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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia
• Intervention / Treatment: Biological: MG1113; Other: Placebo of MG1113

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 120-752
    • Yonsei Cancer Center, Yonsei University Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

<Healthy adult subjects>

• Inclusion Criteria:

  1. Healthy male adult subjects aged 19-60 years (both inclusive) at screening
  2. 50 to 90 kg in weight with calculated BMI between 18.5 and 29.9 kg/m2
  3. 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
  4. 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:

  1. Presence or history of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immune, skin, nervous, or psychiatric disease
  2. Symptoms of acute disease within 28 days of investigational product administration
  3. Medical history that may affect absorption, distribution, metabolism and excretion of drugs
  4. Clinically significant active chronic disease
  5. Clinically significant allergic disease (however, mild allergic rhinitis or allergic dermatitis not requiring any medication is allowed) or history of any anaphylactic reaction
  6. 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)
  7. 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
  8. Used ethical drugs including prescription drugs within 14 days of investigational product administration
  9. 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
  10. Cannot have standard meals provided at the hospital
  11. 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
  12. 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)
  13. 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)
  14. Determined to be ineligible to participate in the study per investigator's judgment due to other reasons including the laboratory test results
  15. History of drug abuse or positive urine drug screen results

<Hemophilia patients>

• Inclusion criteria

  1. Male hemophilia A or B patients aged 19-60 years (both inclusive) at screening
  2. ≥50 kg in weight with calculated BMI between 18.5 and 29.9 kg/m2
  3. 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
  4. 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

  1. Symptoms of acute disease within 28 days of investigational product administration or any surgery planned during the study period
  2. Medical history that may affect absorption, distribution, metabolism and excretion of drugs
  3. Clinically significant active chronic disease
  4. Clinically significant allergic disease (however, mild allergic rhinitis or allergic dermatitis not requiring any medication is allowed) or history of any anaphylactic reaction
  5. Patients having current human factor VIII or IX with an inhibitor titer of >5 Bethesda units or patients requiring treatment with bypassing agent
  6. Patients who has a history of confirmed human factor VIII or IX with an inhibitor titer of >5 Bethesda units at any time
  7. 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
  8. Received factor VIII or factor IX within 48 hours prior to administration of the investigational product
  9. Hemostatic agent, etc. prescribed to control bleeding within 5 days prior to administration of the investigational product
  10. Immune tolerance induction prescribed within 30 days prior to administration of the investigational product
  11. Currently using systemic immunomodulator (e.g., interferon or rituximab)
  12. Be at risk of thrombotic microangiopathy per investigator's judgment or have related medical history or family history
  13. 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)
  14. 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)
  15. Cannot have standard meals provided at the hospital
  16. Participated in another clinical trial within 90 days of investigational product administration
  17. 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)
  18. Determined to be ineligible to participate in the study per investigator's judgment due to other reasons including the laboratory test results
  19. History of drug abuse or positive urine drug screen results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MG1113; 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; MG1113
Placebo Comparator: Placebo of MG1113; Placebo of MG1113; Each vial contains 1mL of study drug	Other: Placebo of MG1113; Placebo of MG1113

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Green Cross Corporation
• Collaborators: Dream CIS, Inc.
• Investigators: Principal Investigator: Ji-Young Park, MD, Korea University Anam Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2019
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): August 31, 2021

Study Registration Dates

• First Submitted: February 12, 2019
• First Submitted That Met QC Criteria: February 24, 2019
• First Posted (Actual): February 27, 2019

Study Record Updates

• Last Update Posted (Actual): October 26, 2021
• Last Update Submitted That Met QC Criteria: October 24, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Hemophilia; MG1113
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: MG1113_P1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No