Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial

Köhler, Wolfgang; Engelen, Marc; Eichler, Florian; Lachmann, Robin; Fatemi, Ali; Sampson, Jacinda B.; Salsano, Ettore; Gamez, Josep; Molnár, Mária Judit; Pascual, Sílvia; Rovira, M; Vilà, A.; Pina, Guillem; Martín-Ugarte, Itziar; Mantilla, Adriana; Pizcueta, Pilar; Rodríguez-Pascau, Laura; Traver, Estefania; Vilalta, Anna; Pascual, Mireia; Martinell, Marc; Meya, Uwe; Mochel, Fanny; Govern, Eavan Mc; Yazbeck, Elise; Barbier, Magali; Luton, Marie-Pierre; Pousset, Françoise; Hogrel, Jean‐Yves; Adanyeguh, Isaac; Bergh, Florian Then; Bergner, Caroline G.; Unterlauft, Astrid; Roicke, Hannes; Hoffmann, Karl‐Titus; Scherlach, Cordula; Kalb, Andrea; Meilick, Bianca; Reuschel, Mandy; Fenu, Silvia; Mauro, Elena; Murphy, Elaine; Krishna, Gauri; Beyene, Tiggy; Sierra, Alba; Quiñoa, Sara; Canovas, Anna Belen; Grosz, Zoltán; Györgyi, Báthori; Stadt, S.I. van de; Huffnagel, Irene C.; Ballegoij, Wouter J. C. van; Voermans, M.M.C.; Seyedsadjadi, Reza; Corre, Camille; Godbole, Neha; Grant, Natalie; Pires, Claudia Maria Brito; Trovato, Melissa; Yeh, Nancy; Goodman, Jordan; Keller, Jennifer; Joseph, Chris; Haren, Keith Van; Sakamuri, Sarada; Duong, Tina; Perrone, Lila; Tran, Stephanie; Young, Sally Dunaway; Hashmi, S. Shahrukh

doi:10.1016/s1474-4422(22)00495-1

Cited by 14 publications

(15 citation statements)

References 27 publications

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“…Moreover, 9 of the 11 patients with cALD who were assessed pre- and post-HSCT showed a decrease in plasma NfL levels at 1 year post-HSCT [ 134 ]. In the same line, the results from the ADVANCE clinical study on plasma biomarker data showed that NfL levels were significantly increased at week 96 in placebo patients with cerebral lesion progression, supportive of a drug effect on reducing axonal degeneration by leriglitazone [ 120 ].…”

Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 98%

“…A phase 2 trial of leriglitazone in men and women with FRDA (FRAMES; NCT03917225) [ 119 ] and a phase 2/3 trial of leriglitazone in men with AMN (ADVANCE; NCT03231878) have recently been completed [ 120 ]. A phase 2/3 open-label clinical study (NEXUS) in pediatric patients with early-stage cerebral ALD (cALD) (EUDRACT number 2019-000654-59) is currently in progress in Europe.…”

Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 99%

“…An additional biomarker implicated in cALD is macrophage inflammatory protein-1β (MIP-1β; also known as chemokine [C-C motif] ligands 4), a proinflammatory chemokine shown to be elevated in the CSF of boys with cALD [ 148 ]. The results from the ADVANCE clinical trial on patients with ALD revealed that leriglitazone significantly reduced the progression of cerebral lesions and myelopathy symptoms such as balance deterioration while preserving the BBB integrity, as observed through a significant reduction in the plasma levels of MMP-9 [ 120 ].…”

Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 99%

“…Leriglitazone was generally well tolerated, and the results from this clinical trial have been published in the Lancet Neurology journal [ 120 ]. The study did not meet the primary outcome for the 6 min walk test.…”

Section: Clinical Development Of Leriglitazonementioning

confidence: 99%

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Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

Pizcueta

Vergara

Emanuele

et al. 2023

IJMS

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Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood–brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.

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Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 98%

Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 99%

Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 99%

Section: Clinical Development Of Leriglitazonementioning

confidence: 99%

See 2 more Smart Citations

Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

Pizcueta

Vergara

Emanuele

et al. 2023

IJMS

Self Cite

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“…In PKAN astrocytes, Leriglitazone was able to ameliorate cell viability, improve mitochondrial functions, and reduce iron accumulation [ 133 ]. The safety and efficacy in patients with Friedreich Ataxia or X-linked adrenoleukodystrophy were already evaluated in two different clinical trials [ 137 , 138 ].…”

Section: Proposed Therapeutic Optionsmentioning

confidence: 99%

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Cavestro

Diodato

Tiranti

et al. 2023

IJMS

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Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.

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Metabolic Treatments of Cerebellar Ataxia

Mochel

2023

Contemporary Clinical Neuroscience

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Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial

Cited by 14 publications

References 27 publications

Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Metabolic Treatments of Cerebellar Ataxia

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