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

Overview

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).

Full Title of Study: “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”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Sequential Assignment
  • Primary Purpose: Treatment
  • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Study Primary Completion Date: November 30, 2024

Detailed Description

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: 1. Part A – Randomized, double-blind, placebo-controlled, parallel group, single ascending dose (SAD) in HV with up to 5 dose cohorts. 2. Part B – Expansion cohort in participants with paroxysmal nocturnal hemoglobinuria (PNH) at selected dose from Part A and will be open label.

Interventions

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

Arms, Groups and Cohorts

• Experimental: PART A – Active ADX-038 administered to HV
  • 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.
• Placebo Comparator: PART A- Placebo administered to HV
  • 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.
• Experimental: PART B – ADX-038 administered to PNH participants
  • 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.

Clinical Trial Outcome Measures

Primary Measures

• Safety in Healthy Volunteers
  • Time Frame: 365 days
  • To evaluate the safety and tolerability of ADX-038 in HVs by incidence, relationship, and severity of adverse events and serious adverse events
• Safety in Healthy Volunteers
  • Time Frame: 365 days
  • To evaluate the safety and tolerability of ADX-038 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals)
• Safety in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 365 days
  • To evaluate the safety and tolerability of ADX-038 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals)
• Safety in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 365 days
  • To evaluate the safety and tolerability of ADX-038 in HAE by incidence, relationship, and severity of adverse events and serious adverse events

Secondary Measures

• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • 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)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • 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)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-∞)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-∞)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F)
• Pharmacokinetics in Healthy Volunteers
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F)
• Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 8 days
  • To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F)
• Pharmacodynamics in Healthy Volunteers
  • Time Frame: 365 days
  • Change from base in plasma concentrations over time in Complement factor B (CFB) protein
• Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 365 days
  • Change from base in plasma concentrations over time in Complement factor B (CFB) protein
• Pharmacodynamics in Healthy Volunteers
  • Time Frame: 365 days
  • Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement
• Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 365 days
  • Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement
• Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 365 days
  • Change from baseline in lactate dehydrogenase
• Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria
  • Time Frame: 365 days
  • Change from baseline in total hemoglobin

Participating in This Clinical Trial

Inclusion Criteria 1. Male and female adults 18 to 55 years old 2. Body mass index (BMI) between 18 and 32 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. Negative urine drug, nicotine/tobacco, and breath alcohol test result 6. Neisseria meningitis vaccination 7. Pneumococcus vaccination 8. Hemophilus influenzae vaccination Exclusion Criteria 9. Any significant medical history 10. Active malignancy and/or history of malignancy in the past 5 years 11. History of liver disease, Gilbert's syndrome, or abnormal liver function test 12. Estimated creatinine clearance <60 mL/min using the Cockcroft-Gault formula 13. Any active infection or acute illness 14. History of meningococcal infection or frequent respiratory, nasopharyngeal or ear infections 15. History of previous or current tuberculosis infection. 16. Prior splenectomy 17. Major surgery or significant traumatic injury occurring within 3 months 18. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion 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 32 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. Inadequate organ function 54. Positive serology tests for human immunodeficiency virus hepatitis B surface antigen or hepatitis C virus 55. Willing to continue after enrollment with their current treatment with a complement inhibitor. 56. Use of vaccines, or changes in any prescription, supplements/vitamins, or over-the counter medication 57. Treatment with another investigational product or biologic agent within 30 days 58. Blood donation within 30 days 59. Pregnancy

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

• Lead Sponsor
  • ADARx Pharmaceuticals, Inc.
• Collaborator
  • ADARx Australia Pty Ltd
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Contact(s)
  • Richard Friend, MD, +61 403 415 925, r.friend@nucleusnetwork.com.au