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

Study Overview
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Brief Summary
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Alzheimer's disease (AD) is the most common type of dementia, accounting for 50-75% of the estimated 47 million people with dementia worldwide. The amyloid cascade hypothesis of AD proposes that amyloid-β (Aβ) peptide accumulation in the brain, caused by an imbalance between Aβ production and clearance, is the initiating factor of a cascade ultimately leading to dementia. Aβ peptides are generated from sequential cleavage of the amyloid precursor protein (APP), including Aβ40 and Aβ42. Aβ40 is the predominant variant (90%) among the secreted Aβ forms and although Aβ42 is more hydrophobic and prone to aggregate, and Aβ42 oligomers are regarded to be the most neurotoxic species, Aβ40 can also produce highly toxic diffusible aggregates, which can be prevented in vitro by specific anti-Aβ40 antibodies. Several studies have proposed that a high concentration of Aβ40 in the brain distinguishes patients with AD from those who have senile plaques but are cognitively normal, pointing to the importance of Aβ40 in the onset of dementia. In keeping with this, previous studies have demonstrated that specific anti-Aβ40 antibodies label NFTs in the entorhinal cortex and the hippocampus of AD brains, and that these do not co-localize with tau NFTs, suggesting the presence of degenerating neuronal populations filled with C-terminal fragments of Aβx-40. In addition, Aβ40 is the main component of amyloid deposition around cerebral arteries causing cerebral amyloid angiopathy (CAA), which has a prevalence of about 80-90% in patients with AD (for more information see Lacosta et al. Alzheimer's Research & Therapy (2018) 10:12 DOI 10.1186/s13195-018-0340-8). Considering those previous results suggesting that strategies targeting Aβ40 could represent novel disease-modifying therapies, we have developed ABvac40, the first active vaccine targeting the C-terminal end of the Aβ40 peptide. The purpose of this Phase II study is to confirm in patients with a-MCI or vm-AD the level of safety and tolerability obtained in the ABvac40 Phase I clinical trial in patients with mm-AD. In addition, the study is aimed to better characterize the immune response elicited by ABvac40 and to explore its effects on AD biomarkers.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled, 24 Months Study in Patients With Amnestic Mild Cognitive Impairment or Very Mild Alzheimer's Disease to Investigate the Safety, Tolerability and Immune Response of Repeated Subcutaneous Injections of ABvac40

Conditions
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Mild Cognitive Impairment, Alzheimer Disease

Intervention / Treatment
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* Biological: ABvac40
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject must meet all the following inclusion criteria: Male or female between 55 and 80 years of age, both inclusive, at the time of signing informed consent. The patient (or legal representative, if applicable) and a close relative/caregiver must read the subject information sheet, agree to participate in the clinical trial and sign the informed consent form (the patient and a close relative/caregiver). Presence of a stable caregiver to attend the patient study visits. Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), according to age and education level. Clinical Dementia Rating (CDR) scale scoring 0.5. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on the Delayed Memory Index (DMI) of 85 or lower. The results of the patient's MRI brain scan must be concordant with the diagnosis of clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and measurement of white matter and past haemorrhages. If the patient is receiving treatment for AD, must have been stable during the two months before the selection visit. Treatment for concomitant diseases must be stable during the previous month before the treatment of the study. Positive assessment of the candidate by the investigator for complying with the requirements and procedures of the study. Exclusion Criteria: A subject meeting any of the following exclusion criteria is NOT eligible for participation in the study. Known allergy to components of the vaccine or prior history of anaphylaxis, a severe allergic reaction or a history of hypersensitivity to any component of the formulation. Allergy to fish or shellfish. Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology. History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis. Presence or history of immunodeficiency (i.e. HIV). Significant kidney and/or liver disease. History of asthma or reactive airway disease with bronchospasm in the last 6 months, or currently on regular treatment. Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, hypertension). History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular carcinoma. Significant alterations in hematological, biochemical or urine analytical parameters, particularly those relating to levels of vitamin B12, folic acid or thyroid tests. History of any other central nervous system disorder, degenerative or non-degenerative neurological or psychiatric condition that, in the investigator's opinion could be the cause of the dementia, or could explain the cognitive impairment, or that might interfere with cognitive function directly or by its treatment. Geriatric Depression Scale (GDS; abbreviated version), score >5 Has a yes answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening. History or signs of cerebrovascular disease (ischemic or haemorrhagic stroke, transient ischemic attack), or diagnosis of possible, probable or clear vascular dementia according to NINDS-AIREN criteria. Presence on MRI of a relevant pattern of microvascular disease (Leukoaraiosis, Fazekas score ≥2 in the deep white matter scale or ≥4 in the global score) or more than one lacunar or territorial infarcts. Any other MRI finding that, in the opinion of the investigator, might be a relevant contributing cause of subject´s cognitive impairment. Presence of up to 3 microhemorrhages will be acceptable. History of bleeding disorder or predisposing conditions, blood clotting or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator. Patients being treated with anticoagulants or antiaggregant therapy (aspirin at a prophylactic dose ≤ 325 mg daily or clopidogrel at a dose ≤75 mg daily are allowed) should not be recruited in the study. Modified Hachinski Ischemic Scale, score higher than 4. Surgery (with general anaesthetic) within the previous three months to be included in the trial, or programed during the study period. Treatment within 30 days prior to visit 0 with systemic corticosteroids or other immunosuppressant's. Vaccination against influenza or any other vaccination within 2 months before first IMP dose. Patients, who have previously been randomized in this trial. Participation in another clinical trial within the previous 1 month to screening visit, or within the previous 12 months after the last dose to the screening visit in the case of subjects who participated in trials with a study drug whose intention was to modify the progression AD unless documentation of receipt of placebo is available. The patient cannot be included in the study if the experimental drug was an immunotherapeutic drug, including IVIG or a vaccine against Alzheimer's disease unless documentation of receipt of placebo is available. Patients with alcohol or drug abuse or dependence. Absolute (having a pacemaker or implantable defibrillator) or relative (bare metal stent or stent implanted in the last six months) contraindications to MRI examination. Feeling of claustrophobic do not let perform MRI or PET scan. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits). Women of childbearing potential, pregnant or nursing. Significant alterations in the EKG that are associated with an added risk for the patient.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABvac40<br>Six administrations of ABvac40; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of ABvac40. | Biological: ABvac40<br>* ABvac40 consists in a conjugate of Aβx-40 with a carrier protein (KLH) vehiculated in phosphate buffer containing 0.35% aluminium hydroxide as adjuvant.<br>|
| Placebo Comparator: Placebo<br>Six administrations of Placebo; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of the vaccine's vehicle buffer without the active component. | Biological: Placebo<br>* Placebo consists in the vaccine's vehicle (phosphate buffer containing 0.35% aluminium hydroxide) without the conjugate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events [safety and tolerability] | Rate of adverse events in the ABvac40 and Placebo arms | 18 months | 
| Immune response | Level of anti-Abeta40 antibodies in plasma | 18 months |