A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy

Eduardo Tolosa, Irene Litvan, Günter U. Höglinger, David Burn, Andrew Lees, María V. Andrés, Belén Gómez-Carrillo, Teresa León, Teodoro Del Ser, J. C. Gómez, B. Tijero, K. Berganzo, J. García de Yebenes, J. L. Lopez Sendón, G. Garcia, E. Tolosa, M. T. Buongiorno, N. Bargalló, J. A. Burguera, I. MartinezJ. Ruiz-Martínez, I. Narrativel, F. Vivancos, I. Ybot, M. Aguilar, P. Quilez, M. Boada, A. Lafuente, I. Hernandez, J. J. López-Lozano, M. Mata, A. Kupsch, A. Lipp, G. Ebersbach, T. Schmidt, K. Hahn, G. Höglinger, M. Höllerhage, W. H. Oertel, G. Respondek, M. Stamelou, H. Reichmann, M. Wolz, C. Schneider, L. Klingelhöfer, D. Berg, W. Maetzler, K. K. Srulijes, A. Ludolph, J. Kassubek, M. Steiger, K. Tyler, D. J. Burn, L. Morris, A. Lees, H. Ling, R. Hauser, T. McClain, D. Truong, S. Jenkins, I. Litvan, D. Houghton, J. Ferrara, Y. Bordelon, A. Gratiano, L. Golbe, M. Mark, R. Uitti, J. Ven Gerpen

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.

Original languageEnglish (US)
Pages (from-to)470-478
Number of pages9
JournalMovement Disorders
Volume29
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Progressive Supranuclear Palsy
Glycogen Synthase Kinase 3
Placebos
Safety
Apathy
tau Proteins
Activities of Daily Living
Transaminases
NP 031112
Alanine Transaminase
England
Cognition
Atrophy
Parkinson Disease
Cerebrospinal Fluid
Dementia
Diarrhea
Randomized Controlled Trials
Biomarkers
Quality of Life

Keywords

  • GSK-3
  • Pharmacological treatment
  • Progressive supranuclear palsy
  • Randomized controlled clinical trial
  • Tideglusib

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Medicine(all)

Cite this

Tolosa, E., Litvan, I., Höglinger, G. U., Burn, D., Lees, A., Andrés, M. V., ... Ven Gerpen, J. (2014). A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Movement Disorders, 29(4), 470-478. https://doi.org/10.1002/mds.25824

A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. / Tolosa, Eduardo; Litvan, Irene; Höglinger, Günter U.; Burn, David; Lees, Andrew; Andrés, María V.; Gómez-Carrillo, Belén; León, Teresa; Del Ser, Teodoro; Gómez, J. C.; Tijero, B.; Berganzo, K.; García de Yebenes, J.; Lopez Sendón, J. L.; Garcia, G.; Tolosa, E.; Buongiorno, M. T.; Bargalló, N.; Burguera, J. A.; Martinez, I.; Ruiz-Martínez, J.; Narrativel, I.; Vivancos, F.; Ybot, I.; Aguilar, M.; Quilez, P.; Boada, M.; Lafuente, A.; Hernandez, I.; López-Lozano, J. J.; Mata, M.; Kupsch, A.; Lipp, A.; Ebersbach, G.; Schmidt, T.; Hahn, K.; Höglinger, G.; Höllerhage, M.; Oertel, W. H.; Respondek, G.; Stamelou, M.; Reichmann, H.; Wolz, M.; Schneider, C.; Klingelhöfer, L.; Berg, D.; Maetzler, W.; Srulijes, K. K.; Ludolph, A.; Kassubek, J.; Steiger, M.; Tyler, K.; Burn, D. J.; Morris, L.; Lees, A.; Ling, H.; Hauser, R.; McClain, T.; Truong, D.; Jenkins, S.; Litvan, I.; Houghton, D.; Ferrara, J.; Bordelon, Y.; Gratiano, A.; Golbe, L.; Mark, M.; Uitti, R.; Ven Gerpen, J.

In: Movement Disorders, Vol. 29, No. 4, 2014, p. 470-478.

