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    Clinical Trial Results:
    A Phase 2a, Proof-of-Concept, Open-Label Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Obicetrapib in Patients with Early Alzheimer’s Disease (Hetero/Homozygote APOE4 Carriers)

    Summary
    EudraCT number
    		 2021-002687-41
    Trial protocol
    		 NL  
    Global end of trial date
    01 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2025
    First version publication date
    06 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TA-8995-AD-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05161715
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NewAmsterdam Pharma BV
    Sponsor organisation address
    Gooimeer 2-35, DC Naarden, Netherlands, 1411
    Public contact
    Study Director, NewAmsterdam Pharma BV, 31 352062971, study.director@newamsterdampharma.com
    Scientific contact
    Study Director, NewAmsterdam Pharma BV, +31 352062971, study.director@newamsterdampharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the pharmacodynamics (PD) (apolipoproteins/lipid particles and cholesterol efflux) of obicetrapib in cerebrospinal fluid (CSF) and plasma (apolipoproteins/lipid particles) in patients with early Alzheimer’s Disease (AD) (hetero/homozygote APOE4 carriers). The exploratory objectives of this study are to evaluate: • other PD markers of obicetrapib (additional lipoproteins, neurodegeneration, and inflammation) in patients with early AD. • the cognitive effects of obicetrapib in patients with early AD. • the pharmacokinetics (PK) of obicetrapib in patients with early AD. The safety objective of this study is to evaluate the safety and tolerability of obicetrapib in patients with early AD.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with Good Clinical Practice Guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    8
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 13 participants were randomized

    Pre-assignment
    Screening details
    		 18 participants were screened

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Obicetrapib
    Arm description
    		 Obicetrapib (10 mg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obicetrapib 5 mg tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily 2 x 5 mg obicetrapib tablet

    Number of subjects in period 1
    		Obicetrapib
    Started
    13
    Completed
    13
    Period 2
    Period 2 title
    Overall Study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Obicetrapib
    Arm description
    		 Obicetrapib (10 mg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obicetrapib 5 mg tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily 2 x 5 mg obicetrapib tablet

    Number of subjects in period 2
    		Obicetrapib
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Obicetrapib
    Reporting group description
    		 Obicetrapib (10 mg)

    Reporting group values
    		 Obicetrapib Total
    Number of subjects
    		 13 13
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Baseline Population is defined as all participants who received at least one dose of study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ( 6.2 ) -
    Gender categorical
    Baseline Population is defined as all participants who received at least one dose of study drug.
    Units: Subjects
        Female
    		 12 12
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Obicetrapib
    Reporting group description
    		 Obicetrapib (10 mg)
    Reporting group title
    Obicetrapib
    Reporting group description
    		 Obicetrapib (10 mg)

    Subject analysis set title
    Baseline Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline Population is defined as all participants who received at least one dose of study drug.

    Primary: 1. Mean Percent Change in Apolipoprotein A-I (ApoA-I) In Cerebrospinal Fluid (CSF)

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    End point title
    		 1. Mean Percent Change in Apolipoprotein A-I (ApoA-I) In Cerebrospinal Fluid (CSF)
    End point description
    Mean percent change from screening (V1) to end of treatment (V6) in ApoA-I in CSF
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Obicetrapib Obicetrapib
    Number of subjects analysed
    12 [1]
    12 [2]
    Units: Percentage Change from Screening Visit
        arithmetic mean (standard deviation)
    -8.4 ( 13.6 )
    -8.4 ( 13.6 )
    Notes
    [1] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    [2] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Obicetrapib v Obicetrapib
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.425 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - No multiple testing correction was performed

    Primary: 2. Mean Percent Change in Apolipoprotein A-I (ApoA-I) in Plasma

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    End point title
    		 2. Mean Percent Change in Apolipoprotein A-I (ApoA-I) in Plasma
    End point description
    Mean percent change in ApoA-I in plasma from baseline (V2) to week 24 (V6)
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Obicetrapib Obicetrapib
    Number of subjects analysed
    13 [4]
    13
    Units: Percent Change from Baseline
        arithmetic mean (standard deviation)
    37.5 ( 25.2 )
    37.5 ( 25.2 )
    Notes
    [4] - For the PD endpoints in plasma, analyses were conducted on all 13 patients.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Obicetrapib v Obicetrapib
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0002
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - No multiple testing correction was performed

    Primary: 3. Mean Percent Change in Apolipoprotein-E (ApoE) in Cerebrospinal Fluid (CSF)

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    End point title
    		 3. Mean Percent Change in Apolipoprotein-E (ApoE) in Cerebrospinal Fluid (CSF)
    End point description
    Mean percent change from screening (V1) to end of treatment (V6) in ApoE
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Obicetrapib Obicetrapib
    Number of subjects analysed
    12 [6]
    12 [7]
    Units: Percent Change from Baseline
        arithmetic mean (standard deviation)
    3.9 ( 10.3 )
    3.9 ( 10.3 )
    Notes
    [6] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    [7] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Obicetrapib v Obicetrapib
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0424 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - No multiple testing correction was performed

    Primary: 4. Mean Percent Change in Apolipoprotein-E (ApoE) in Plasma

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    End point title
    		 4. Mean Percent Change in Apolipoprotein-E (ApoE) in Plasma
    End point description
    Mean percent change from baseline (V2) to week 24 (V6) in plasma in ApoE
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Obicetrapib Obicetrapib
    Number of subjects analysed
    13 [9]
    13
    Units: Percent Change from Baseline
        arithmetic mean (standard deviation)
    47.8 ( 46.9 )
    47.8 ( 46.9 )
    Notes
    [9] - For the PD endpoints in plasma, analyses were conducted on all 13 patients.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Obicetrapib v Obicetrapib
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - No multiple testing correction was performed

