarroya, F, Portero-Otín, M, Artuch, R, Pamplona, R & Pujol, A 2019, 'Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study', Neurotherapeutics. https://doi.org/10.1007/s13311-019-00735-2

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy : a Phase II Pilot Study. / Casasnovas, Carlos; Ruiz, Montserrat; Schlüter, Agatha; Naudí, Alba; Fourcade, Stéphane; Veciana, Misericordia; Castañer, Sara; Albertí, Antonia; Bargalló, Nuria; Johnson, Maria; Raymond, Gerald; Fatemi, Ali; Moser, Ann B.; Villarroya, Francesc; Portero-Otín, Manuel; Artuch, Rafael; Pamplona, Reinald; Pujol, Aurora.

In: Neurotherapeutics, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy

T2 - a Phase II Pilot Study

AU - Casasnovas, Carlos

AU - Ruiz, Montserrat

AU - Schlüter, Agatha

AU - Naudí, Alba

AU - Fourcade, Stéphane

AU - Veciana, Misericordia

AU - Castañer, Sara

AU - Albertí, Antonia

AU - Bargalló, Nuria

AU - Johnson, Maria

AU - Raymond, Gerald

AU - Fatemi, Ali

AU - Moser, Ann B.

AU - Villarroya, Francesc

AU - Portero-Otín, Manuel

AU - Artuch, Rafael

AU - Pamplona, Reinald

AU - Pujol, Aurora

PY - 2019/1/1

Y1 - 2019/1/1

N2 - X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.

AB - X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.

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