Ascending Multiple Intravenous Doses of AON-D21 in Healthy Male Subjects.

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic parameters after multiple ascending intravenous doses of AON-D21 in healthy male subjects.

Detailed Description
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This study will potentially include 2 two sequential cohorts with 8 healthy male subjects per cohort, then 16 enrolled subjects in total. Within each dose group 6 subjects will be randomized to receive AON-D21 and 2 subjects will be randomly assigned to placebo.

Official Title
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A Randomized, Single-center, Double-blind, Placebo Controlled Trial With Ascending Multiple Intravenous Doses to Determine Safety, Tolerability and Pharmacokinetics of AON-D21 in Healthy Male Subjects.

Conditions
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Healthy

Intervention / Treatment
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* Drug: AON-D21
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 55 years of age inclusive, at the time of signing the informed consent. Body mass index (BMI) within the range 18 - 30 kg/m2 with a body weight between 50 kg and 120 kg. Male subjects Subject is healthy as determined by medical evaluation Subject provided written informed consent Subject is willing to comply with all requirements and restrictions according to the study protocol. Exclusion Criteria: Any concomitant disease, condition, or treatment that could interfere with the conduct of the study. Any acquired or congenital immune deficiency. Acute infection (including viral infections) in the preceding 6 weeks (8 weeks for respiratory infections). Clinically relevant abnormality following the Investigator's review of the physical examination, vital signs, ECG and clinical study protocol-defined clinical laboratory tests that, in the opinion of the Investigator, would preclude inclusion in the trial at screening and admission. Evidence of COVID-19 signs or symptoms, exposure to infected person or confirmed COVID-19 infection within the last 2 weeks. Use of any concomitant medication or prescribed or non-prescribed drugs within 2 weeks or 5 times the half-life, whichever is longer, prior to the first study treatment administration. Administration of vaccine(s) within 2 weeks prior to screening or plans to receive such vaccines during the study. Use of any investigational drug or participation in any clinical study within 30 days or 5 half-life times, whichever is longer, prior to dosing. Positive drug or alcohol screen at screening and admission. Any significant blood loss, donated one unit (450 mL) of blood or more, or donated plasma, or received a transfusion of any blood or blood products within 30 days prior to dosing. Subjects who are unable to refrain from the consumption of Seville oranges, grapefruit or grapefruit juice and /or pomelos, exotic citrus fruits, grapefruit hybrids, starfruit or fruit juices from 72 hours prior to dosing on Day 1, until completion of the last PK blood sample time point. Legal incapacity or limited legal capacity, or incarceration. Inability to understand or communicate reliably with the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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
Interventional Model Description: Sequential: Two groups of participants will be assigned to receive AON-D21 or placebo in ascending dose order. Dose will be escalated based on safety and pharmacokinetic data.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AON-D21<br>Multiple ascending doses by iv infusion | Drug: AON-D21<br>* AON-D21 is a PEGylated L-configured aptamer that binds and thereby neutralizes the complement component C5a from activating both C5a receptors.<br>|
| Placebo Comparator: Placebo<br>Placebo medication identical in appearance to active | Drug: Placebo<br>* Isotonic glucose solution identical in appearance to AON-D21.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Nature, occurrence, and severity of treatment-emergent adverse events. | 27 days | 
| Per dosing cohort number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0. | Overall number of participants with treatment related treatment-emergent adverse events (TEAEs) as assessed by CTCAE v5.0 per dosing cohort. | 27 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics assessment | Area under the concentration-time curve (AUC) over the dosing interval at steady state (AUC0-tau) of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Maximum concentration at steady state (Cmax) of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Average drug concentration at steady state (Cav) of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Trough concentrations (Ctrough) of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Time of maximum concentration at steady state (Tmax) of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Terminal half-life at steady state (t1/2) of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Accumulation ratios for Cmax and AUC of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Clearance (CL) of AON-D21 in plasma at steady state. | 27 days | 
| Pharmacokinetics assessment | Volume of distribution (Vz) of AON-D21 in plasma at steady state. | 27 days | 
| Pharmacokinetics assessment | AUC from 0 to 48 hours (AUC0-48) after the first dose of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | AUC from 0 extrapolated to infinity (AUC0-inf) after the first dose of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Maximum concentration (Cmax) after the first dose of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Time to maximum concentration (Tmax) after the first dose of AON-D21 in plasma. | 27 days | 
| Pharmacokinetics assessment | Terminal half life (t1/2) after the first dose of AON-D21 in plasma. | 27 days | 
| Pharmacodynamics assessment | Measurement of concentration of C5 in plasma. | 27 days | 
| Pharmacodynamics assessment | Measurement of concentration of C5a in plasma. | 27 days | 
| Pharmacodynamics assessment | Measurement of concentration of C5b-9 in plasma. | 27 days | 
| Pharmacodynamics assessment | Qualitative assessment of terminal complement complex (TCC) formation in plasma. | 27 days | 
| To assess potential for immunogenicity | Measurement of anti-drug antibodies (ADA) in plasma. | 27 days | 
| To assess potential for immunogenicity | Measurement of anti-polyethylene glycol (PEG) antibodies in plasma. | 27 days |