A First-in-Human Study to Assess Single Doses of APNmAb005 in Healthy Participants

Study Overview
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Brief Summary
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This is a Phase 1, first-in-human (FIH), double-blinded, placebo-controlled study where healthy subjects are randomly allocated to receive APNmAb005 or placebo. Approximately 5 dosing groups (cohorts) are planned with 8 subjects (randomized to 6 active: 2 placebo) per cohort. the starting dose of APNmAb005 is 5 mg/kg and the anticipated doses for subsequent cohorts are 10, 25, 50 and 70 mg/kg. A Safety Review Team (SRT) will review data on an ongoing basis throughout the study and before progression to the next dose level cohort. Subjects will receive a single dose of either APNmAb005 or placebo administered as a single IV infusion on Day 1 of the study and will remain in the study center until Day 3 (48 hours after dosing). They will return to the study center for 7 outpatient visits. The duration of the study, excluding screening, is approximately 71 days.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of APNmAb005 in Healthy Subjects

Conditions
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Healthy Volunteers, Tauopathies, Alzheimer Disease

Intervention / Treatment
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* Drug: APNmAb005
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI) of 18.5 to 32 kg/m² inclusive, at screening. Female subjects of childbearing potential must use an acceptable method of birth control from screening until at least 90 days after study drug dosing; OR be surgically sterile; OR be postmenopausal. All female subjects must have a negative pregnancy test at screening and before the first dose of the study drug. Female subjects must also agree to refrain from egg donation during the study and for at least 90 days after study drug dosing. Male subjects must agree to use a condom when sexually active with a female partner of childbearing potential during the study and for at least 90 days after study drug dosing (or be surgically sterile); OR agree to practice abstinence during the study and for at least 90 days after study drug dosing. Male subjects must also agree to refrain from sperm donation during the study and for at least 90 days after study drug dosing. Agree to comply with all protocol requirements. Provide written informed consent. Exclusion Criteria: Unable or unwilling to undergo venipuncture or tolerate venous access, or is unable or unwilling to undergo lumbar puncture. Has any significant acute or chronic medical illness that would impact the subject's ability to complete all study requirements or impact assessment of study data; or subject as had a clinically significant illness within 30 days prior to study drug dosing. Any medical condition or documented history that is a contraindication to lumbar puncture (e.g. bleeding disorder, spinal deformity). Positive COVID-19 molecular diagnostic test result at screening or prior to study drug dosing; or subject has known or suspected consequence from prior COVID-19 infection. History of cardiac, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal or oncogenic (with the exception of resected skin basal cell carcinoma) disease within 5 years prior to screening). NOTE: Subjects with treated stable psychiatric conditions (e.g. anxiety, depression) are not allowed. Clinically significant neurological or psychiatric disorder. Major surgery, as determined by investigator, within 4 weeks prior to study drug dosing. Systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg. Received any vaccine or used any prescription or over-the-counter medications (except paracetamol [up to 2 g per day]), including herbal or nutritional supplements, within 14 days prior to study drug dosing. Consumed caffeine- or xanthine-containing products within 48 hours prior to study drug dosing. Subject is a smoker or has regularly used nicotine or nicotine-containing products (e.g. snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) within 3 months prior to study drug dosing. Subject is involved in vigorous or strenuous physical activity or contact sports within 24 hours prior to study drug dosing. Subject has donated blood or blood products >450 mL within 3 months prior to study drug dosing. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: APNmAb005 (5mg/kg) vs Placebo<br>Single Ascending Dose (SAD) | Drug: APNmAb005<br>* Administered by IV infusion<br>Drug: Placebo<br>* Administered by IV infusion<br>|
| Active Comparator: APNmAb005 (10 mg/kg) vs Placebo<br>Single Ascending Dose (SAD) | Drug: APNmAb005<br>* Administered by IV infusion<br>Drug: Placebo<br>* Administered by IV infusion<br>|
| Active Comparator: APNmAb005 (25 mg/kg) vs Placebo<br>Single Ascending Dose (SAD) | Drug: APNmAb005<br>* Administered by IV infusion<br>Drug: Placebo<br>* Administered by IV infusion<br>|
| Active Comparator: APNmAb005 (50 mg/kg) vs Placebo<br>Single Ascending Dose (SAD) | Drug: APNmAb005<br>* Administered by IV infusion<br>Drug: Placebo<br>* Administered by IV infusion<br>|
| Active Comparator: APNmAb005 (70 mg/kg) vs Placebo<br>Single Ascending Dose (SAD) | Drug: APNmAb005<br>* Administered by IV infusion<br>Drug: Placebo<br>* Administered by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Adverse Events (AEs) | Defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Data collected by subject observations and data collected on AE page of electronic Case Report Form (eCRF), or other documents relevant to subject safety. | Day 70 | 
