Clinical Pharmacology of p38 MAP Kinase Inhibitor, VX-745, in Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD

A Randomized, Open-Label, Multiple Dose Clinical Pharmacology Study of Two Doses of a Selective p38 MAP Kinase Inhibitor, VX-745 in Patients With Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) or With Mild AD

This study will assess the effects of VX-745 on markers of disease in the central nervous system of patients with MCI due to AD or with mild AD. The study will also evaluate the safety and tolerability of VX-745 in these patients during 6 weeks of dosing, as well as the plasma and cerebrospinal fluid concentrations of VX-745 during dosing.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: VX-745

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Parexel International

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 60 - 85 (inclusive)
• Willing and able to provide informed consent

• Clinical presentation consistent with MCI due to AD or of mild AD

  • Gradual progressive decline in memory function over >6 months
  • Amnestic presentation on neuropsychological testing with rapid forgetting (% reduction 1.5 standard deviations below the mean)
  • Clinical Dementia Rating (CDR) Sum of Box (SOB) score ≥0.5
  • Mini-Mental State Examination (MMSE) range: 20 to 30
• Brain hypometabolism by 18F-2-fluoro-2-deoxyglucose (FDG)-PET
• Participants may be taking medications for AD, provided that the dose of these medications has been stable for >3 months.

Exclusion Criteria:

• Evidence of neurodegenerative disease other than AD
• Inability for any reason to undergo MRI scans (e.g. pacemaker, vascular stent or stent graft). Patients who require sedation for screening procedures such as MRI may receive a short-acting sedative.
• Psychiatric disorder that would compromise ability to comply with study requirements
• History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years
• Significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder or metabolic/endocrine disorders or other disease that would preclude treatment with p38 MAP kinase inhibitor and/or assessment of drug safety and efficacy
• Recent (<90 days) changes to AD medications prescribed for cognitive reasons or with the potential to impact cognition
• Psychotropic drugs taken within 1 month. Anticoagulant drugs taken within 1 week.
• Participation in a study of an investigational drug less than 6 months or 5 half-lives of the investigational drug, whichever is longer, before enrollment in the study
• Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements
• Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingoophorectomy
• Positive urine or serum pregnancy test or plans desires to become pregnant during the course of the trial
• Donation of >500 mL of blood or blood products within 2 months
• History of alcohol and/or illicit drug abuse within 6 months.
• Infection with hepatitis A, B or C or HIV.
• Any factor deemed by the investigator to be likely to interfere with study conduction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VX-745 dose level 1; Active Group 1: VX-745 dose level 1 twice daily	Drug: VX-745; Orally-active P38 MAP kinase alpha-selective inhibitor
Experimental: VX-745 dose level 2; Active Group 1: VX-745 dose level 2 twice daily	Drug: VX-745; Orally-active P38 MAP kinase alpha-selective inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines	Cytokines: Of nine cytokines assessed, only CSF IL-8 quantifiable at all time points. And so, only IL-8 levels are being reported herein. The analysis was exploratory and no statistical analysis was performed.	Baseline and Day 42 of dosing with VX-745

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe or Serious Adverse Events	Number of patients with severe or serious adverse events	At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing
Maximal CSF VX-745 Concentration	Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken	All samples with quantifiable CSF drug levels were included (n=12). Eight were obtained 3-hours post-dose, either on Day 1 (n=4) or Day 42 (n=4). 3 samples were at 6-hours post-dose on Day 42; and one was at 6-hours post-dose on Day 1.
Episodic Memory Function	Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function.	Change from baseline to Day 42

Collaborators and Investigators

• Sponsor: EIP Pharma Inc
• Investigators: Principal Investigator: Hakop Gevorkyan, MD, Parexel

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: April 3, 2015
• First Submitted That Met QC Criteria: April 17, 2015
• First Posted (Estimate): April 22, 2015

Study Record Updates

• Last Update Posted (Actual): April 3, 2018
• Last Update Submitted That Met QC Criteria: April 2, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: EIP14-745-303