Proof-of-Concept Study of a Selective p38 MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer's Disease

NCT03402659 | Completed Phase 2 Results FDA Drug

• 1 other identifier: EIP-VX17-745-304
• Study Type: interventional
• Target: 161
• Locations: 5 countries
• Sites: 38

Brief Summary

This is a phase 2b, double-blind, placebo controlled proof-of-concept study of a an oral small molecule selective inhibitor of p38 alpha kinase, neflamapimod, administered for 24 weeks in subjects with mild Alzheimer's disease. The primary objective is to demonstrate significant improvement relative to placebo-treatment in episodic memory function, as assessed by the Hopkins Verbal Learning Test. Secondary endpoints include Clinical Dementia Rating scale (CDR), Wechsler Memory Scale (WMS), Mini-Mental-Status-Examination (MMSE) and Cerebrospinal fluid (CSF) biomarkers of AD disease activity and progression.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (1)

• Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)

  Combined change from baseline in z-scores of total and delayed recall on the Hopkins Verbal Learning Test - Revised (HVLT-R) in neflamapimod-treated subjects compared to placebo. The primary endpoint was analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. For baseline total and delayed recall, a z-score for each subject is defined by z=(x-m)/s where x is the subject's recall at baseline, and m and s are the overall mean and overall standard deviation of recall at baseline across all subjects. A composite baseline z-score for each subject is calculated using equal weighting in the following way: Z=0.5\*z-score for total recall at baseline + 0.5\*z-score for delayed recall at baseline. For HVLT-R, higher score indicates improvement.

  Baseline and 24 weeks

Secondary Outcomes (10)

• Wechsler Memory Scale (WMS) Immediate and Delayed Recall

  Baseline and 24 weeks

• Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)

  Baseline and 24 weeks

• Mini-Mental State Examination (MMSE)

  Baseline and 26 Weeks (Follow-up visit, 2 weeks from end of dosing)

• Cerebrospinal Fluid Total Tau

  Baseline and 24 weeks

• Cerebrospinal Fluid Phospho-tau

  Baseline and 24 weeks

Study Arms (2)

neflamapimod

EXPERIMENTAL

40 mg hard gelatin capsules, taken twice daily with food.

Drug: neflamapimod

placebo

PLACEBO COMPARATOR

hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.

Other: placebo

Interventions

neflamapimod DRUG

40 mg neflamapimod capsule

Also known as: VX-745

neflamapimod

placebo OTHER

matching placebo capsule

placebo

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women age 55 to 85 years, inclusive.
• Willing and able to provide informed consent.
• Must have mild cognitive impairment (MCI) or mild AD with evidence of progression ("Mild-AD"), as defined by the following:
• CDR-Global Score of 0.5 or 1.0, with CDR memory subscore of at least 0.5.
• MMSE score ranging from 20 to 28, inclusive.
• Positive biomarker for AD, as defined by a CSF Aβ1-42R below the threshold and phospho-tau above the threshold for the assay utilized in the study and assessed by the central laboratory.
• Computed tomography (CT) or magnetic resonance imaging (MRI) findings within 2 years of Screening that are compatible with AD and no other pathologic processes that might potentially account for the subject's cognitive impairment.
• If the subject is taking a single drug for AD (e.g., donepezil or other cholinesterase inhibitors or memantine; dual therapy is excluded), he/she has been on a stable dose for at least 2 months prior to baseline, and the dose must remain unchanged during the study unless required for management of adverse events (AEs).
• Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
• Must have reliable informant or caregiver.

You may not qualify if:

• Evidence that the primary basis for cognitive impairment is neurodegenerative disease other than AD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and Parkinson's disease.
• Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
• History of major and active psychiatric disorder, moderate to severe depressive symptoms, and or other concurrent medical condition that, EIP-VX17-745-304, Version 1.0, 17 November, 2017 Page 7 of 46 EIP Pharma, LLC Confidential in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
• Diagnosis of alcohol or drug abuse within the previous 2 years.
• History of cancer within the last 5 years, except basal cell carcinoma, squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.
• Poorly controlled clinically significant medical illness.
• History of serum B12 abnormality, anemia with hemoglobin ≤10 g/dL, thyroid function abnormality, electrolyte abnormality, or positive syphilis serology that have not been corrected and/or otherwise addressed.
• History of epilepsy or unexplained seizure within the past 5 years.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 × the upper limit of normal (ULN), total bilirubin \>2 × ULN, and/or International Normalized Ratio (INR) \>1.5
• Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
• Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of the investigation drug, whichever is longer, before enrollment in this study.

