Safety, Tolerability, PK and PD of ADX-038 in Healthy Participants and Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients (PNH)

A Phase 1, Randomized, Double Blind, Placebo-Controlled, Single Ascending Dose Study in Healthy Participants Followed by a Phase 2a Open Label Study in Participants With PNH and Residual Anemia to Evaluate the Safety, Tolerability, PK and PD of ADX-038

The first-in-human Phase 1/Phase 2a study described herein will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ADX-038 in both healthy participants (HP) and in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Study Overview

• Status: Recruiting
• Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Intervention / Treatment: Drug: Placebo; Drug: ADX-038

Detailed Description

The clinical study described in this protocol is a Phase 1/Phase 2a study evaluating safety, tolerability, PK, and PD of ADX-038.

The study consists of 2 parts:

1. Phase 1 - Randomized, double-blind, placebo-controlled, parallel group, single ascending dose (SAD) in HP with up to 5 dose cohorts.
2. Phase 2a - Open label, single-arm (ADX-038), 2 dose study in participants with paroxysmal nocturnal hemoglobinuria (PNH) and residual anemia on a standard-of-care (SOC) anti-C5 regimen of ravulizumab or eculizumab.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Lyle Gee; Phone Number: 877-232-7974; Email: lgee@adarx.com

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4006
      • Active, not recruiting
      • Nucleus Network Brisbane
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Not yet recruiting
      • Peter MacCallum Cancer Centre
      • Contact: Jeff Szer, MD; Phone Number: +61385595000; Email: PCCTU.HaemA@petermac.org
    • Parkville, Victoria, Australia, 3052
      • Recruiting
      • Royal Melbourne Hospital
      • Contact: Jeff Szer, MD; Phone Number: +61385595000; Email: PCCTU.HaemA@petermac.org
• United Kingdom
  • London, United Kingdom, SE1 1YR
    • Active, not recruiting
    • Richmond Pharmacology Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Phase 1 Key Inclusion Criteria

• 18 to 55 years of age
• Participants who are healthy as determined by medical evaluation
• History of recent meningococcal, pneumococcal and Haemophilus influenzae type B vaccinations or willing to be vaccinated
• Screening tests negative for illicit drug, nicotine, and alcohol use

Phase 1 Key Exclusion Criteria

• History of any significant medical conditions, except for completely excised non-melanoma skin cancer or low grade cervical intraepithelial neoplasia without evidence of recurrence within the prior 3 months
• Any viral, bacterial, parasitic, or fungal infection within the prior 30 days
• Frequent respiratory, nasopharyngeal or ear infections (more than 5 infections per year)
• History of environmental exposure or sick contact that increase the risk of meningococcal, pneumococcal and/or Haemophilus influenza type B infections
• Complement deficiency or immunodeficiency syndrome
• Major surgery or significant traumatic injury within the prior 3 months
• History of anaphylaxis or hypersensitivity reactions
• History of penicillin allergy
• History of splenectomy
• History of alcohol abuse or illicit drug use
• Donated plasma within the prior 7 days
• Donated blood or loss more than 400 milliliters of blood (excluding blood volume drawn at screening) within the prior 90 days
• Screening estimated creatinine clearance of less than 60 milliliters per minute
• Screening hematology, serum chemistry, or coagulation parameters that are outside the normal range
• Screening vital signs that are abnormal per protocol specification
• Screening electrocardiogram findings that are clinically significant
• Pregnant or lactating females
• Use of prescription (except for contraceptives and study-related prophylactic antibiotics) or over-the counter medications (except for paracetamol or ibuprofen) or vitamins/supplements within the prior 7 days
• Use of medications that may reduce the effectiveness of hormonal contraceptives within the prior 28 days
• Use of an investigational therapeutics within the prior 30 days or within the expected washout (at least 5 half-lives)
• Unwilling or unable to adhere to study-related prophylactic antibiotics requirements

Phase 2a Key Inclusion Criteria

• at least 18 years of age
• Diagnosis of paroxysmal nocturnal hemoglobinuria based on documented clone size
• Hemoglobin concentration of less than 12 gram per deciliter
• History of recent meningococcal, pneumococcal and Haemophilus influenzae type b vaccinations or willing to be vaccinated
• On a stable anti-C5 regimen for greater than or equal to 12 weeks prior to Day 1

Phase 2a Key Exclusion Criteria

• Any viral, bacterial, parasitic, or fungal infection within the prior 14 days
• HIV, active hepatitis C or hepatitis B infection
• History of meningococcal or tuberculosis infection
• History of malignancy in the past 5 years, except for completely excised non-melanoma skin cancer or low grade cervical intraepithelial neoplasia with no evidence of recurrence within the prior 3 months
• Complement deficiency syndrome
• History of hematopoietic stem cell transplantation
• History of splenectomy
• Inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, or chronic liver disease
• Clinically significant and uncontrolled medical conditions including, but not limited to, thromboembolic disease, acute coronary syndrome, and diabetes
• Pregnant or lactating females
• Use of an investigational therapeutics within the prior 30 days or within the expected washout period (at lest 5 half-lives)
• Abstain from alcohol consumption for 48 hrs before day of dosing and restrict to no more than an average of 14 standard drinks per week

