Alzheimer Disease
Conditions
Brief summary
This project seeks to develop a novel disease-modifying compound for Alzheimer's disease (AD).
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.
Interventions
DRUGBMS-984923
Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.
Sponsors
National Institute on Aging (NIA)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
The study will enroll four cohorts of 6 participants each. Study drug will be administered in sequentially increasing dose groups. For all 6 participants at a dose cohort, a safety assessment review will be completed prior to advancing the next higher dose level.
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Clinically Significant Changes in Safety Assessments | Up to 7 days after last dose | 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 |
| Count of Treatment Emergent Adverse Events (TEAEs) | Up to 7 days after last dose | 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. |
| Count of Lab Abnormalities | Up to 7 days after last dose | Count of participants with clinical lab abnormalities. |
| Area Under the Curve From 0 to 24h (AUC 24h) | Up to 7 days after last dose | Plasma drug exposure as determined by pharmacokinetic modeling, AUC is represented as ng∙h/mL. |
| Maximum Plasma Concentration (Cmax) | Up to 7 days after last dose | Maximum plasma concentration as determined by pharmacokinetic modeling |
| Time of Cmax (Tmax) | Up to 7 days after last dose | Time of Cmax as determined by pharmacokinetic modeling |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Receptor Occupancy | Up to 24 hours after last dose | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 10 mg BMS-984923 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. | 6 |
| 40 mg BMS-984923 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. | 6 |
| 70 mg BMS-984923 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. | 6 |
| 100 mg BMS-984923 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. | 6 |
| 150 mg BMS-984923 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. | 6 |
| 200 mg BMS-984923 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. | 6 |
| Total | 36 |
Baseline characteristics
| Characteristic | 40 mg BMS-984923 | 70 mg BMS-984923 | 100 mg BMS-984923 | 150 mg BMS-984923 | 200 mg BMS-984923 | Total | 10 mg BMS-984923 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 71.3 years STANDARD_DEVIATION 5.6 | 70.3 years STANDARD_DEVIATION 2.5 | 68.3 years STANDARD_DEVIATION 3.5 | 72.8 years STANDARD_DEVIATION 6.1 | 68.1 years STANDARD_DEVIATION 9.1 | 70.3 years STANDARD_DEVIATION 5.6 | 70.9 years STANDARD_DEVIATION 3.2 |
| Body Mass Index (BMI) | 27.8 kg/m^2 STANDARD_DEVIATION 6.2 | 24.8 kg/m^2 STANDARD_DEVIATION 3.3 | 26.7 kg/m^2 STANDARD_DEVIATION 3.5 | 26.0 kg/m^2 STANDARD_DEVIATION 2.2 | 24.8 kg/m^2 STANDARD_DEVIATION 3.5 | 26.1 kg/m^2 STANDARD_DEVIATION 3.9 | 26.5 kg/m^2 STANDARD_DEVIATION 4.6 |
| Clinical Dementia Rating scale (CDR) | 0 units on a scale STANDARD_DEVIATION 0 | 0 units on a scale STANDARD_DEVIATION 0 | 0 units on a scale STANDARD_DEVIATION 0 | 0 units on a scale STANDARD_DEVIATION 0 | 0 units on a scale STANDARD_DEVIATION 0 | 0 units on a scale STANDARD_DEVIATION 0 | 0 units on a scale STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 33 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Geriatric Depression Scale (GDS) | 0.3 units on a scale STANDARD_DEVIATION 0.8 | 1.5 units on a scale STANDARD_DEVIATION 1.5 | 0.8 units on a scale STANDARD_DEVIATION 1 | 1.2 units on a scale STANDARD_DEVIATION 1.9 | 1.0 units on a scale STANDARD_DEVIATION 0.9 | 0.8 units on a scale STANDARD_DEVIATION 1.2 | 0.0 units on a scale STANDARD_DEVIATION 0 |
| Glasgow Coma Scale (GCS) | 15.0 units on a scale STANDARD_DEVIATION 0 | 15.0 units on a scale STANDARD_DEVIATION 0 | 15.0 units on a scale STANDARD_DEVIATION 0 | 15.0 units on a scale STANDARD_DEVIATION 0 | 15.0 units on a scale STANDARD_DEVIATION 0 | 15.0 units on a scale STANDARD_DEVIATION 0 | 15.0 units on a scale STANDARD_DEVIATION 0 |
| Logical Memory II Subscale, Delayed | 13.8 units on a scale STANDARD_DEVIATION 2.4 | 11.2 units on a scale STANDARD_DEVIATION 4 | 11.3 units on a scale STANDARD_DEVIATION 3.6 | 13.2 units on a scale STANDARD_DEVIATION 3.4 | 13.8 units on a scale STANDARD_DEVIATION 4.4 | 12.9 units on a scale STANDARD_DEVIATION 3.5 | 14.2 units on a scale STANDARD_DEVIATION 3.1 |
| Mini Mental State Exam (MMSE) | 28.8 units on a scale STANDARD_DEVIATION 1.5 | 29.5 units on a scale STANDARD_DEVIATION 0.5 | 29.0 units on a scale STANDARD_DEVIATION 0.6 | 29.5 units on a scale STANDARD_DEVIATION 0.8 | 29.5 units on a scale STANDARD_DEVIATION 0.8 | 29.3 units on a scale STANDARD_DEVIATION 0.8 | 29.3 units on a scale STANDARD_DEVIATION 0.5 |
| Montreal Cognitive Assessment (MoCA) | 26.8 units on a scale STANDARD_DEVIATION 2.3 | 26.5 units on a scale STANDARD_DEVIATION 3.4 | 26.0 units on a scale STANDARD_DEVIATION 2.9 | 27.5 units on a scale STANDARD_DEVIATION 1.4 | 27.2 units on a scale STANDARD_DEVIATION 1.6 | 27.0 units on a scale STANDARD_DEVIATION 2.3 | 28.2 units on a scale STANDARD_DEVIATION 2.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 35 Participants | 6 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 36 participants | 6 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 2 Participants | 21 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 15 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 2 / 6 | 2 / 6 | 2 / 6 | 1 / 6 | 3 / 6 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
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.