Sponsors & Collaborators

• EIP Pharma Inc: lead
• Worldwide Clinical Trials: collaborator
• Amsterdam UMC, location VUmc: collaborator

Study Sites (38)

Alliance for Research

Long Beach, California, 90807, United States

Location

Pacific Research Network

San Diego, California, 92103, United States

Location

CITrials

Santa Ana, California, 92705, United States

Location

Southern California Research, LLC

Simi Valley, California, 93065, United States

Location

Viking Clinical Research

Temecula, California, 92591, United States

Location

Miami Dade Medical Research Institute

Miami, Florida, 33176, United States

Location

Sensible Healthcare, LLC

Ocoee, Florida, 34761, United States

Location

Anchor Neuroscience

Pensacola, Florida, 32502, United States

Location

Progressive Medical Research

Port Orange, Florida, 32127, United States

Location

Suncoast Neuroscience Associates, Inc.

St. Petersburg, Florida, 33713, United States

Location

Florida Premier Research Institute

Winter Park, Florida, 32789, United States

Location

Northwest Clinical Trials

Boise, Idaho, 83704, United States

Location

MassGeneral Institute for Neurodegenerative Disease

Charlestown, Massachusetts, 02129, United States

Location

Manhattan Behavioral Medicine

New York, New York, 10036, United States

Location

Alzheimer's Memory Center and Research Institute

Charlotte, North Carolina, 28270, United States

Location

Northwest Clinical Research Center

Seattle, Washington, 98007, United States

Location

Neuro HK, s.r.o. POLIKLINIKA CHOCEŇ, a.s.

Choceň, 565 01, Czechia

Location

Cerebrovaskulární poradna s.r.o.

Moravská Ostrava, 702 00, Czechia

Location

Clintrial S.R.O

Prague, 100 00, Czechia

Location

Private Psychiatric Centre

Prague, 109 00, Czechia

Location

Vestra Clinics S.R.O

Rychnov nad Kněžnou, 516 01, Czechia

Location

CCBR Clinical Research, Aalborg

Aalborg, DK-9000, Denmark

Location

CCBR Clinical Research, Ballerup

Ballerup Municipality, DK-2750, Denmark

Location

CCBR Clinical Research, Vejle

Vejle, DK-7100, Denmark

Location

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, 5223 GZ, Netherlands

Location

Alzheimer Research Center

Amsterdam, 1081 GM, Netherlands

Location

Amphia Ziekhuis

Breda, 4817 CK, Netherlands

Location

MAC Clinical Research Tankersley

Barnsley, S75 3DL, United Kingdom

Location

Re:Cognition Health Birmingham

Birmingham, B16 8LT, United Kingdom

Location

MAC Clinical Research Blackpool

Blackpool, FY2 0JH, United Kingdom

Location

Fulbourn Hospital

Cambridge, CB21 5EF, United Kingdom

Location

MAC Clinical Research Leeds

Leeds, LS10 1DU, United Kingdom

Location

MAC Clinical Research Liverpool

Liverpool, L34 1BH, United Kingdom

Location

Re:Cognition Health London

London, W1G 9JF, United Kingdom

Location

St. Pancras Clinical Research

London, WC1X 8QD, United Kingdom

Location

MAC Clinical Research Manchester

Manchester, M13 9NQ, United Kingdom

Location

Re:Cognition Health Plymouth

Plymouth, PL5 8BT, United Kingdom

Location

5 Boroughs/North West Boroughs Healthcare NHS Foundation Trust

Warrington, WA22 8WA, United Kingdom

Location

Related Publications (2)

• Prins ND, Harrison JE, Chu HM, Blackburn K, Alam JJ, Scheltens P; REVERSE-SD Study Investigators. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease. Alzheimers Res Ther. 2021 May 27;13(1):106. doi: 10.1186/s13195-021-00843-2.

  PMID: 34044875 DERIVED

• Tormahlen NM, Martorelli M, Kuhn A, Maier F, Guezguez J, Burnet M, Albrecht W, Laufer SA, Koch P. Design and Synthesis of Highly Selective Brain Penetrant p38alpha Mitogen-Activated Protein Kinase Inhibitors. J Med Chem. 2022 Jan 27;65(2):1225-1242. doi: 10.1021/acs.jmedchem.0c01773. Epub 2021 May 11.

  PMID: 33974419 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

VX-745

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Jennifer Conway, Associate Director of Clinical Development
• Organization: EIP Pharma

jconway@eippharma.com

(617) 744-4400

Study Officials

• John Alam, MD

  EIP Pharma

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Double-blind, placebo-controlled

Study Record Dates

• First Submitted: January 11, 2018
• First Posted: January 18, 2018
• Study Start: December 29, 2017
• Primary Completion: June 30, 2019
• Study Completion: July 31, 2019
• Last Updated: October 27, 2021
• Results First Posted: October 27, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

DK (3); NL (3); US (16); CZ (5); GB (11)