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 - Active ADX-038 administered to HP; For each cohort in Phase 1 (SAD), 8 participants will be randomized in a 3:1 ratio; 6 participants to active (ADX-038): 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-038; siRNA duplex oligonucleotide; Other Names: siRNA
Placebo Comparator: Phase 1- Placebo administered to HP; For each cohort in Phase 1 (SAD), 8 participants will be randomized in a 3:1 ratio; 6 participants to active (ADX-038): 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: Phase 2a - ADX-038 administered to PNH participants; This will be initiated at the dose level determined by the Safety Review Committee from SAD in HPs. The treatment of PNH participants is an open-label study.	Drug: ADX-038; 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-038 in HVs by incidence, relationship, and severity of adverse events and serious adverse events	365 days
Safety in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate the safety and tolerability of ADX-038 by incidence, relationship, and treatment-emergent adverse events and serious adverse events.	365 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics in Healthy Participants	To characterize the Pharmacokinetics of ADX-038 in HPs by measuring the Maximum observed plasma concentration (Cmax)	8 days
Pharmacodynamics in Healthy Participants	Change from base in plasma concentrations over time in Complement factor B (CFB) protein via assay measurement	365 days
Pharmacodynamics in Paraxysmal Nocturnal Hemoglobinuria	Evaluate the changes in hemoglobin concentrations	365 days
Pharmacodynamics in Paraxysmal Nocturnal Hemoglobinuria	Characterize the changes in serum concentration of complement factor B (CFB) protein and complement alternative pathway activity level.	365 days
Pharmacodynamics in Healthy Participants	Change in complement alternative pathway activity via assay measurement	365 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Response in Healthy Participants	Anti-polyethylene glycol (PEG) antibody titers and anti-drug antibody titers	365 days
Pharmacodynamics in Healthy Participants	Change in complement classical pathway activity via assay measurement	365 days
Safety in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate the change from baseline in follow up visits for safety assesments	365 days
Clinical Effect in Paroxysmal Nocturnal Hemoglobinuria Participants	Look at time (number of days) from dosing (Day 1) to diminished therapeutics effect (DTE)	365 days
Efficacy in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate changes in lactate dehydrogenase (LDH) (U/L)	365 days
Effects on Hemolysis in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate incidence of clinical breakthrough hemolysis, blood transfusions and Incidence of major adverse vascular events (MAVEs)	365 days
Pharmacokinetics in Paraxysmal Nocturnal Hemoglobinuria	Characterize PK parameters of ADX-038 by plasma C(max)	8 days
Pharmacodynamics in Paraxysmal Nocturnal Hemoglobinuria	Characterize changes in complement classical pathway activity level	365 days
Immune Response in Paraxysmal Nocturnal Hemoglobinuria	Determine Anti-PEG and anti-drug antibody titers	365 days
Efficacy in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate changes in serum free hemoglobin	365 days
Efficacy in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate changes in Haptoglobin Concentrations	365 days
Efficacy in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate changes in Reticulocyte Counts (%)	365 days
Efficacy in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate changes in Bilirubin (umol/L)	365 days
Efficacy in Paroxysmal Nocturnal Hemoglobinuria Participants	Evaluate changes in Aspartate aminotransferase (U/L)	365 days
Pharmacokinetics in Paraxysmal Nocturnal Hemoglobinuria	Characterize PK parameters of ADX-038 by plasma AUC (0-infinity)	8 days
Pharmacokinetics in Paraxysmal Nocturnal Hemoglobinuria	Characterize PK parameters of ADX-038 by plasma AUC(0-last)	8 days
Pharmacokinetics in Paraxysmal Nocturnal Hemoglobinuria	Characterize PK parameters of ADX-038 by plasma T(max)	8 days

Collaborators and Investigators

• Sponsor: ADARx Pharmaceuticals, Inc.
• Collaborators: Novotech (Australia) Pty Limited; ADARx Australia Pty Ltd

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2023
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): July 31, 2028

Study Registration Dates

• First Submitted: May 17, 2023
• First Submitted That Met QC Criteria: May 17, 2023
• First Posted (Actual): May 25, 2023

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 20, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: PNH; siRNA
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Anemia, Hemolytic; Anemia; Myelodysplastic Syndromes; Hemic and Lymphatic Diseases; Hemoglobinuria, Paroxysmal; Nucleic Acids; Nucleic Acids, Nucleotides, and Nucleosides; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; RNA, Antisense; Antisense Elements (Genetics); RNA; RNA, Small Untranslated; RNA, Untranslated; Sodium Chloride; RNA, Small Interfering
• Other Study ID Numbers: ADX-038-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No