safety, tolerability, pk and pd of adx-038 in healthy participants and paroxysmal nocturnal hemoglobinuria (pnh) patients

Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)

Summary: 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.

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

Keywords: sirna pnh