A Study to Investigate the Safety, Tolerability, PK and PD of MG1113 in Healthy Subjects and Hemophilia Patients

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of MG1113 in the single ascending dose study (IV injection or SC injection) in healthy subjects and hemophiia patients.

Detailed Description
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This is a single-dose study that explore the safety, tolerability, PK, and PD of the study drug by sequentially increasing the study drug in 4 dose levels. The route of administration is either subcutaneous (SC) injection or intravenous (IV) injection. For healthy subjects, 6 subjects will be assigned to the study group and 2 subjects will be assigned to the placebo group to explore the safety and tolerability, and PK/PD of the study drug in comparison with placebo. Hemophilia patients will be assigned only to the study group with 3 and 6 subjects in each cohort, respectively. The investigator and subjects will know which cohort the healthy subjects have been assigned to, but they will be double-blinded as to whether the subjects are assigned to the study group (study drug) or the placebo group (placebo) within each cohort. The doses planned in healthy subjects are 0.5 mg/kg, 1.7 mg/kg, and 3.3 mg/kg by SC injection; 3.3 mg/kg by IV injection. In hemophilia patients, 1.7 mg/kg and 3.3 mg/kg will be administered by SC injection. The planned dose will be administered after checking the safety and tolerability at the previous dose to the extent not exceeding the criteria for discontinuation of dose escalation. The dose escalation will be decided by the Data Monitoring Committee(DMC) and Data and Safety Monitoring Boards (DSMB) in the blinded evaluation of the safety and tolerability data obtained from each previous cohort for 7 days after administration. Before deciding dose escalation and proceeding to the next step, the safety, tolerability, PK, and PD data obtained from all healty subjects and hemophilia patients up to cohort 6 will be evaluated by the Data and Safety Monitoring Boards (DSMB) in an unblinded manner. In addition, if necessary, the analysis result of cohort that has completed all the scheduled visits can be reviewed in an unblinded manner.

Official Title
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A Phase I, Randomized, Double-blind, Placebo-Controlled, Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MG1113 in Healthy Subjects and Hemophilia Patients

Conditions
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Hemophilia

Intervention / Treatment
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* Biological: MG1113
* Other: Placebo of MG1113