| Number of subjects with Treatment-emergent AEs (TEAEs) | Defined as any event not present before exposure to study drug or any event already present that worsens in intensity or frequency after exposure. Data collected by subject observations and data collected on AE page of electronic Case Report Form (eCRF), or other documents relevant to subject safety. | Day 70 | 
| Number of subjects with Serious Adverse Events (SAEs) | Defined as any AE for which there is a reasonable possibility that the study drug caused the AE. Data collected by subject observations and data collected on AE page of electronic Case Report Form (eCRF), or other documents relevant to subject safety. | Day 70 | 
| Number of subjects with AEs resulting in Study Discontinuation | Data collected by subject observations and data collected on AE page of electronic Case Report Form (eCRF), or other documents relevant to subject safety. | Day 70 | 
| Number of participants with Vital Sign Abnormalities | Measured by systolic and diastolic blood pressures, pulse rate, respiratory rate and body temperature. | Day 70 | 
| Number of participants with Electrocardiogram (ECG) Abnormalities | Measured by 12-lead ECG | Day 70 | 
| Number of participants with Clinical Laboratory Abnormalities | Measured by hematology, coagulation, serum chemistry and urinalysis. | Day 70 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t of APNmAb005 in plasma | Area under the curve from time zero to last quantifiable concentration of APNmAb005. Measured by blood sample analysis. | Thru Day 70 | 
| AUC0-t of APNmAb005 in CSF | Area under the curve from time zero to last quantifiable concentration of APNmAb005. Measured by cerebrospinal fluid (CSF) sample analysis. | Thru Day 14 | 
| Cmax of APNmAb005 in blood | Maximum observed plasma concentration of APNmAb005. Measured by blood sample analysis | Thru Day 70 | 
| Cmax of APNmAb005 in CSF | Maximum observed plasma concentration of APNmAb005. Measured by cerebrospinal fluid (CSF) sample analysis. | Thru Day 14 | 
| Tmax of APNmAb005 in blood | Time to maximum observed plasma concentration following APNmAb005 administration. Measured by blood sample analysis | Thru Day 70 | 
| Tmax of APNmAb005 in CSF | Time to maximum observed plasma concentration following APNmAb005 administration. Measured by cerebrospinal fluid (CSF) sample analysis. | Thru Day 14 | 
| t1/2 of APNmAb005 in plasma | Terminal phase half-life of APNmAb005. Measured by blood sample analysis | Thru Day 70 | 
| t1/2 of APNmAb005 in CSF | Terminal phase half-life of APNmAb005. Measured by cerebrospinal fluid (CSF) sample analysis | Thru Day 14 | 
| CL of APNmAb005 in blood. | Total body clearance of APNmAb005 from plasma. Measured by blood sample analysis | Thru Day 70 | 
| CL of APNmAb005 in CSF | Total body clearance of APNmAb005 from plasma. Measured by cerebrospinal fluid (CSF) sample analysis | Thru Day 14 | 
| Vd of APNmAb005 in plasma | Volume of distribution of APNmAb005. Measured by blood sample analysis | Thru Day 70 | 
| Vd of APNmAb005 in CSF | Volume of distribution of APNmAb005. Measured by cerebrospinal fluid (CSF) sample analysis | Thru Day 14 | 
| Number of participants with ADA formation against APNmAb005 | Anti-drug antibody (ADA) presence measured by blood sample analysis | Thru Day 70 | 
| Number of participants with no ADA formation against APNmAb005 | Anti-drug antibody (ADA) presence measured by blood sample analysis | Thru Day 70 | 
| Mean Total tau concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Thru Day 70 | 
| Mean change in Total tau concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Baseline and Day 70 | 
| Mean Total tau concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Thru Day 14 | 
| Mean change in Total tau concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Baseline and Day 14 | 
| Mean p-tau 181 concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Thru Day 70 | 
| Mean change in p-tau 181 concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Baseline and Day 70 | 
| Mean p-tau 181 concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Thru Day 14 | 
| Mean change in p-tau 181 concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Baseline and Day 14 | 
| Mean p-tau 217 concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Thru Day 70 | 
| Mean change in p-tau 217 concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Baseline and Day 70 | 
| Mean p-tau 217 concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Thru Day 14 | 
| Mean change in p-tau 217 concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Baseline and Day 14 | 
| Mean p-tau 231 concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Thru Day 70 | 
| Mean change in p-tau 231 concentration in plasma | Pharmacodynamic biomarker concentration measured by blood sample analysis | Baseline and Day 70 | 
| Mean p-tau 231 concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Thru Day 14 | 
| Mean change in p-tau 231 concentration in CSF | Pharmacodynamic biomarker concentration measured by CSF analysis | Baseline and Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy Volunteers, Alzheimer's Disease, Alzheimer Disease, AD, Tauopathies, Tau