Time frame: Up to 7 days after last dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg BMS-984923 | Area Under the Curve From 0 to 24h (AUC 24h) | 105.29 ng∙h/mL | Standard Deviation 48.48 |
| 40 mg BMS-984923 | Area Under the Curve From 0 to 24h (AUC 24h) | 993.74 ng∙h/mL | Standard Deviation 345.23 |
| 70 mg BMS-984923 | Area Under the Curve From 0 to 24h (AUC 24h) | 1547.62 ng∙h/mL | Standard Deviation 765.72 |
| 100 mg BMS-984923 | Area Under the Curve From 0 to 24h (AUC 24h) | 967.56 ng∙h/mL | Standard Deviation 3130.23 |
| 150 mg BMS-984923 | Area Under the Curve From 0 to 24h (AUC 24h) | 3130.23 ng∙h/mL | Standard Deviation 1655.51 |
| 200 mg BMS-984923 | Area Under the Curve From 0 to 24h (AUC 24h) | 3752.1 ng∙h/mL | Standard Deviation 1259.84 |
Primary
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
Time frame: Up to 7 days after last dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg BMS-984923 | Count of Clinically Significant Changes in Safety Assessments | 0 Participants |
| 40 mg BMS-984923 | Count of Clinically Significant Changes in Safety Assessments | 0 Participants |
| 70 mg BMS-984923 | Count of Clinically Significant Changes in Safety Assessments | 0 Participants |
| 100 mg BMS-984923 | Count of Clinically Significant Changes in Safety Assessments | 0 Participants |
| 150 mg BMS-984923 | Count of Clinically Significant Changes in Safety Assessments | 0 Participants |
| 200 mg BMS-984923 | Count of Clinically Significant Changes in Safety Assessments | 0 Participants |
Primary
Count of Lab Abnormalities
Count of participants with clinical lab abnormalities.
Time frame: Up to 7 days after last dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg BMS-984923 | Count of Lab Abnormalities | 0 Participants |
| 40 mg BMS-984923 | Count of Lab Abnormalities | 0 Participants |
| 70 mg BMS-984923 | Count of Lab Abnormalities | 0 Participants |
| 100 mg BMS-984923 | Count of Lab Abnormalities | 0 Participants |
| 150 mg BMS-984923 | Count of Lab Abnormalities | 0 Participants |
| 200 mg BMS-984923 | Count of Lab Abnormalities | 0 Participants |
Primary
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.
Time frame: Up to 7 days after last dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg BMS-984923 | Count of Treatment Emergent Adverse Events (TEAEs) | 2 Participants |
| 40 mg BMS-984923 | Count of Treatment Emergent Adverse Events (TEAEs) | 2 Participants |
| 70 mg BMS-984923 | Count of Treatment Emergent Adverse Events (TEAEs) | 2 Participants |
| 100 mg BMS-984923 | Count of Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
| 150 mg BMS-984923 | Count of Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| 200 mg BMS-984923 | Count of Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
Primary
Maximum Plasma Concentration (Cmax)
Maximum plasma concentration as determined by pharmacokinetic modeling
Time frame: Up to 7 days after last dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg BMS-984923 | Maximum Plasma Concentration (Cmax) | 21.86 ng/mL | Standard Deviation 7.85 |
| 40 mg BMS-984923 | Maximum Plasma Concentration (Cmax) | 189.15 ng/mL | Standard Deviation 82.18 |
| 70 mg BMS-984923 | Maximum Plasma Concentration (Cmax) | 293.22 ng/mL | Standard Deviation 150.56 |
| 100 mg BMS-984923 | Maximum Plasma Concentration (Cmax) | 125.85 ng/mL | Standard Deviation 62.72 |
| 150 mg BMS-984923 | Maximum Plasma Concentration (Cmax) | 480.83 ng/mL | Standard Deviation 235.19 |
| 200 mg BMS-984923 | Maximum Plasma Concentration (Cmax) | 455.65 ng/mL | Standard Deviation 167.88 |
Primary
Time of Cmax (Tmax)
Time of Cmax as determined by pharmacokinetic modeling
Time frame: Up to 7 days after last dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg BMS-984923 | Time of Cmax (Tmax) | 1.5 hours | Standard Deviation 0.548 |
| 40 mg BMS-984923 | Time of Cmax (Tmax) | 1.67 hours | Standard Deviation 0.516 |
| 70 mg BMS-984923 | Time of Cmax (Tmax) | 2.17 hours | Standard Deviation 1.472 |
| 100 mg BMS-984923 | Time of Cmax (Tmax) | 2.17 hours | Standard Deviation 0.983 |
| 150 mg BMS-984923 | Time of Cmax (Tmax) | 1.83 hours | Standard Deviation 0.408 |
| 200 mg BMS-984923 | Time of Cmax (Tmax) | 3.33 hours | Standard Deviation 1.03 |
Secondary
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.
Time frame: Up to 24 hours after last dose
Population: Receptor Occupancy is calculated as one value for all participants who underwent \[18F\]FPEB PET.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg BMS-984923 | Receptor Occupancy | IC50 | 33.9 ng/mL | Standard Error 4 |
| 10 mg BMS-984923 | Receptor Occupancy | IC80 | 136.7 ng/mL | Standard Error 16 |