Evaluating the Safety, Tolerability, Pharmacokinetics and Receptor Occupancy of BMS-984923

An Open-Label, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Receptor Occupancy of BMS-984923

This project seeks to develop a novel disease-modifying compound for Alzheimer's disease (AD).

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: BMS-984923

Detailed Description

The primary objective of this study is to evaluate the safety, tolerability, and pharmacokinetics of BMS-984923 in healthy participants. A secondary objective of this study is to conduct a receptor occupancy sub-study aimed at determining drug receptor occupancy at each dose using [18F]FPEB Positron Emission Tomography.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• No history of cognitive impairment
• Capable of providing written informed consent and willing to comply with all study requirements and procedures

• Participant is not pregnant, lactating, or of childbearing potential

  1. Non-childbearing potential for women is defined as postmenopausal (last natural menses greater than 24 months; menopausal status will be documented with serum follicle stimulating hormone (FSH) or documentation of bilateral tubal ligation or hysterectomy
  2. Male participants who are sexually active with a woman of child-bearing potential must agree to use condoms during the trial and for 3 months after the last dose unless the woman is using an acceptable means of birth control. Acceptable forms of birth control include abstinence, birth control pills, or any double combination of: intrauterine device (IUD), male or female condom, diaphragm, sponge, and cervical cap.
  3. Male participants must also agree not to donate sperm for 90 days after the last dose. -
• Glasgow Coma Scale Score of 15 (97)
• Clinical Dementia Rating Score of 0 (93)
• Has a reliable study partner who has frequent contact with the participant (e.g., average of 10 hours per week or more), who can be available for study partner assessments, who can accompany the participant for 48 hours, without absence, after discharge from Visit 2.

Score on the Mini Mental Status Exam > 26 (95)

• Objective memory scores within normal range for age evidenced by a score no more than 1.5 standard deviations below the education adjusted cutoff on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale - Revised (the maximum score is 25).

  1. >8 for 16 or more years of education
  2. >4 for 8-15 years of education
  3. >2 for 0-7 years of education

Receptor Occupancy Substudy Eligibility Criteria

• Eligibility for and enrollment in Main Study
• Participant consent to the optional substudy

Exclusion Criteria:

• Body mass index (BMI) ≥ 35 kg/m2 or body weight < 50 kg.
• Significant cerebrovascular disease: Modified Hachinski score > 4.
• Any significant neurologic disease, such as AD, Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.
• Major depression, bipolar disorder as described in DSM-IV within the past 1 year.
• Psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty complying with the protocol.
• History of schizophrenia (DSM IV criteria).
• History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
• Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the PI, may either put the patient at risk because of participation in the study, or influence the results, or the patient's ability to participate in the study.
• Clinically significant abnormalities in B12 or Thyroid Function Tests that might interfere with the study.

Use of psychoactive medications (typical neuroleptics, narcotic analgesics, antiparkinsonian medications, systemic corticosteroids, or medications with significant central anticholinergic activity) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.

• Use of medications with significant CYP1A2, 2D6, or 3A4 inhibitor or inducer activity (See appendix for a list of these medications) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
• Use of anticoagulants within 30 days or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
• Use of investigational amyloid lowering therapies within 2 months prior to study drug administration and for the duration of the trial.
• Use of another investigational agent within 30 days or 5 half-lives (whichever is greater) prior to screening and for the duration of the trial.
• Neutropenia defined as absolute neutrophils count of < 1,500/microliter.
• Thrombocytopenia defined as platelet count < 100,000/microliter.
• Clinically significant abnormalities in screening laboratories, including Aspartate aminotransferase (AST) >1.5 times upper limit of normal (ULN); Alanine aminotransferase (ALT) >1.5 times ULN; Total bilirubin >1.5 times ULN; Serum creatinine >2.0 times ULN.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 10 mg BMS-984923	Drug: BMS-984923; Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.
Experimental: 40 mg BMS-984923	Drug: BMS-984923; Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.
Experimental: 70 mg BMS-984923	Drug: BMS-984923; Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.
Experimental: 100 mg BMS-984923	Drug: BMS-984923; Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.
Experimental: 150 mg BMS-984923	Drug: BMS-984923; Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.
Experimental: 200 mg BMS-984923	Drug: BMS-984923; Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax)	Maximum plasma concentration as determined by pharmacokinetic modeling	Up to 7 days after last dose
Time of Cmax (Tmax)	Time of Cmax as determined by pharmacokinetic modeling	Up to 7 days after last dose
Count of Treatment Emergent Adverse Events (TEAEs)	A count of participants that experience any adverse events found to be associated with treatment. All adverse events are summarized in the adverse events section.	Up to 7 days after last dose
Count of Lab Abnormalities	Count of participants with clinical lab abnormalities.	Up to 7 days after last dose
Count of Clinically Significant Changes in Safety Assessments	A count of participants that experienced any clinically significant changes in: Vital Signs, Physical Exam, Electrocardiogram, Neuropsychiatric Inventory - Q, Geriatric Depression Scale, Glasgow Coma Scale, Montreal Cognitive Assessment	Up to 7 days after last dose
Area Under the Curve From 0 to 24h (AUC 24h)	Plasma drug exposure as determined by pharmacokinetic modeling, AUC is represented as ng∙h/mL.	Up to 7 days after last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Receptor Occupancy	Metabotropic glutamate receptor subtype 5 (mGluR5) occupancy using [18F]FPEB Positron Emission Tomography calculated using the percentage of total mGluR5 availability and plasma concentrations of study drug were used to model the relationship between plasma concentration (CP) and receptor occupancy with the conventional sigmoidal maximum receptor occupancy (r_max) model where IC50 is the CP required to produce 50% of the r_max. A nonlinear least squares analysis was used to estimate the parameters from all scans. The data supported a model with 1 parameter (IC50, r_max = 100%). IC80 is the CP required to produce 80% of the r_max. The outcomes of relevance are the IC50 and IC80 calculated for the model.	Up to 24 hours after last dose

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Adam Mecca, MD, PhD, Assistant Professor of Psychiatry; Associate Director, Alzheimer's Disease Research Unit; Faculty, Alzheimer's Disease Research Center (ADRC)

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2021
• Primary Completion (Actual): April 24, 2022
• Study Completion (Actual): April 24, 2022

Study Registration Dates

• First Submitted: March 14, 2021
• First Submitted That Met QC Criteria: March 16, 2021
• First Posted (Actual): March 18, 2021

Study Record Updates

• Last Update Posted (Actual): August 27, 2024
• Last Update Submitted That Met QC Criteria: July 31, 2024
• Last Verified: July 1, 2024

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; Alzheimer Disease
• Other Study ID Numbers: 2000028864; 1U01AG058608-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No