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

Official title

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

Overview

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).

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.

Interventions

• Drug ADX-038
  siRNA duplex oligonucleotide
• Drug Placebo
  Saline

Primary outcome measures

• Safety in Healthy Volunteers [Time frame: 365 days]
• Safety in Paroxysmal Nocturnal Hemoglobinuria Participants [Time frame: 365 days]

Secondary outcome measures (5)

• Pharmacokinetics in Healthy Participants [Time frame: 8 days]
• Pharmacodynamics in Healthy Participants [Time frame: 365 days]
• Pharmacodynamics in Paraxysmal Nocturnal Hemoglobinuria [Time frame: 365 days]
• Pharmacodynamics in Paraxysmal Nocturnal Hemoglobinuria [Time frame: 365 days]
• Pharmacodynamics in Healthy Participants [Time frame: 365 days]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Australia · 3 centers

• Nucleus Network Brisbane — Brisbane
• Peter MacCallum Cancer Centre — Melbourne
• Royal Melbourne Hospital — Parkville

United Kingdom · 1 center

• Richmond Pharmacology Ltd — London

Identifiers

NCT: NCT05876312 · ADX-038-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