Research output: Contribution to journalArticle

Tolosa, E, Litvan, I, Höglinger, GU, Burn, D, Lees, A, Andrés, MV, Gómez-Carrillo, B, León, T, Del Ser, T, Gómez, JC, Tijero, B, Berganzo, K, García de Yebenes, J, Lopez Sendón, JL, Garcia, G, Tolosa, E, Buongiorno, MT, Bargalló, N, Burguera, JA, Martinez, I, Ruiz-Martínez, J, Narrativel, I, Vivancos, F, Ybot, I, Aguilar, M, Quilez, P, Boada, M, Lafuente, A, Hernandez, I, López-Lozano, JJ, Mata, M, Kupsch, A, Lipp, A, Ebersbach, G, Schmidt, T, Hahn, K, Höglinger, G, Höllerhage, M, Oertel, WH, Respondek, G, Stamelou, M, Reichmann, H, Wolz, M, Schneider, C, Klingelhöfer, L, Berg, D, Maetzler, W, Srulijes, KK, Ludolph, A, Kassubek, J, Steiger, M, Tyler, K, Burn, DJ, Morris, L, Lees, A, Ling, H, Hauser, R, McClain, T, Truong, D, Jenkins, S, Litvan, I, Houghton, D, Ferrara, J, Bordelon, Y, Gratiano, A, Golbe, L, Mark, M, Uitti, R & Ven Gerpen, J 2014, 'A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy', Movement Disorders, vol. 29, no. 4, pp. 470-478. https://doi.org/10.1002/mds.25824
Tolosa E, Litvan I, Höglinger GU, Burn D, Lees A, Andrés MV et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Movement Disorders. 2014;29(4):470-478. https://doi.org/10.1002/mds.25824
Tolosa, Eduardo ; Litvan, Irene ; Höglinger, Günter U. ; Burn, David ; Lees, Andrew ; Andrés, María V. ; Gómez-Carrillo, Belén ; León, Teresa ; Del Ser, Teodoro ; Gómez, J. C. ; Tijero, B. ; Berganzo, K. ; García de Yebenes, J. ; Lopez Sendón, J. L. ; Garcia, G. ; Tolosa, E. ; Buongiorno, M. T. ; Bargalló, N. ; Burguera, J. A. ; Martinez, I. ; Ruiz-Martínez, J. ; Narrativel, I. ; Vivancos, F. ; Ybot, I. ; Aguilar, M. ; Quilez, P. ; Boada, M. ; Lafuente, A. ; Hernandez, I. ; López-Lozano, J. J. ; Mata, M. ; Kupsch, A. ; Lipp, A. ; Ebersbach, G. ; Schmidt, T. ; Hahn, K. ; Höglinger, G. ; Höllerhage, M. ; Oertel, W. H. ; Respondek, G. ; Stamelou, M. ; Reichmann, H. ; Wolz, M. ; Schneider, C. ; Klingelhöfer, L. ; Berg, D. ; Maetzler, W. ; Srulijes, K. K. ; Ludolph, A. ; Kassubek, J. ; Steiger, M. ; Tyler, K. ; Burn, D. J. ; Morris, L. ; Lees, A. ; Ling, H. ; Hauser, R. ; McClain, T. ; Truong, D. ; Jenkins, S. ; Litvan, I. ; Houghton, D. ; Ferrara, J. ; Bordelon, Y. ; Gratiano, A. ; Golbe, L. ; Mark, M. ; Uitti, R. ; Ven Gerpen, J. / A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. In: Movement Disorders. 2014 ; Vol. 29, No. 4. pp. 470-478.
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abstract = "It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9{\%} of patients, and diarrhea in 13{\%} of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.",
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T1 - A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy

AU - Tolosa, Eduardo

AU - Litvan, Irene

AU - Höglinger, Günter U.

AU - Burn, David

AU - Lees, Andrew

AU - Andrés, María V.

AU - Gómez-Carrillo, Belén

AU - León, Teresa

AU - Del Ser, Teodoro

AU - Gómez, J. C.

AU - Tijero, B.

AU - Berganzo, K.

AU - García de Yebenes, J.

AU - Lopez Sendón, J. L.

AU - Garcia, G.

AU - Tolosa, E.

AU - Buongiorno, M. T.

AU - Bargalló, N.

AU - Burguera, J. A.

AU - Martinez, I.

AU - Ruiz-Martínez, J.

AU - Narrativel, I.

AU - Vivancos, F.

AU - Ybot, I.

AU - Aguilar, M.

AU - Quilez, P.

AU - Boada, M.

AU - Lafuente, A.

AU - Hernandez, I.

AU - López-Lozano, J. J.

AU - Mata, M.

AU - Kupsch, A.

AU - Lipp, A.

AU - Ebersbach, G.

AU - Schmidt, T.

AU - Hahn, K.

AU - Höglinger, G.

AU - Höllerhage, M.

AU - Oertel, W. H.

AU - Respondek, G.

AU - Stamelou, M.

AU - Reichmann, H.

AU - Wolz, M.

AU - Schneider, C.

AU - Klingelhöfer, L.

AU - Berg, D.

AU - Maetzler, W.

AU - Srulijes, K. K.

AU - Ludolph, A.

AU - Kassubek, J.

AU - Steiger, M.

AU - Tyler, K.

AU - Burn, D. J.

AU - Morris, L.

AU - Lees, A.

AU - Ling, H.

AU - Hauser, R.

AU - McClain, T.

AU - Truong, D.

AU - Jenkins, S.

AU - Litvan, I.

AU - Houghton, D.

AU - Ferrara, J.

AU - Bordelon, Y.

AU - Gratiano, A.

AU - Golbe, L.

AU - Mark, M.

AU - Uitti, R.

AU - Ven Gerpen, J.

PY - 2014

Y1 - 2014

N2 - It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.

AB - It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.

KW - GSK-3

KW - Pharmacological treatment

KW - Progressive supranuclear palsy

KW - Randomized controlled clinical trial

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