Davunetide in patients with progressive supranuclear palsy: A randomised, double-blind, placebo-controlled phase 2/3 trial

Adam L. Boxer, Anthony E. Lang, Murray Grossman, David S Knopman, Bruce L. Miller, Lon S. Schneider, Rachelle S. Doody, Andrew Lees, Lawrence I. Golbe, David R. Williams, Jean Cristophe Corvol, Albert Ludolph, David Burn, Stefan Lorenzl, Irene Litvan, Erik D. Roberson, Günter U. Höglinger, Mary Koestler, Clifford R Jr. Jack, Viviana Van DeerlinChristopher Randolph, Iryna V. Lobach, Hilary W. Heuer, Illana Gozes, Lesley Parker, Steve Whitaker, Joe Hirman, Alistair J. Stewart, Michael Gold, Bruce H. Morimoto

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Background: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. Methods: In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. Findings: 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). Interpretation: Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding: Allon Therapeutics.

Original languageEnglish (US)
Pages (from-to)676-685
Number of pages10
JournalThe Lancet Neurology
Volume13
Issue number7
DOIs
StatePublished - 2014

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Progressive Supranuclear Palsy
Placebos
Activities of Daily Living
England
Nose
Therapeutics
davunetide
Epistaxis
Intention to Treat Analysis
Natural History
Microtubules
France
Canada
Germany
Phosphorylation

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Davunetide in patients with progressive supranuclear palsy : A randomised, double-blind, placebo-controlled phase 2/3 trial. / Boxer, Adam L.; Lang, Anthony E.; Grossman, Murray; Knopman, David S; Miller, Bruce L.; Schneider, Lon S.; Doody, Rachelle S.; Lees, Andrew; Golbe, Lawrence I.; Williams, David R.; Corvol, Jean Cristophe; Ludolph, Albert; Burn, David; Lorenzl, Stefan; Litvan, Irene; Roberson, Erik D.; Höglinger, Günter U.; Koestler, Mary; Jack, Clifford R Jr.; Van Deerlin, Viviana; Randolph, Christopher; Lobach, Iryna V.; Heuer, Hilary W.; Gozes, Illana; Parker, Lesley; Whitaker, Steve; Hirman, Joe; Stewart, Alistair J.; Gold, Michael; Morimoto, Bruce H.

In: The Lancet Neurology, Vol. 13, No. 7, 2014, p. 676-685.

Research output: Contribution to journalArticle

Boxer, AL, Lang, AE, Grossman, M, Knopman, DS, Miller, BL, Schneider, LS, Doody, RS, Lees, A, Golbe, LI, Williams, DR, Corvol, JC, Ludolph, A, Burn, D, Lorenzl, S, Litvan, I, Roberson, ED, Höglinger, GU, Koestler, M, Jack, CRJ, Van Deerlin, V, Randolph, C, Lobach, IV, Heuer, HW, Gozes, I, Parker, L, Whitaker, S, Hirman, J, Stewart, AJ, Gold, M & Morimoto, BH 2014, 'Davunetide in patients with progressive supranuclear palsy: A randomised, double-blind, placebo-controlled phase 2/3 trial', The Lancet Neurology, vol. 13, no. 7, pp. 676-685. https://doi.org/10.1016/S1474-4422(14)70088-2
Boxer, Adam L. ; Lang, Anthony E. ; Grossman, Murray ; Knopman, David S ; Miller, Bruce L. ; Schneider, Lon S. ; Doody, Rachelle S. ; Lees, Andrew ; Golbe, Lawrence I. ; Williams, David R. ; Corvol, Jean Cristophe ; Ludolph, Albert ; Burn, David ; Lorenzl, Stefan ; Litvan, Irene ; Roberson, Erik D. ; Höglinger, Günter U. ; Koestler, Mary ; Jack, Clifford R Jr. ; Van Deerlin, Viviana ; Randolph, Christopher ; Lobach, Iryna V. ; Heuer, Hilary W. ; Gozes, Illana ; Parker, Lesley ; Whitaker, Steve ; Hirman, Joe ; Stewart, Alistair J. ; Gold, Michael ; Morimoto, Bruce H. / Davunetide in patients with progressive supranuclear palsy : A randomised, double-blind, placebo-controlled phase 2/3 trial. In: The Lancet Neurology. 2014 ; Vol. 13, No. 7. pp. 676-685.
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abstract = "Background: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. Methods: In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. Findings: 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77{\%}) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95{\%} CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12{\%}] of 156 vs 13 [8{\%}] of 156, rhinorrhoea 15 [10{\%}] vs eight [5{\%}], and nasal discomfort 15 [10{\%}] vs one [<1{\%}]). Interpretation: Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding: Allon Therapeutics.",
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TY - JOUR

T1 - Davunetide in patients with progressive supranuclear palsy

T2 - A randomised, double-blind, placebo-controlled phase 2/3 trial

AU - Boxer, Adam L.

AU - Lang, Anthony E.

AU - Grossman, Murray

AU - Knopman, David S

AU - Miller, Bruce L.

AU - Schneider, Lon S.

AU - Doody, Rachelle S.

AU - Lees, Andrew

AU - Golbe, Lawrence I.

AU - Williams, David R.

AU - Corvol, Jean Cristophe

AU - Ludolph, Albert

AU - Burn, David

AU - Lorenzl, Stefan

AU - Litvan, Irene

AU - Roberson, Erik D.

AU - Höglinger, Günter U.

AU - Koestler, Mary

AU - Jack, Clifford R Jr.

AU - Van Deerlin, Viviana

AU - Randolph, Christopher

AU - Lobach, Iryna V.

AU - Heuer, Hilary W.

AU - Gozes, Illana

AU - Parker, Lesley

AU - Whitaker, Steve

AU - Hirman, Joe

AU - Stewart, Alistair J.

AU - Gold, Michael

AU - Morimoto, Bruce H.

PY - 2014

Y1 - 2014

N2 - Background: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. Methods: In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. Findings: 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). Interpretation: Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding: Allon Therapeutics.

AB - Background: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. Methods: In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. Findings: 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). Interpretation: Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding: Allon Therapeutics.

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