A Study to Investigate the Safety, Pharmacokinetics and Efficacy of APG-5918 in Healthy Subjects or Anemic Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics and efficacy of APG-5918 in Healthy Subjects or Anemic Patients.

Detailed Description
-----------------
The trial has two parts. Part A is a randomized, double-blind, placebo- controlled, single-dose escalation study in up to 7 cohorts to evaluate the safety, tolerability, and PK characteristics of APG-5918 in healthy subjects and to explore whether MTDS will be achieved within the range of projected therapeutic doses for anemia. Part B is a randomized, double-blind, placebo-controlled, multi-dose escalation trial in up to 7 cohorts to evaluate the safety, tolerability, PK and preliminary efficacy of APG-5918 in anemic subjects.

Official Title
-----------------
A Phase 1 Randomized, Double-Blinded, Placebo-Controlled, Dose-Escalating Study to Evaluate Safety and Tolerability, Pharmacokinetics and Efficacy of APG-5918 in Healthy Subjects or Anemic Patients

Conditions
-----------------
Anemia

Intervention / Treatment
-----------------
* Drug: APG-5918
* Drug: Placebo
* Drug: APG-5918
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - 1.Inclusion criteria for healthy subjects Age ≥ 18 years and ≤ 55 years. Body mass index (BMI) 18 28kg/m² (inclusive). Hb: 120 g/L 160 g/L (inclusive). Normal iron stores (normal serum iron and serum ferritin). 2.Inclusion criteria for anemic subjects Age ≥ 18 years. Chronic patients with anemia, including but not limited to β-thalassemia, with Hb ≤ 100 g/L at screening. BMI: 16 32 kg/m2 (inclusive). Serum folate and vitamin B12 levels above lower limit of normal (LLN). Ferritin ≥ 40 ng/mL. Serum transferrin saturation (TSAT) ≥20%. ALT, AST ≤ 2 × ULN, or total bilirubin (TBIL) ≤ 3.0× ULN. No active or chronic bleeding. ECOG performance status score of 0 to 1. 3. Female subjects of childbearing potential who have a negative serum pregnancy test within 7 days prior to the first dose. 4. Subjects and their partners volunteer to use protocol-specified effective contraception during treatment and for at least 3 months after the last dose of study drug (see Section 8.7 for details). 5. Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the subject prior to any study-specific procedures). Exclusion criteria 1.Exclusion criteria for healthy subjects History of any disease or clinical condition that, in the opinion of the investigator, could confound the results of the study or pose an additional risk to the subject by administering study drug. Including but not limited to history or presence of cardiac, endocrine, hematologic, hepatic, gastrointestinal, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other diseases. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN), or total bilirubin (TBIL) > 1.5 × ULN at screening. Surgery (except minor cosmetic surgery or minor dental surgery) within 3 months prior to screening. Blood donation or blood loss of more than 400 ml within 3 months before screening or plans to donate blood or blood components during the study. Use of another investigational product within 30 days or 5 half-lives, whichever is longer, or currently participating in a prospective study of an investigational product or medical device. History of addictive substance abuse. Alcohol breath test fails. 2.Exclusion criteria for anemic subjects Clinically significant or uncontrolled persistent autoimmune diseases (e.g., rheumatoid arthritis, Crohn's disease, celiac disease, etc.). Uncontrolled hypertension (diastolic blood pressure > 110 mmHg or systolic blood pressure > 170 mmHg at screening) or diabetes as judged by the investigator. New York Heart Association Class II to IV congestive heart failure, or recent myocardial infarction or acute coronary syndrome. History of diagnosis of persistent hemolysis or hemolytic syndrome except for beta-thalassemia. History of thrombosis or new blood clots within 4 weeks prior to screening. Any active infection requiring systemic antibiotics within 14 days prior to screening. Intravenous iron within 28 days prior to screening. Previous history of organ transplantation. Patients who participated in other clinical studies within 4 weeks and were still taking other study drugs or had not exceeded 5 half-lives. 3.Positive screening results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus antibody (HIV Ab), or treponema pallidum antibody at screening. 4.Standard 12-lead ECG QTcB > 450 ms in men and > 470 ms in women. 5. History of regular alcohol consumption within 6 months before screening, daily average intake of ethanol ≥ 30 grams (male) or ≥ 20 grams (female). 6. Female subjects who are pregnant, planning to become pregnant, or breastfeeding, or male subjects whose partners intend to become pregnant. 7. Any subject who is not suitable for participating in this study as judged by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Dose (SAD) cohorts in Healthy Subjects (Part A)<br>Subjects will be randomized to receive a single dose of APG-5918 or placebo. | Drug: APG-5918<br>* oral tablets 10mg, 50mg.<br>Drug: Placebo<br>* Matching placebo<br>|
| Experimental: Multiple Ascending Dose (MAD) cohorts in Anemic Patients (Part B)<br>Subjects will be randomized to receive once daily APG-5918 or placebo for 28 days. | Drug: APG-5918<br>* oral tablets 10mg, 50mg.<br>Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Emergent Adverse Events (TEAEs) | TEAEs will be assessed via CTCAE version 5.0 based on the frequency of adverse events/serious adverse events (AEs/SAEs), clinically significant laboratory test results, 12-lead ECGs, and vital signs. | up to 7 days in Part A and 42 days in Part B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of APG-5918 | Blood samples will be collected to measure the plasma concentration of APG-5918 by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. | Days 1, 2 and 3 in Part A; Days 1, 8, 15, 22 and 28 in Part B | 
| Measurement of Hemoglobin | Change from baseline in hemoglobin will be measured in peripheral whole blood by flow cytometry. | up to 28 days in Part B | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
APG-5918, Anemia