Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients

Study Overview
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Brief Summary
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The first-in-human Phase 1 study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ADX-324 in healthy volunteers (HV) and in patients with Hereditary Angioedema (HAE).

Detailed Description
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The clinical study described in this protocol is a Phase 1, single-center study evaluating safety, tolerability, PK, and PD of ADX-324. The study consists of 2 parts: Randomized, double-blind, placebo-controlled, parallel group, single ascending dose (SAD) in HV with up to 6 dose cohorts. For SAD cohorts and planned dosing; and, Expansion cohort in participants with Hereditary Angioedema (HAE) at selected dose from Part A and will be open label.

Official Title
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A Phase 1, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in Healthy Volunteers and an Expansion Cohort in Patients With Hereditary Angioedema to Evaluate the Safety, Tolerability, PK and PD of ADX-324

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Drug: ADX-324
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Part A - HV Inclusion Criteria: Male and female adults 18 to 55 years old Body mass index (BMI) between 18 and 30 kg/m2 Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Willing and able to provide informed consent and comply with all study visits Exclusion Criteria: Any significant medical history Active malignancy and/or history of malignancy in the past 5 years History of liver disease, Gilbert's syndrome, or abnormal liver function test Estimated creatinine clearance <60 mL/min or serum creatinine > 1.5-fold upper limit of normal. Any active infection or acute illness Major surgery or significant traumatic injury occurring within 3 months Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study. Positive serology tests (HepB, Hep C, HIV) Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication Treatment with another investigational product within 30 days prior to the first study drug administration Known any clinically significant allergic reactions which, in the opinion of the Investigator, would interfere with the volunteer's ability to participate in the study Known hypersensitivity to any of the study drug ingredients. Pregnancy, intent to become pregnant during the course of the study, or lactating women Part B - HAE Inclusion Criteria: Male and female ≥18 years old, inclusive, at the time of signing the PICF Confirmed diagnosis of HAE Types I or II Evidence of an average of (at least) one HAE attack per month Participants must have access to, and the ability to use, acute medication(s) to treat angioedema attacks. Body mass index (BMI) between 18 and 30 kg/m2 Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Willing and able to provide informed consent and comply with all study visits Exclusion Criteria: Concurrent diagnosis of any other type of chronic angioedema History of clinically significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk. Any significant medical history Active malignancy and/or history of malignancy in the past 5 years Any active infection or acute illness, inclusive of cold/flu or COVID-19, within 30 days prior to the first study drug administration. Major surgery or significant traumatic injury occurring within 3 months prior to signature of the PICF Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study. Positive serology tests for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV). Use of C1-INH products, androgens, antifibrinolytics or other small molecule medications for routine prophylaxis within four half-lives prior to screening Must have documented evidence of medical history of HAE attacks Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication (with the exception of oral contraceptives) within 7 days prior to the first study drug administration. Treatment with another investigational product or biologic agent within 30 days prior to the study drug administration History or presence of alcohol abuse or drug use within 30 days prior to the first study drug administration and throughout the study. Blood donation of 50 to 499 mL within 30 days prior to the first study drug administration or of >499 mL within 60 days prior to the first study drug administration. Pregnancy, intent to become pregnant during the course of the study, or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Interventional Model Description: Phase 1, Single-Center, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in HV with expansion into HAE
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PART A - Active ADX-324 administered to HV<br>For each cohort in Part A (SAD), 8 participants will be randomized in a 3:1 ratio; 6 participants to active (ADX-324): 2 participants to control (matched placebo). Randomization will be on Day 1. Initially, 2 sentinel participants (1 active and 1 placebo) will be randomized and dosed. The sentinel participants will be evaluated for safety. The investigator's assessment and the independent medical monitor will decide upon the randomization and dosing of the 6 remaining participants (5 active and 1 placebo) according to the randomization schedule. | Drug: ADX-324<br>* siRNA duplex oligonucleotide<br>* Other names: siRNA;|
| Placebo Comparator: PART A- Placebo administered to HV<br>For each cohort in Part A (SAD), 8 participants will be randomized in a 3:1 ratio; 6 participants to active (ADX-324): 2 participants to control (matched placebo). Randomization will be on Day 1. Initially, 2 sentinel participants (1 active and 1 placebo) will be randomized and dosed. The sentinel participants will be evaluated for safety. The investigator's assessment and the independent medical monitor will decide upon the randomization and dosing of the 6 remaining participants (5 active and 1 placebo) according to the randomization schedule. | Drug: Placebo<br>* saline<br>* Other names: Saline;|
| Experimental: PART B - ADX-324 administered to HAE participants<br>This will be initiated at the dose level determined by the Safety Review Committee from SAD in HVs. The treatment of HAE participants is an open-label study. | Drug: ADX-324<br>* siRNA duplex oligonucleotide<br>* Other names: siRNA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety in Healthy Volunteers | To evaluate the safety and tolerability of ADX-324 in HVs by incidence, relationship, and severity of adverse events and serious adverse events | 365 days | 
| Safety in Healthy Volunteers | To evaluate the safety and tolerability of ADX-324 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals) | 365 days | 
| Safety in Hereditary Angioedema | To evaluate the safety and tolerability of ADX-324 in HAE by incidence, relationship, and severity of adverse events and serious adverse events | 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Maximum observed concentration (Cmax) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Time to Cmax (Tmax) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-∞) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Apparent terminal half-life (t½) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Terminal elimination rate constant (λz) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Total apparent body clearance (CL/F) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Apparent volume of distribution (Vz/F) | 8 days | 
| Pharmacodynamics in Healthy Volunteers | To characterize the PD of ADX-324 in HVs by the Change from base in plasma concentrations over time of pre Kallikrein (PKK) | 365 days | 
| Pharmacodynamics in Healthy Volunteers | To characterize the PD of ADX-324 in HVs by the Change from base in plasma concentrations over time of Kallikrein (KK) | 365 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Maximum observed concentration (Cmax) of ADX-324 | 365 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Time to Cmax (Tmax) of ADX-324 | 8 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last) of ADX-324 | 8 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Area under the concentration-time curve from 0 to infinity (AUC0-∞) of ADX-324 | 8 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Apparent terminal half-life (t½) | 8 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Terminal elimination rate constant (λz) | 8 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Total apparent body clearance (CL/F) | 8 days | 
| Pharmacokinetics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Apparent volume of distribution (Vz/F) | 8 days | 
| Pharmacodynamics in Hereditary Angioedema | To characterize the PD of ADX-324 in HV by Change from base in plasma concentrations over time pre-kallikrein (PKK) | 365 days | 
| Pharmacodynamics in Hereditary Angioedema | To characterize the PD of ADX-324 in HAE by Change from base in plasma concentrations over time kallikren (KK) | 365 days |