Safety and Immunogenicity of Repeated Doses of ABvac40 in Patients With a-MCI or Vm-AD

Subject Discontinuations Due to TEAEs

Number of withdrawn subjects due to treatment-emergent adverse events (TEAEs) during the whole study.

Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)

Number of Subjects With Clinically Significant Abnormalities in Physical Examination

Clinically significant (CS) abnormalities in physical examination reported during the study.

Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)

Number of Subjects With Clinically Significant Abnormalities in Neurological Examination

Clinically significant (CS) abnormalities in neurological examination reported during the study.

Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)

Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology

Clinically significant (CS) abnormalities in hematology parameters reported during the study.

Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)

Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry

Clinically significant (CS) abnormalities in biochemistry parameters reported during the study.

Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)

Number of Subjects With Clinically Significant Abnormalities in Coagulation

Clinically significant (CS) abnormalities in coagulation parameters reported during the study.

Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)

Level of Anti-Aβ40 Antibodies in CSF

The change in levels of anti-Aβ40 antibodies in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Level of Anti-Aβ40 Antibodies in Plasma

The change in levels of anti-Aβ40 antibodies in plasma from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)

Level of Antibody-secreting Cells

The change in levels of antibody-secreting cells from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)

Level of Aβ40 Peptides in Plasma - ABtest-IA

The change in levels of anti-Aβ40 peptides in plasma (ABtest-IA) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)

Level of Aβ42 Peptides in Plasma - ABtest-IA

The change in levels of anti-Aβ42 peptides in plasma (ABtest-IA) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)

Level of Aβ40 Peptides in Plasma - ABtest-MS

The change in levels of anti-Aβ40 peptides in plasma (ABtest-MS) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)

Level of Aβ42 Peptides in Plasma - ABtest-MS

The change in levels of anti-Aβ42 peptides in plasma (ABtest-MS) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)

Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans

The change in amyloid-PET (a-PET) standard centiloid global cortical area (reference Pons) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Percentage of Change in Brain Volume

The percent change in brain volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 24A, Week 50A, and Week 104A)

Percentage of Change in Hippocampal Volume

The percent change in right and left hippocampal volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 24A, Week 50A, Week 104A)

Percentage of Change in Ventricular Volume

The percent change in ventricular volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 24A, Week 50A, and Week 104A)

Level of Aβ42 Peptides in CSF

The change in levels of Aβ42 peptides in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Level of Aβ40 Peptides in CSF

The change in levels of Aβ40 peptides in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Aβ42/Aβ40 Ratio in CSF

The change in Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Level of Total Tau in CSF

The change in levels of total Tau in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Level of p-Tau 181 in CSF

The change in levels of p-Tau 181 in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Level of Neurofilament Light in CSF

The change in levels of neurofilament light in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Level of Neurogranin in CSF

The change in levels of neurogranin in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, and treatment-by-visit interaction as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).

Time frame: Part A (Week 50A and Week 104A)

Mini Mental State Examination Score

The change in Mini Mental State Examination score (MMSE) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. MMSE is an 11-question measure that testes five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. MMSE score ranges from 0 to 30, with lower scores indicating worst cognition.

Time frame: Part A (baseline, and post-baseline at Week 24A, Week 50A, Week 77A, and Week 104A)

Clinical Dementia Rating-Sum of Boxes Score

The change in clinical dementia rating-sum of boxes (CDR-SB) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. CDR-SB is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment \& Problem Solving, Community Affairs, Home \& Hobbies, and Personal Care. CDR-SB, derived as the sum of the six individual domain scores and can range from 0 to 18. The higher scores mean a worst outcome.

Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)

Repeatable Battery for the Assessment of Neuropsychological Status Score

The change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. RBANS assesses five cognitive domains, i.e., Immediate Memory, Visuospatial/constructional, Language, Attention, and Delayed Memory. The test consists of 12 subtests and the score on each subtest contributes to one of the five domains. Total score, which can range from 40 to 160, derived as the sum of the five domain scores. The higher scores mean a better outcome.

Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)

Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score

The change in Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI) total score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. ADCS-ADL MCI is a 24-item scale that includes 6 basic activities of daily living (BADL) items and 16 instrumental activities of daily living (IADL) items that provide a total score from 0-78, with a lower score indicating greater severity.

Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)

Trail Making Test Scores

The change in Trail Making Test (TMT) scores (Trail A and Trail B) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. TMT consists of two parts in which the patient is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first, the targets are all numbers from 1 to 25 and the test taker needs to connect them in sequential order; in the second part, the dots go from 1 to 13 and include letters from A to L. The lower timings mean a better outcome.

Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)

Investigator Global Evaluation Score

The change in Investigator Global Evaluation (IGE) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. IGE score range at baseline: 1-Good general status; 2-Slight deterioration; 3-Moderate deterioration; 4-Bad general status. IGE score range after baseline: 1-Marked improvement; 2-Moderate improvement; 3-Slight improvement; 4-No change; 5-Slight worsening; 6-Moderate worsening; 7-Marked worsening.

Time frame: Part A (Week 24A, Week 50A, and Week 104A)

Columbia Suicide Severity Rating Scale

Subjects with suicidal ideation or suicidal behavior since last visit.

Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)

EuroQol 5 Dimensions 5 Levels Overall Severity Index Score

The change in Euroqol 5 Dimensions 5 Levels (EQ-5D-5L) - overall severity index score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The EQ-5D-5L descriptive system comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), with each dimension measured on the following increasing scale of severity: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems.

Time frame: Part A (Week 50A and Week 104A)

EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score

The change in Euroqol 5 Dimensions 5 levels (EQ-5D-5L) - visual analogue scale (VAS) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. VAS records the patient's self-rated health on a vertical scale, ranging from 100 = 'Best imaginable health state' down to 0 = 'Worst imaginable health state'.

Time frame: Part A (Week 50A and Week 104A)