Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial

Adam L. Boxer, Irfan Qureshi, Michael Ahlijanian, Michael Grundman, Lawrence I. Golbe, Irene Litvan, Lawrence S. Honig, Paul Tuite, Nikolaus R. McFarland, Padraig O'Suilleabhain, Tao Xie, Giridhar S. Tirucherai, Clifford Bechtold, Yvette Bordelon, David S. Geldmacher, Murray Grossman, Stuart Isaacson, Theresa Zesiewicz, Tina Olsson, Kumar Kandadi MuralidharanDanielle L. Graham, John O'Gorman, Samantha Budd Haeberlein, Tien Dam

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Abstract

Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41–86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. Funding: Bristol-Myers Squibb, Biogen.

Original languageEnglish (US)
Pages (from-to)549-558
Number of pages10
JournalThe Lancet Neurology
Volume18
Issue number6
DOIs
StatePublished - Jun 2019

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Progressive Supranuclear Palsy
Monoclonal Antibodies
Placebos
Safety
Urinary Tract Infections
Antibodies, Monoclonal, Humanized
Aspiration Pneumonia
tau Proteins
Contusions
Rare Diseases
Neurodegenerative Diseases
Pharmaceutical Preparations
Headache
Outpatients
Demography
Therapeutics
Population

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  • Journal Article

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Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy : a randomised, placebo-controlled, multiple ascending dose phase 1b trial. / Boxer, Adam L.; Qureshi, Irfan; Ahlijanian, Michael; Grundman, Michael; Golbe, Lawrence I.; Litvan, Irene; Honig, Lawrence S.; Tuite, Paul; McFarland, Nikolaus R.; O'Suilleabhain, Padraig; Xie, Tao; Tirucherai, Giridhar S.; Bechtold, Clifford; Bordelon, Yvette; Geldmacher, David S.; Grossman, Murray; Isaacson, Stuart; Zesiewicz, Theresa; Olsson, Tina; Muralidharan, Kumar Kandadi; Graham, Danielle L.; O'Gorman, John; Haeberlein, Samantha Budd; Dam, Tien.

In: The Lancet Neurology, Vol. 18, No. 6, 06.2019, p. 549-558.

Research output: Contribution to journalArticle

Boxer, AL, Qureshi, I, Ahlijanian, M, Grundman, M, Golbe, LI, Litvan, I, Honig, LS, Tuite, P, McFarland, NR, O'Suilleabhain, P, Xie, T, Tirucherai, GS, Bechtold, C, Bordelon, Y, Geldmacher, DS, Grossman, M, Isaacson, S, Zesiewicz, T, Olsson, T, Muralidharan, KK, Graham, DL, O'Gorman, J, Haeberlein, SB & Dam, T 2019, 'Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial', The Lancet Neurology, vol. 18, no. 6, pp. 549-558. https://doi.org/10.1016/S1474-4422(19)30139-5
Boxer, Adam L. ; Qureshi, Irfan ; Ahlijanian, Michael ; Grundman, Michael ; Golbe, Lawrence I. ; Litvan, Irene ; Honig, Lawrence S. ; Tuite, Paul ; McFarland, Nikolaus R. ; O'Suilleabhain, Padraig ; Xie, Tao ; Tirucherai, Giridhar S. ; Bechtold, Clifford ; Bordelon, Yvette ; Geldmacher, David S. ; Grossman, Murray ; Isaacson, Stuart ; Zesiewicz, Theresa ; Olsson, Tina ; Muralidharan, Kumar Kandadi ; Graham, Danielle L. ; O'Gorman, John ; Haeberlein, Samantha Budd ; Dam, Tien. / Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy : a randomised, placebo-controlled, multiple ascending dose phase 1b trial. In: The Lancet Neurology. 2019 ; Vol. 18, No. 6. pp. 549-558.
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abstract = "Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41–86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17{\%}] of 12 patients and in ten [28{\%}] of 36 patients), urinary tract infections (in one [8{\%}] of 12 and in six [17{\%}] of 36), contusions (in one [8{\%}] of 12 and in five [14{\%}] of 36), and headaches (in none and in five [14{\%}] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. Funding: Bristol-Myers Squibb, Biogen.",
author = "Boxer, {Adam L.} and Irfan Qureshi and Michael Ahlijanian and Michael Grundman and Golbe, {Lawrence I.} and Irene Litvan and Honig, {Lawrence S.} and Paul Tuite and McFarland, {Nikolaus R.} and Padraig O'Suilleabhain and Tao Xie and Tirucherai, {Giridhar S.} and Clifford Bechtold and Yvette Bordelon and Geldmacher, {David S.} and Murray Grossman and Stuart Isaacson and Theresa Zesiewicz and Tina Olsson and Muralidharan, {Kumar Kandadi} and Graham, {Danielle L.} and John O'Gorman and Haeberlein, {Samantha Budd} and Tien Dam",
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TY - JOUR

T1 - Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy

T2 - a randomised, placebo-controlled, multiple ascending dose phase 1b trial

AU - Boxer, Adam L.

AU - Qureshi, Irfan

AU - Ahlijanian, Michael

AU - Grundman, Michael

AU - Golbe, Lawrence I.

AU - Litvan, Irene

AU - Honig, Lawrence S.

AU - Tuite, Paul

AU - McFarland, Nikolaus R.

AU - O'Suilleabhain, Padraig

AU - Xie, Tao

AU - Tirucherai, Giridhar S.

AU - Bechtold, Clifford

AU - Bordelon, Yvette

AU - Geldmacher, David S.

AU - Grossman, Murray

AU - Isaacson, Stuart

AU - Zesiewicz, Theresa

AU - Olsson, Tina

AU - Muralidharan, Kumar Kandadi

AU - Graham, Danielle L.

AU - O'Gorman, John

AU - Haeberlein, Samantha Budd

AU - Dam, Tien

PY - 2019/6

Y1 - 2019/6

N2 - Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41–86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. Funding: Bristol-Myers Squibb, Biogen.

AB - Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41–86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. Funding: Bristol-Myers Squibb, Biogen.

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