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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: ADX-324; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: CMAX Reception; Phone Number: +610870887900; Email: Jane.kelly@cmax.com.au

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • CMAX Clinical Research
      • Contact: CMAX Reception; Phone Number: +61 0870887900; Email: jane.kelly@cmax.com.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Part A - HV

Inclusion Criteria:

1. Male and female adults 18 to 55 years old
2. Body mass index (BMI) between 18 and 30 kg/m2
3. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
4. Willing and able to provide informed consent and comply with all study visits

Exclusion Criteria:

1. Any significant medical history
2. Active malignancy and/or history of malignancy in the past 5 years
3. History of liver disease, Gilbert's syndrome, or abnormal liver function test
4. Estimated creatinine clearance <60 mL/min or serum creatinine > 1.5-fold upper limit of normal.
5. Any active infection or acute illness
6. Major surgery or significant traumatic injury occurring within 3 months
7. 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.
8. Positive serology tests (HepB, Hep C, HIV)
9. Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication
10. Treatment with another investigational product within 30 days prior to the first study drug administration
11. 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
12. Known hypersensitivity to any of the study drug ingredients.
13. Pregnancy, intent to become pregnant during the course of the study, or lactating women

Part B - HAE

Inclusion Criteria:

1. Male and female ≥18 years old, inclusive, at the time of signing the PICF
2. Confirmed diagnosis of HAE Types I or II
3. Evidence of an average of (at least) one HAE attack per month
4. Participants must have access to, and the ability to use, acute medication(s) to treat angioedema attacks.
5. Body mass index (BMI) between 18 and 30 kg/m2
6. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
7. Willing and able to provide informed consent and comply with all study visits

Exclusion Criteria:

1. Concurrent diagnosis of any other type of chronic angioedema
2. History of clinically significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk.
3. Any significant medical history
4. Active malignancy and/or history of malignancy in the past 5 years
5. Any active infection or acute illness, inclusive of cold/flu or COVID-19, within 30 days prior to the first study drug administration.
6. Major surgery or significant traumatic injury occurring within 3 months prior to signature of the PICF
7. 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.
8. Positive serology tests for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
9. Use of C1-INH products, androgens, antifibrinolytics or other small molecule medications for routine prophylaxis within four half-lives prior to screening
10. Must have documented evidence of medical history of HAE attacks
11. 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.
12. Treatment with another investigational product or biologic agent within 30 days prior to the study drug administration
13. History or presence of alcohol abuse or drug use within 30 days prior to the first study drug administration and throughout the study.
14. 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.
15. Pregnancy, intent to become pregnant during the course of the study, or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PART A - Active ADX-324 administered to HV; 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; siRNA duplex oligonucleotide; Other Names: siRNA
Placebo Comparator: PART A- Placebo administered to HV; 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; saline; Other Names: Saline
Experimental: PART B - ADX-324 administered to HAE participants; 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; siRNA duplex oligonucleotide; Other Names: siRNA

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ADARx Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Nicholas Farinola, MD, CMAX Clinical Research Pty Ltd

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2022
• Primary Completion (Estimated): January 2, 2025
• Study Completion (Estimated): December 26, 2025

Study Registration Dates

• First Submitted: December 16, 2022
• First Submitted That Met QC Criteria: January 10, 2023
• First Posted (Actual): January 20, 2023

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: ADX-324-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No