Participation Criteria
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Eligibility Criteria
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<Healthy adult subjects> Inclusion Criteria: Healthy male adult subjects aged 19-60 years (both inclusive) at screening 50 to 90 kg in weight with calculated BMI between 18.5 and 29.9 kg/m2 Agree to use medically acceptable adequate dual contraceptive methods (condom, vasectomy, spermicide, oral contraceptives, intrauterine device, and complete sexual abstinence, etc.) and not to donate sperm until 3 months after administration of the investigational product Voluntarily decided to participate in the study and provided written consent to follow precautions after receiving a detailed explanation on this study and fully understanding the information Exclusion Criteria: Presence or history of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immune, skin, nervous, or psychiatric disease Symptoms of acute disease within 28 days of investigational product administration Medical history that may affect absorption, distribution, metabolism and excretion of drugs Clinically significant active chronic disease Clinically significant allergic disease (however, mild allergic rhinitis or allergic dermatitis not requiring any medication is allowed) or history of any anaphylactic reaction Any of the following results from laboratory tests: 1) AST (sGOT) or ALT (sGPT) >2 x UNL 2) Hb < 9.0 g/dL 3) Absolute Neutrophil Count < 1500 mm2 4) Platelet count < 100 x 103 mm2 5) aPTT, PT > 1.5 x UNL 6) Have hepatitis B (HBsAg positive) or C (anti-HCV positive), or have positive HIV test result 7) Creatinine clearance ≤80 mL/min (calculated by the Cockcroft-Gault formula) Have a family history or be considered to be at risk of thromboembolic events, or have the following test results: 1) Antithrombin level ≤LNL 2) Protein C or S activity ≤LNL 3) Factor V Leiden mutation 4) Prothrombin G20210A mutation Used ethical drugs including prescription drugs within 14 days of investigational product administration Used drugs (over-the-counter drugs, herbal medicines, and nutritional agents and vitamins for the purpose of same efficacy) within 7 days of investigational product administration Cannot have standard meals provided at the hospital Donated whole blood within 60 days of investigational product administration, or donated blood components within 20 days of investigational product administration, or received blood transfusion within 1 month before administration Participated in another clinical trial or bioequivalence study within 90 days of investigational product administration (If participating in a clinical trial after 12/06/2019, not within 90 days, but within 6 months is applied) Individuals who consume caffeine (caffeine >5 cups/day) or alcohol (alcohol >30 g/day) continuously, who cannot abstain from drinking during the study, or heavy smoker (>10 cigarettes/day) Determined to be ineligible to participate in the study per investigator's judgment due to other reasons including the laboratory test results History of drug abuse or positive urine drug screen results <Hemophilia patients> Inclusion criteria Male hemophilia A or B patients aged 19-60 years (both inclusive) at screening ≥50 kg in weight with calculated BMI between 18.5 and 29.9 kg/m2 Agree to use medically acceptable adequate dual contraceptive methods (condom, vasectomy, spermicide, oral contraceptives, intrauterine device, and complete sexual abstinence, etc.) and not to donate sperm until 60 days after administration of the investigational product Voluntarily decided to participate in the study and provided written consent to follow precautions after receiving a detailed explanation on this study and fully understanding the information Exclusion criteria Symptoms of acute disease within 28 days of investigational product administration or any surgery planned during the study period Medical history that may affect absorption, distribution, metabolism and excretion of drugs Clinically significant active chronic disease Clinically significant allergic disease (however, mild allergic rhinitis or allergic dermatitis not requiring any medication is allowed) or history of any anaphylactic reaction Patients having current human factor VIII or IX with an inhibitor titer of >5 Bethesda units or patients requiring treatment with bypassing agent Patients who has a history of confirmed human factor VIII or IX with an inhibitor titer of >5 Bethesda units at any time History of ≥6 bleeding episodes despite temporary bypassing agent administered for 24 weeks before screening, or ≥2 bleeding episodes despite the bypassing agent administered prophylactically Received factor VIII or factor IX within 48 hours prior to administration of the investigational product Hemostatic agent, etc. prescribed to control bleeding within 5 days prior to administration of the investigational product Immune tolerance induction prescribed within 30 days prior to administration of the investigational product Currently using systemic immunomodulator (e.g., interferon or rituximab) Be at risk of thrombotic microangiopathy per investigator's judgment or have related medical history or family history Congenital or acquired anticoagulant disorders other than hemophilia A or B, or conditions of other diseases that increase the risk of bleeding or thrombus (e.g., autoimmune disease) Any of the following results from laboratory tests: 1) AST (sGOT) or ALT (sGPT) >3 x UNL 2) Hb < 9.0 g/dL 3) Absolute Neutrophil Count < 1500 mm2 4) Platelet count < 100 x 103 mm2 5) Have hepatitis B (HBs Ag positive) or C (anti-HCV positive), or have HIV positive test result 6) Creatinine clearance ≤80 mL/min (calculated by the Cockcroft-Gault formula) Cannot have standard meals provided at the hospital Participated in another clinical trial within 90 days of investigational product administration Individuals who consume caffeine (caffeine >5 cups/day) or alcohol (alcohol >30 g/day) continuously, who cannot abstain from drinking during the study, or heavy smoker (>10 cigarettes/day) Determined to be ineligible to participate in the study per investigator's judgment due to other reasons including the laboratory test results History of drug abuse or positive urine drug screen results

