A Study of Avatrombopag in Adults With Aplastic Anemia Who Did Not Respond to, Cannot Receive, or Had Return of Disease After Standard Treatment

An Open-label, Single-arm, Multicenter Phase 2/3 Clinical Trial Evaluating Avatrombopag in Adult Patients With Aplastic Anemia (AA) Refractory to or Ineligible for Immunosuppressive Therapy or With Relapsed AA After Immunosuppressive Therapy

This research study is testing a medicine called avatrombopag in adults with aplastic anemia, a rare condition where the bone marrow does not produce enough blood cells. The study will include about 26 participants from Japan, South Korea, and Taiwan whose disease has not responded to standard treatment, who cannot receive standard treatment, or whose disease has returned after previous treatment. The goal is to learn how well avatrombopag works and how safe it is for these patients.

This phase 2/3 open-label trial will evaluate the efficacy and safety of avatrombopag in adult patients with AA refractory to or ineligible f or immunosuppressive therapy or with relapsed AA after immunosuppressive therapy. Approximately 26 patients in Japan, South Korea and Taiwan who meet all the eligibility requirements will be enrolled to evaluate the efficacy and safety of avatrombopag. The trial will consist of 3 phases: Screening Phase, Primary Investigation Phase (Core Phase), and Extension Phase. The Screening Phase lasts 6 weeks. The Primary Investigation Phase (Core Phase) will be 26 weeks in duration, and the Extension Phase will be conducted for at least 52 weeks and continue until product is commercially available in Japan, South Korea and Taiwan, respectively.

Informed consent must be obtained from each patient in writing prior to screening. Their eligibility should be confirmed at screening and prior to the first avatrombopag administration.

All trial participants will receive an initial dose of 60 mg avatrombopag once daily with food. The dose and dosing frequency will be adjusted upwards or downwards (maximum dose: 80 mg once daily; minimum dose: 20 mg three times a week) based on their individual responses for platelet counts. However, trial participants who are being treated with moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5 will receive an initial dose of 60 mg avatrombopag three times a week with food, and their dose and dosing frequency can be adjusted (maximum dose: 80 mg three times a week; minimum dose: 20 mg once weekly) based on their individual platelet counts.

The overall goal of dose adjustment is to identify the minimum dose that maintains platelet counts within the target range of ≥50×10⁹/L and <200×10⁹/L.

Trial participants will have visits weekly (Visits 2, 3, 4, 5, 6), bi-weekly (Visits 7, 8, 9, 10, 11), then every 4 weeks (Visits 12, 13, 14) during the 26-week Primary Investigation Phase (Core Phase) to collect the required data on platelet count, reticulocyte count (absolute and/or %), hemoglobin level, neutrophil count (absolute neutrophil count; ANC), bleeding events, and other adverse events (AEs). All trial participants who complete the Primary Investigation Phase (Core Phase) can continue to receive avatrombopag in the Extension Phase until product is commercially available. Safety and efficacy data will be collected every 4 weeks in the Extension Phase, which will be conducted for at least 52 weeks.

Inclusion Criteria:

Primary Investigation Phase (Core Phase)

1. Patients must be able to provide informed consent.
2. Age ≥18.
3. Diagnosis of aplastic anemia confirmed by peripheral blood and bone-marrow aspirate/biopsy.
4. Refractory to or relapsed after at least one course of immunosuppressive therapy including horse or rabbit anti-thymocyte globulin (ATG); or ineligible for ATG treatment and refractory to or relapsed after CyA.
5. Thrombocytopenia defined as a platelet count of ≤ 30 × 109/L.
6. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) score (refer to Appendix D) of 0 to 2 at screening.
7. Women of childbearing potential must have a negative pregnancy test at screening and baseline.
8. Patients who agree to use an effective method of contraception, as defined in Section 6.4.4, from the time of informed consent until 30 days after the final dose of avatrombopag.

Extension Phase

1. No significant safety or tolerability concerns with the trial participant's participation in the Primary Investigation Phase (Core Phase) as determined by the Investigator.

Exclusion Criteria:

Primary Investigation Phase (Core Phase)

1. Patients with bone marrow fibrosis MF-2 or MF-3 at screening, graded according to the WHO/European Consensus Reticulin Fibrosis Grading System (MF-0 to MF-3; Appendix E) documented on a bone marrow aspirate/biopsy obtained during screening.

