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

Study Overview
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Brief Summary
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The first-in-human Phase 1 study described herein will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ADX-038 in both healthy volunteers (HV) and in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Detailed Description
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The clinical study described in this protocol is a Phase 1, single-center study evaluating safety, tolerability, PK, and PD of ADX-038. The study consists of 2 parts: Part A - Randomized, double-blind, placebo-controlled, parallel group, single ascending dose (SAD) in HV with up to 5 dose cohorts. Part B - Expansion cohort in participants with paroxysmal nocturnal hemoglobinuria (PNH) at selected dose from Part A and will be open label.

Official Title
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A Phase 1, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in Healthy Volunteers Followed by Open Label Treatment in Patients With PNH to Evaluate the Safety, Tolerability, PK and PD of ADX-038

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: ADX-038
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 1. Male and female adults 18 to 65 years old 2. Serum LDH levels are at least 1.25-fold above the ULN at screening 3. Mean hemoglobin (Hb) <12 g/dL 4. A history of red blood cell (RBC) transfusion due to PNH within at least 3 months of screening 5. 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 and procedures 5. Neisseria meningitis vaccination 6. Pneumococcus vaccination 7. Hemophilus influenzae vaccination Exclusion Criteria Known or suspected hereditary or acquired complement deficiency History of clinically significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk History of hematopoietic stem cell transplantation History of meningococcal infection Any significant medical history Active malignancy and/or history of malignancy in the past 5 years Any active viral, bacterial, parasitic, or fungal infection or acute illness, inclusive of cold/flu, herpes zoster, or COVID-19, within 30 days prior to the first study drug administration Any evidence of sero-positive autoimmune connective tissue diseases Any evidence of active inflammatory conditions (including inflammatory bowel disease or cryoglobulinemia) History of previous or current tuberculosis infection Prior splenectomy Major surgery or significant traumatic injury occurring within 3 months prior to signature of the PICF. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion Liver impairment, history of liver disease, Gilbert's syndrome, or abnormal liver function tests at screening and/or admission. 19. Positive serology tests for human immunodeficiency virus hepatitis B surface antigen or hepatitis C virus 20. Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication 21. Treatment with another investigational product within 30 days 22. Known any clinically significant allergic reactions 23. Known hypersensitivity to any of the study drug ingredients or penicillin. 24. History or presence of alcohol 25. Blood donation 26. Pregnancy 27. May have a higher risk to be exposed to infected individuals, for example active healthcare employees. Criteria (Part B) Inclusion Criteria 28. Male and female adults 18-65 years old 29. Confirmed diagnosis of PNH based on documented clone size of PNH blood cells by flow cytometry. 30. Serum LDH levels are at least 1.25-fold above the ULN for non-treated participants 31. Liver function test values are less than 2x ULN 32. Mean hemoglobin (Hb) <12 g/dL. 33. A history of red blood cell transfusion within at least 3 months 34. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, at screening. 35. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 36. Willing and able to provide informed consent and comply with all study visits and procedures 37. Neisseria meningitis vaccination 38. Pneumococcus vaccination 39. Hemophilus influenzae vaccination Exclusion Criteria 40. Known or suspected hereditary or acquired complement deficiency 41. History of clinically significant arterial or venous thrombosis 42. History of hematopoietic stem cell transplantation 43. History of meningococcal infection 44. Any significant medical history 45. Active malignancy and/or history of malignancy in the past 5 years 46. Any active viral, bacterial, parasitic, or fungal infection or acute illness 47. Any evidence of sero-positive autoimmune connective tissue diseases 48. Any evidence of active inflammatory conditions 49. History of previous or current tuberculosis infection 50. Prior splenectomy 51. Major surgery or significant traumatic injury occurring within 3 months 52. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion 53. Liver impairment, history of liver disease, Gilbert's syndrome, or abnormal liver function tests 54. Inadequate organ function 55. Supine systolic blood pressure <90 or >160 mmHg, supine diastolic blood pressure <50 or >95 mmHg, pulse rate <45 or >100 beats per minute (bpm), or elevated body temperature (>37.5 ºC) prior to dosing. 56. Positive serology tests for human immunodeficiency virus hepatitis B surface antigen or hepatitis C virus 57. Willing to continue after enrollment with their current treatment with a complement inhibitor. 58. Use of vaccines, or changes in any prescription, supplements/vitamins, or over-the counter medication 59. Treatment with another investigational product or biologic agent within 30 days 60. History or presence of alcohol abuse 61. Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1, Single-Center, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in HV with expansion into PNH
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PART A - Active ADX-038 administered to HV<br>For each cohort in Part A (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<br>* siRNA duplex oligonucleotide<br>* Other names: siRNA;|
| Placebo Comparator: PART A- Placebo administered to HV<br>For each cohort in Part A (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<br>* Saline<br>* Other names: Saline;|
| Experimental: PART B - ADX-038 administered to PNH participants<br>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-038<br>* siRNA duplex oligonucleotide<br>* Other names: siRNA;|

What is the study measuring?
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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 Healthy Volunteers | To evaluate the safety and tolerability of ADX-038 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals) | 365 days | 
| Safety in Paroxysmal Nocturnal Hemoglobinuria | To evaluate the safety and tolerability of ADX-038 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals) | 365 days | 
| Safety in Paroxysmal Nocturnal Hemoglobinuria | To evaluate the safety and tolerability of ADX-038 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-038 in HVs by measuring the Maximum observed concentration (Cmax) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-038 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 Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 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-038 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-∞) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 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-038 in HVs by measuring the Apparent terminal half-life (t½) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F) | 8 days | 
| Pharmacokinetics in Healthy Volunteers | To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F) | 8 days | 
| Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria | To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F) | 8 days | 
| Pharmacodynamics in Healthy Volunteers | Change from base in plasma concentrations over time in Complement factor B (CFB) protein | 365 days | 
| Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria | Change from base in plasma concentrations over time in Complement factor B (CFB) protein | 365 days | 
| Pharmacodynamics in Healthy Volunteers | Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement | 365 days | 
| Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria | Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement | 365 days | 
| Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria | Change from baseline in lactate dehydrogenase | 365 days | 
| Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria | Change from baseline in total hemoglobin | 365 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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siRNA, PNH