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential dose escalation model
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MG1113<br>Anti-tissue factor pathway inhibitor (TFPI) recombinant antibody Each vial contains 1mL of study drug The doses planned in healthy subjects are 0.5 mg/kg, 1.7 mg/kg, and 3.3 mg/kg by SC injection; 3.3 mg/kg by IV injection. In hemophilia patients, 1.7 mg/kg and 3.3 mg/kg will be administered by SC injection. | Biological: MG1113<br>* MG1113<br>|
| Placebo Comparator: Placebo of MG1113<br>Placebo of MG1113 Each vial contains 1mL of study drug | Other: Placebo of MG1113<br>* Placebo of MG1113<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Adverse events such as subjective and objective symptoms | Through study completion ( 50 day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity assay | ADA [Anti-Drug Ab] | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - Cmax | Cmax | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - Tmax | Tmax | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - AUClast | AUClast | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - AUCinf | AUCinf | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - half-life | half-life | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - CL/F (for SC) | CL/F (for SC) | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - CL (for IV) | CL (for IV) | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - Vd/F (for SC) | Vd/F (for SC) | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - Vd (for IV) | Vd (for IV) | Through study completion ( 50 day) | 
| Pharmacokinetic assessment - Bioavailability (F) | Bioavailability (F) Bioavailability (F) = AUCinf (at SC dosing [3.3 mg/kg])/AUCinf (at IV dosing [3.3 mg/kg]) | Through study completion ( 50 day) | 
| Pharmacodynamic assessment - Free TFPI in plasma | Free TFPI in plasma (ng/mL) | Through study completion ( 50 day) | 
| Pharmacodynamic assessment - Diluted PT | Diluted PT (sec) | Through study completion ( 50 day) | 
| Pharmacodynamic assessment - residual TFPI activity | residual TFPI activity | Through study completion ( 50 day) | 
| Pharmacodynamic assessment - Thrombin generation | Thrombin generation (lag time, peak generation, Endogenous thrombin generation potential [ETP]) | Through study completion ( 50 day) | 
| Pharmacodynamic assessment - Pro-coagulant effect | Pro-coagulant effect (D-dimer, Fibrinogen, prothrombin fragments 1+2) | Through study completion ( 50 day) | 
| Physical examination | Physical examination | Through study completion ( 50 day) | 
| Incidence of participant abnormalities in 12-lead ECG (Ventricular rate in beat/min, Interval for PR in msec, QRS in msec, QTc in msec) for physiological parameter | The result for 12-lead ECG will be reported as Clinical Significant or Not-Clinical Significant. Ventricular rate in beat/min Interval for PR in msec QRS in msec QTc in msec | Through study completion ( 50 day) | 
| Vital signs - blood pressure (Systolic, Diastolic) | Vital signs - blood pressure (Systolic, Diastolic) | Through study completion ( 50 day) | 
| Vital signs - pulse rate | Vital signs - pulse rate | Through study completion ( 50 day) | 
| Vital signs - body temperature | Vital signs - body temperature | Through study completion ( 50 day) | 
| Frequency of Bleeding (only for hemophilia patients) | Bleeding evaluation (only for hemophilia patients) by questionnaire; Occurrence date, Persistence in yes or no questionnaire, Causes (blood in naturally occurring/Traumatic bleeding), Severity (mild/moderate/Severe) | Through study completion ( 50 day) | 
| Local reaction in injection site | Pain or tenderness, itching, rash, redness (in mm), and induration (in mm) will be reported. Local stimulation test in injection site: Occurrence date, Persistence, Causes, Severity (mild/moderate/Severe) The occurrence of pain or tenderness, itching and rash will be reported by Yes or No questionnaire. The size of redness and induration will be measured in millmeters(mm). | Through study completion ( 50 day) | 
| Incidence of participant abnormalities in laboratory tests by physiological parameter (Hematology, clinical chemistry, urinalysis, and blood coagulation test) | Parameters for laboratory tests include Hematology(WBC in 10**3/mcL,Neutrophils in %,ANC in mcL,Lymphosyte in %,Monocyte in %,Eosinophils in %,Basophils in %,RBC in 10**6/mcL,Hemoglobin in g/dL,Hematocrit in %,MCV in fL, MCH in pg,MCHC in g/dL,Platelets in 10**3/mcL,MPV in fL),Clinical chemistry(Glucose in mg/dL,BUN in mg/dL,Uric adic in mg/dL,Total cholesterol in mg/dL,Triglyceride in mg/dL,Protein,Albumin in g/dL,Total bilirubin in mg/dL,Alkaline phosphatase in IU/L,AST in IU/L,ALT in IU/L,r-GT in IU/L,LDH in IU/L,Serum creatinine in mg/dL,Na in mmol/L,K in mmol/L,Cl in mmol/L,CPK in IU/L,Troponin I in ng/mL,Troponin T in ng/mL,Creatinine Clearance),Urinalysis(These values are reported only as a number;Specific garavity,Color,pH,Protein,Glucose,Ketone,Bilirubin,Blood,Urobilinogen,Nitrite,WBC,Squma EP cell,Casts,Crystal,Clarity,RBC),Blood coagulation test (aPTT in sec,PT in sec,Fibronogen in mg/dL,Antithrombon III in %,Protein C in %,Protein S in%) | Through study completion ( 50 day) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MG1113, Hemophilia