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

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).

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.

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