A Study of Efficacy and Safety of AND017 in Patients With Myelodysplastic Syndrome

An Efficacy and Safety Study of AND017 for the Treatment of Anemia Due to Lower Risk Myelodysplastic Syndromes (MDS)

This is a Phase 2, multicenter, randomized, open-lable, dose ranging study to evaluate the efficacy and safety of AND017 for the treatment of anemia due to lower risk Myelodysplastic syndromes (MDS) in patients subjects who are Red blood cell (RBC) non-transfusion dependent (NTD) and low transfusion burden (LTB).

Inclusion Criteria:

1. Diagnosed of primary myelodysplastic syndrome with a PISS-R grading of very low, low or intermediate risk and a bone marrow primitive cell count < 5%, the time frame for this grading assessment should be at least 12 weeks prior to the first dose

2. Non-5q(del)-associated myelodysplastic syndrome.

3. Two non-transfused hemoglobin ≥ 6.0 g/dL and < 10.0 g/dL, averaged over the screening period, at least one week and more apart, and with no more than 1.3 g/dL difference between the two Hb.

4. Non-transfused subjects (NTD cohort) defined as no red blood cell transfusion in the 16 weeks prior to randomization or low transfusion load subjects defined as 3-7 pRBC units transfused in the 16 weeks prior to randomization and at least two different time points (LTB-1 cohort) or 1-2 pRBC units transfused at one time point in the 16 weeks prior to randomization ( LTB-2 cohort) (except in the case of transfusion for treatment of other comorbidities such as blood loss, surgery, etc.);

5. Baseline EPO level ≤ 500 mU/mL

6. Platelets ≥ 30,000 /mm3 and absolute neutrophil count ≥ 800/mm3

7. Adequate liver function with:

   • Total bilirubin <2 x upper limit of normal (ULN) (subjects with Gilbert's syndrome, i.e., unconjugated hyperbilirubinemia, have a total bilirubin <3 x ULN)
   • Aspartate aminotransferase (AST) <3 x ULN
   • Alanine aminotransferase (ALT) <3×ULN

Exclusion Criteria:

1. Diagnosed of secondary myelodysplastic syndrome or concurrent anemia from a cause other than the primary myelodysplastic syndrome.
2. Significant myelofibrosis (fibrosis ≥ 2+).
3. Planned clearing chemotherapy or whole brain spinal cord radiotherapy during the study period.
4. Previous diagnosis of MDS IPSS-R high or very high risk.
5. Prior or planned hematopoietic stem cell transplant during the study period.
6. Received granulocyte colony-stimulating factor (G-CSF), or thrombopoietin, or thrombopoietin receptor agonist therapy within 8 weeks prior to the first dose;
7. Treatment with antithymocyte globulin, azacitidine, decitabine, cyclosporine, thalidomide, or lenalidomide within 12 weeks prior to the first dose.
8. The presence of active infection or inflammatory disease requiring systemic anti-infective therapy, including concomitant autoimmune disease with inflammatory symptoms (e.g., generalized erythema, ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, dry syndrome, celiac disease, etc.)
9. Concurrent retinal neovascularization requiring treatment (diabetic proliferative retinopathy, age-related exudative macular degeneration, retinal vein occlusion, macular edema, etc.)
10. Inability to take oral medications, or a history of gastrectomy, concomitant gastroparesis, or other conditions that may have an impact on the absorption of gastrointestinal medications (excluding gastric polyps or colonic polypectomy)
11. Clinically significant bleeding (including transfusions required to treat bleeding or bleeding resulting in a decrease in hemoglobin ≥ 2 g/dL) within 4 weeks prior to the first dose, or a bleeding constitutional or bleeding risk that has not been medically or surgically corrected.
12. Uncontrolled hypertension (more than one-third of identifiable diastolic blood pressure values ≥ 100 mmHg and/or systolic blood pressure ≥ 160 mmHg at 16 weeks prior to and including screening testing)
13. Comorbid heart failure (New York Heart Association [NYHA] class III or higher)
14. Medical history of significant liver disease or active liver disease at screening assessment
15. Have been treated with any other hypoxia-inducing factor-prolyl hydroxylase inhibitor (HIF-PHI) in the 8 weeks prior to the first dose
16. Have been treated with an erythropoietic ESA within 8 weeks prior to the first dose
17. Have been treated with an androgenic anabolic steroid, testosterone enanthate or methandrostenolone within 8 weeks prior to the first dose
18. Have been treated with an iron chelator within 8 weeks prior to the first dose