    Primary: 5. Small HDL (s-HDL) Particle Concentration in Cerebrospinal Fluid (CSF) at Baseline

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    End point title
    		 5. Small HDL (s-HDL) Particle Concentration in Cerebrospinal Fluid (CSF) at Baseline [11]
    End point description
    Small high-density lipoprotein (s-HDL) particle concentration in cerebrospinal fluid (CSF) measured by Ion Mobility Assay (https://doi.org/10.1002/alz.12649)
    End point type
    Primary
    End point timeframe
    At Baseline
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Average relative abundance was reported and statistical analysis was not performed. Small high-density lipoprotein (s-HDL) particle concentration in CSF measured by Ion Mobility Assay (https://doi.org/10.1002/alz.12649)
    End point values
    		 Obicetrapib
    Number of subjects analysed
    12 [12]
    Units: Average relative abundance
        arithmetic mean (standard deviation)
    0.542 ( 0.138 )
    Notes
    [12] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    No statistical analyses for this end point

    Primary: 6. Small HDL (s-HDL) Particle Concentration in Cerebrospinal Fluid (CSF) at Week 24

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    End point title
    		 6. Small HDL (s-HDL) Particle Concentration in Cerebrospinal Fluid (CSF) at Week 24 [13]
    End point description
    Small high-density lipoprotein (s-HDL) particle concentration in CSF measured by Ion Mobility Assay (https://doi.org/10.1002/alz.12649)
    End point type
    Primary
    End point timeframe
    At Week 24
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Average relative abundance was reported and statistical analysis was not performed. Small high-density lipoprotein (s-HDL) particle concentration in CSF measured by Ion Mobility Assay (https://doi.org/10.1002/alz.12649)
    End point values
    		 Obicetrapib
    Number of subjects analysed
    12 [14]
    Units: Average Relative Abundance
        arithmetic mean (standard deviation)
    0.542 ( 0.106 )
    Notes
    [14] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    No statistical analyses for this end point

    Primary: 7. Small HDL (s-HDL) Particle Concentration in Plasma at Baseline

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    End point title
    		 7. Small HDL (s-HDL) Particle Concentration in Plasma at Baseline [15]
    End point description
    Small high-density lipoprotein (s-HDL) particle concentration plasma measured by Ion Mobility Assay. For more information on the measurement used please refer to this article: https://doi.org/10.1002/alz.12649
    End point type
    Primary
    End point timeframe
    At Baseline
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to a non-optimal sample preparation procedure, a number of the samples allocated for the small HDL-C particle analysis were lost and therefore no samples were assessed for this measure.
    End point values
    		 Obicetrapib
    Number of subjects analysed
    0 [16]
    Units: Average Relative Abundance
        arithmetic mean (standard deviation)
    ( )
    Notes
    [16] - Due to a non-optimal sample prep, samples were not able to be assessed for this measure.
    No statistical analyses for this end point

    Primary: 8. Small HDL (s-HDL) Particle Concentration in Plasma at Week 24

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    End point title
    		 8. Small HDL (s-HDL) Particle Concentration in Plasma at Week 24 [17]
    End point description
    Small high-density lipoprotein (s-HDL) particle concentration in plasma measured by Ion Mobility Assay at Week 24 For more information on the measurement used please refer to this article: https://doi.org/10.1002/alz.12649
    End point type
    Primary
    End point timeframe
    At Week 24
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to a non-optimal sample preparation procedure, a number of the samples allocated for the small HDL-C particle analysis were lost and therefore no samples were assessed for this measure.
    End point values
    		 Obicetrapib
    Number of subjects analysed
    0 [18]
    Units: Average Relative Abundance
        arithmetic mean (standard deviation)
    ( )
    Notes
    [18] - Due to a non-optimal sample prep, samples were not able to be assessed for this measure.
    No statistical analyses for this end point

    Primary: 9. Mean Percent Change in Cholesterol Efflux Capacity in Cerebrospinal Fluid (CSF)

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    End point title
    		 9. Mean Percent Change in Cholesterol Efflux Capacity in Cerebrospinal Fluid (CSF)
    End point description
    Mean percent change in cholesterol efflux capacity in CSF from screening (V1) to week 24 (V6)
    End point type
    Primary
    End point timeframe
    24 Weeks
    End point values
    		 Obicetrapib Obicetrapib
    Number of subjects analysed
    12 [19]
    12 [20]
    Units: Percent Change from Screening
        arithmetic mean (standard deviation)
    1.9 ( 24.1 )
    1.9 ( 24.1 )
    Notes
    [19] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    [20] - Lumbar puncture was not possible for 1 patient at EOT (Day 168, Visit 6); hence n=12 for CSF
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Obicetrapib v Obicetrapib
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.556 [21]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [21] - No multiple testing correction was performed

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through Week 24.5
    Adverse event reporting additional description
    Safety Population included all participants who received at least 1 dose of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Obicetrapib
    Reporting group description
    		 Obicetrapib (10 mg)

    Serious adverse events
    		 Obicetrapib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Obicetrapib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    basal cell carcinoma face
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    unilateral leg swelling
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Investigations
    weight loss
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Lumbar puncture headache
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    rib contusion
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    headache
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Normocytic anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Ear and labyrinth disorders
    benign paroxysmal positional vertigo
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    loose stool
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    obstipation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    reflux esophagitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    hair loss
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    hand arthritis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Lateral epicondylitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    low back pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    lumbago
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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