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. Martinez; J. 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; 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

doi:10.1002/mds.25824

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, 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

Neurology

Research output: Contribution to journal › Article › peer-review

176 Scopus citations

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 language	English (US)
Pages (from-to)	470-478
Number of pages	9
Journal	Movement Disorders
Volume	29
Issue number	4
DOIs	https://doi.org/10.1002/mds.25824
State	Published - Apr 1 2014

Keywords

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

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/mds.25824

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Tolosa, E., Litvan, I., Höglinger, G. U., Burn, D., Lees, A., Andrés, M. V., Gómez-Carrillo, B., León, T., Del Ser, T., 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., ... 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.; 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, 01.04.2014, p. 470-478.

Research output: Contribution to journal › Article › peer-review

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, 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, 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. ; 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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title = "A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy",

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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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 - 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 - 2014/4/1

Y1 - 2014/4/1

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.

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

Abstract

Keywords

ASJC Scopus subject areas

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