2. Patients with >2% bone marrow blasts documented on a bone marrow aspirate/biopsy obtained during screening.

3. Patients with MDS-defining cytogenetic abnormalities per WHO 2022 (5th Edition), including -7/del(7q), -5/del(5q), complex (≥3) or monosomal karyotype, 3q26/EVI1 rearrangements, and other recognized MDS/AML-defining lesions, or with unequivocal dysplasia/blast excess; isolated +8, -Y, del(20q), or small (<10%) non-dysplastic clones are eligible with enhanced surveillance.

4. Patients with a history of cirrhosis, portal hypertension, or chronic active hepatitis.

5. Patients with clinically significant cardiac disease (class III or IV of the New York Heart Association classification); unstable angina pectoris; myocardial infarction within 6 months before enrollment; cardiac disease accompanied by angioplasty or stenting within 6 months before enrollment; or clinically significant cardiac arrhythmias, including history of torsades de pointes; uncontrollable hypertension.

6. Patients with known diagnosis or clinical suspicion of inherited bone marrow failure syndrome, including but not limited to Fanconi Anaemia.

7. Patients with thrombocytopenia due to any other causes (e.g., myelodysplastic syndrome [MDS], idiopathic thrombocytopenic purpura, human immunodeficiency virus [HIV], hepatitis C virus [HCV], systemic lupus erythematosus [SLE], or cirrhosis).

8. Patients with concurrent occurrence of hemolytic predominant paroxysmal nocturnal haemoglobinuria (PNH). Hemolytic predominant is defined as lactate dehydrogenase >1.5 times the upper limit of the laboratory normal range.

9. Patients with a clinically significant PNH clone size, defined as a granulocyte or monocyte PNH clone ≥50% or any clone size considered by the Investigator to confer increased thrombosis risk (e.g., rapid expansion or laboratory evidence of active hemolysis).

10. Patients with PNH being treated with a complement-inhibiting therapy, including C5 inhibitors, C3 inhibitors, or proximal complement pathway inhibitors.

11. Patients with a history of malignant disease within the past 5 years, or with concurrent malignant disease or receiving cytotoxic chemotherapy for a reason other than AA treatment (except for basal cell carcinoma or squamous cell carcinoma of the skin, or in situ carcinoma of the cervix).

12. Patients with medical history of thromboembolism within 6 months or current use of anticoagulants. Patients with antiphospholipid antibody syndrome.

13. Pregnant or breastfeeding women, and women of childbearing potential who are unwilling or unable to use effective contraception as defined in Section 6.4.4, or who have a positive pregnancy test at screening or baseline.

14. Patients with known allergy to avatrombopag or any of its excipients.

15. Patients with creatinine clearance ≤30 mL/min calculated using the Cockroft and Gault formula.

16. Patients receiving any medication or treatment for AA, including the following before avatrombopag treatment initiation:

    • Use of ATG (either horse or rabbit) within 90 days of Day 1/Baseline.
    • Use of CyA or anabolic steroid within 6 weeks of Day 1/Baseline. However, patients who have been receiving CyA or anabolic steroid at least 8 weeks before Day 1/Baseline may be enrolled if the blood cell count is stable at screening and the dosage regimen is maintained stable for 6 weeks prior to the initiation of avatrombopag treatment and during the trial treatment.
    • Any prior hematopoietic stem cell transplantation

17. Patients with a history of use of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor, recombinant human TPO, or romiplostim.

18. Patients received eltrombopag within 7 days of Day 1/Baseline.

19. Patients received treatment with another investigational drug within 30 days or 5 half-lives (whichever is longer) before Day 1/Baseline.

20. Any clinically relevant abnormality which makes the patient unsuitable for participation in the trial, in the opinion of the Investigator.

21. Patients who are considered unable or unwilling to comply with the trial protocol requirements, as determined by the Investigator.

Extension Phase

1. Patients for whom participation in the Extension Phase is considered inappropriate, based on the Investigator's judgment.
2. Patients considered unable or unwilling to comply with the trial protocol requirements, as determined by the Investigator.