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

• Sponsor: ADARx Pharmaceuticals, Inc. (Industry)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05876312
• Collaborator: ADARx Australia Pty Ltd (Other)
• Enrollment: 53
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 24
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Paroxysmal Nocturnal Hemoglobinuria (PNH)	Drug: ADX-038; Drug: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Phase 1, Single-Center, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in HV with expansion into PNHPhase 1, Single-Center, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in HV with expansion into PNH
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blinded
• Primary Purpose: Treatment
• Official Title: 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
• Anticipated Study Start Date: Jun 30, 2023
• Anticipated Primary Completion Date: Nov 30, 2024
• Anticipated Study Completion Date: Jun 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: ADX-038; siRNA duplex oligonucleotide; Other Names: siRNA
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.	Drug: Placebo; Saline; Other Names: Saline
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.	Drug: ADX-038; siRNA duplex oligonucleotide; Other Names: siRNA

Outcome Measures

Primary Outcome Measures

1. Safety in Healthy Volunteers [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

2. Safety in Healthy Volunteers [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)

3. Safety in Paroxysmal Nocturnal Hemoglobinuria [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)

4. Safety in Paroxysmal Nocturnal Hemoglobinuria [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 Outcome Measures

1. Pharmacokinetics in Healthy Volunteers [8 days]

   To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax)

2. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [8 days]

   To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax)

3. Pharmacokinetics in Healthy Volunteers [8 days]

   To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax)

4. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [8 days]

   To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax)

5. Pharmacokinetics in Healthy Volunteers [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)

6. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [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)

7. Pharmacokinetics in Healthy Volunteers [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-∞)

8. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [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-∞)

9. Pharmacokinetics in Healthy Volunteers [8 days]

   To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½)

10. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½)

11. Pharmacokinetics in Healthy Volunteers [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz)

12. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz)

13. Pharmacokinetics in Healthy Volunteers [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F)

14. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F)

15. Pharmacokinetics in Healthy Volunteers [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F)

16. Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria [8 days]

    To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F)

17. Pharmacodynamics in Healthy Volunteers [365 days]

    Change from base in plasma concentrations over time in Complement factor B (CFB) protein

18. Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria [365 days]

    Change from base in plasma concentrations over time in Complement factor B (CFB) protein

19. Pharmacodynamics in Healthy Volunteers [365 days]

    Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement

20. Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria [365 days]

    Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement

21. Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria [365 days]

    Change from baseline in lactate dehydrogenase

22. Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria [365 days]

    Change from baseline in total hemoglobin

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

1. Male and female adults 18-65 years old

2. Confirmed diagnosis of PNH based on documented clone size of PNH blood cells by flow cytometry.

3. Serum LDH levels are at least 1.25-fold above the ULN for non-treated participants

4. Liver function test values are less than 2x ULN

5. Mean hemoglobin (Hb) <12 g/dL.

6. A history of red blood cell transfusion within at least 3 months

7. Body mass index (BMI) between 18 and 32 kg/m2, inclusive, at screening.

8. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

9. Willing and able to provide informed consent and comply with all study visits and procedures

10. Neisseria meningitis vaccination

11. Pneumococcus vaccination

12. Hemophilus influenzae vaccination

Exclusion Criteria

1. Known or suspected hereditary or acquired complement deficiency

2. History of clinically significant arterial or venous thrombosis

3. History of hematopoietic stem cell transplantation

4. History of meningococcal infection

5. Any significant medical history

6. Active malignancy and/or history of malignancy in the past 5 years

7. Any active viral, bacterial, parasitic, or fungal infection or acute illness

8. Any evidence of sero-positive autoimmune connective tissue diseases

9. Any evidence of active inflammatory conditions

10. History of previous or current tuberculosis infection.

11. Prior splenectomy

12. Major surgery or significant traumatic injury occurring within 3 months

13. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion

14. Inadequate organ function

15. Positive serology tests for human immunodeficiency virus hepatitis B surface antigen or hepatitis C virus

16. Willing to continue after enrollment with their current treatment with a complement inhibitor.

17. Use of vaccines, or changes in any prescription, supplements/vitamins, or over-the counter medication

18. Treatment with another investigational product or biologic agent within 30 days

19. Blood donation within 30 days

20. Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nucleus Network Brisbane	Brisbane	Queensland	Australia	4006

Sponsors and Collaborators

• ADARx Pharmaceuticals, Inc.
• ADARx Australia Pty Ltd

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ADARx Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT05876312
• Other Study ID Numbers: ADX-038-101
• First Posted: May 25, 2023
• Last Update Posted: May 25, 2023
• Last Verified: May 1, 2023

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by ADARx Pharmaceuticals, Inc.: siRNA; PNH
• Additional relevant MeSH terms: Hemoglobinuria; Hemoglobinuria, Paroxysmal

Study Results

No Results Posted as of May 25, 2023