A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease

REVERSE-SD Study Investigators

doi:10.1186/s13195-021-00843-2

A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease

REVERSE-SD Study Investigators

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Abstract

BACKGROUND: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.

METHODS: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aβ1-40, Aβ1-42, neurogranin, and neurofilament light chain].

RESULTS: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.

CONCLUSIONS AND RELEVANCE: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.

Original language	English
Article number	106
Pages (from-to)	106
Journal	Alzheimer's research & therapy
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13195-021-00843-2 https://doi.org/10.1186/s13195-021-00843-2
Publication status	Published - 27 May 2021

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@article{96c12344e5964d2c802c9df6037d8259,

title = "A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease",

abstract = "BACKGROUND: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.METHODS: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aβ1-40, Aβ1-42, neurogranin, and neurofilament light chain].RESULTS: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.CONCLUSIONS AND RELEVANCE: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.",

author = "Harrison, {John E} and {REVERSE-SD Study Investigators} and Prins, {Niels D} and Hui-May Chu and Kelly Blackburn and Alam, {John J} and Philip Scheltens",

note = "Funding Information: The trial was sponsored and funded by EIP Pharma, Inc., which also provided the study drug. NDP and PS were compensated for their time towards protocol development, participation in joint project team and study steering committee meetings, and for manuscript preparation. HMC and JEH were engaged as consultants by EIP Pharma, Inc. JJA and KB are employees of EIP Pharma, Inc. Funding Information: REVERSE-SD Clinical Sites (Site principal investigator): USA: Massachusetts General Hospital (Arnold); CITrials, Inc (Coskinas); Florida Premier Research Institute (Gonzales); Manhattan Behavioral Medicine LLC (Joseph); Northwest Clinical Research Center (Khan); Northwest Clinical Trials (McConnehey); Miami Dade Medical Research Institute (Paricio); Sensible Healthcare LLC (Taylor); Alliance Research (Zarate Rowell); Anchor Neuroscience (Groom); Southern California Research LLC (Summers); Progressive Medica Research (White); Pacific Research Network, LLC (Thein); Alzheimer?s Memory Center (Bolouri); Viking Clinical Research, Ltd (Schwartz); Suncoast Neuroscience Associate (Vasquez). UK: MAC Clinical Research Manchester (Asher); MAC Clinical Research Leeds (Ball); MAC Clinical Research Liverpool (Munthali); MAC Clinical Research Blackpool (Kabir); St Pancras Clinical Research (Langford); S Boroughs/North West Boroughs Healthcare (Komuravelli); Clinical Research Tankerlsey (Lynch); Cognition Health Ltd (MacSweeney); Cognition Health Ltd (Pearson); Cognition Health Birmingham (Faulkner); Cognition Health Ltd (Miller); Fulbourn Hospital (Underwood). Netherlands: Brain Research Center (Prins); Jeroen Bosch Ziekenhuis (Dautzenberg); Amphia Ziekhuis (Van Norden). Czech Republic: Vestra Clinics s.r.o. (Pazdera); Cerbrovaskularni poradn s.r.o. (Bar) Private Psychiatric Centre (Dvacka); Neruo HK s.r.o., Poliklinika Chocen (Valis); Clintrial s.r.o. (Votypkova). Denmark: CCBR Clinical Research, Aalborg (Areovimata); CCBR Clinical Research, Vejle (Justesen); and CCBR Clinical Research, Ballerup (Schmidt). We are very grateful to all patients and caregivers who participated in this study and to the many staff members at the clinical sites for their dedication and commitment to the study. We also acknowledge the study project teams at EIP Pharma and WCT, and specifically, the excellent leadership of those project teams by Jennifer Conway and Nadia Bodjarian, respectively, as well the tremendous contributions of Natalia Drosopolou (project supervision) and Shuhua Qi (statistics) at WCT. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

day = "27",

doi = "10.1186/s13195-021-00843-2",

language = "English",

volume = "13",

pages = "106",

journal = "Alzheimer's research & therapy",

issn = "1758-9193",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease

AU - Harrison, John E

AU - REVERSE-SD Study Investigators

AU - Prins, Niels D

AU - Chu, Hui-May

AU - Blackburn, Kelly

AU - Alam, John J

AU - Scheltens, Philip

N1 - Funding Information: The trial was sponsored and funded by EIP Pharma, Inc., which also provided the study drug. NDP and PS were compensated for their time towards protocol development, participation in joint project team and study steering committee meetings, and for manuscript preparation. HMC and JEH were engaged as consultants by EIP Pharma, Inc. JJA and KB are employees of EIP Pharma, Inc. Funding Information: REVERSE-SD Clinical Sites (Site principal investigator): USA: Massachusetts General Hospital (Arnold); CITrials, Inc (Coskinas); Florida Premier Research Institute (Gonzales); Manhattan Behavioral Medicine LLC (Joseph); Northwest Clinical Research Center (Khan); Northwest Clinical Trials (McConnehey); Miami Dade Medical Research Institute (Paricio); Sensible Healthcare LLC (Taylor); Alliance Research (Zarate Rowell); Anchor Neuroscience (Groom); Southern California Research LLC (Summers); Progressive Medica Research (White); Pacific Research Network, LLC (Thein); Alzheimer?s Memory Center (Bolouri); Viking Clinical Research, Ltd (Schwartz); Suncoast Neuroscience Associate (Vasquez). UK: MAC Clinical Research Manchester (Asher); MAC Clinical Research Leeds (Ball); MAC Clinical Research Liverpool (Munthali); MAC Clinical Research Blackpool (Kabir); St Pancras Clinical Research (Langford); S Boroughs/North West Boroughs Healthcare (Komuravelli); Clinical Research Tankerlsey (Lynch); Cognition Health Ltd (MacSweeney); Cognition Health Ltd (Pearson); Cognition Health Birmingham (Faulkner); Cognition Health Ltd (Miller); Fulbourn Hospital (Underwood). Netherlands: Brain Research Center (Prins); Jeroen Bosch Ziekenhuis (Dautzenberg); Amphia Ziekhuis (Van Norden). Czech Republic: Vestra Clinics s.r.o. (Pazdera); Cerbrovaskularni poradn s.r.o. (Bar) Private Psychiatric Centre (Dvacka); Neruo HK s.r.o., Poliklinika Chocen (Valis); Clintrial s.r.o. (Votypkova). Denmark: CCBR Clinical Research, Aalborg (Areovimata); CCBR Clinical Research, Vejle (Justesen); and CCBR Clinical Research, Ballerup (Schmidt). We are very grateful to all patients and caregivers who participated in this study and to the many staff members at the clinical sites for their dedication and commitment to the study. We also acknowledge the study project teams at EIP Pharma and WCT, and specifically, the excellent leadership of those project teams by Jennifer Conway and Nadia Bodjarian, respectively, as well the tremendous contributions of Natalia Drosopolou (project supervision) and Shuhua Qi (statistics) at WCT. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5/27

Y1 - 2021/5/27

N2 - BACKGROUND: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.METHODS: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aβ1-40, Aβ1-42, neurogranin, and neurofilament light chain].RESULTS: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.CONCLUSIONS AND RELEVANCE: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.

AB - BACKGROUND: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.METHODS: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aβ1-40, Aβ1-42, neurogranin, and neurofilament light chain].RESULTS: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.CONCLUSIONS AND RELEVANCE: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.

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U2 - 10.1186/s13195-021-00843-2

DO - 10.1186/s13195-021-00843-2

M3 - Article

C2 - 34044875

SN - 1758-9193

VL - 13

SP - 106

JO - Alzheimer's research & therapy

JF - Alzheimer's research & therapy

IS - 1

M1 - 106

ER -

A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease

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