A Single Escalating Dose and Multiple Dose Study of BAY 1093884 in Subjects With Severe Hemophilia Types A or B, With or Without Inhibitors

Study Overview
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Brief Summary
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Investigate the safety, tolerability and pharmacokinetics of BAY1093884 after Intravenous (IV) and subcutaneous (SC) administration of increasing single doses and SC administration of multiple doses.

Official Title
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A Phase 1, First in Man, Multicenter, Open Label, Single Escalating Dose Study of BAY1093884 in Subjects With Severe Hemophilia Types A or B, With or Without Inhibitors

Conditions
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Hemophilia A, Hemophilia B

Intervention / Treatment
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* Drug: BAY1093884
* Drug: BAY1093884


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males with severe congenital Hemophilia A or B defined as <1% FVIII or Factor IX (FIX) concentration by measurement at the time of screening or from reliable prior documentation For subjects in Cohorts I-IV, I-SC1 and I-SC2; If history of inhibitors is evident, inhibitor titer of ≥5 Bethesda Units (BU) at screening or prior to screening at any time from medical records. Age: 18 to 65 years of age at screening Body mass index (BMI): 18 to 29.9 kg/m² Exclusion Criteria: Subjects with known bleeding disorders (such as von Willebrand factor [vWF] deficiency, FXI deficiency, platelet disorders, or known acquired or inherited thrombophilia etc.) other than congenital Hemophilia A or B with or without inhibitors History of angina pectoris or treatment for angina pectoris History of coronary and/or peripheral atherosclerotic disease, congestive heart failure, disseminated intravascular coagulopathy, or stage 2 hypertension defined as systolic blood pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) ≥100 mmHg even if controlled History of thrombophlebitis, venous / arterial thromboembolic diseases (particularly deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, cerebrovascular accident, ischemic heart disease, transient ischemic attack) Known or suspected hypersensitivity of the immune system, history of anaphylactic reaction, known (clinically relevant) allergies, non-allergic drug reactions, or multiple drug allergies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Without inhibitors<br>Dose escalation steps for participants without inhibitors - intravenous infusion and subcutaneous injection | Drug: BAY1093884<br>* Single escalating dose with a starting dose of 0.3 mg/kg for the first cohort. Drug will be administered via IV infusion over 1 hour and SC injection. Based on safety, PK and PD results the doses for the other cohorts will be determined.<br>|
| Experimental: With inhibitors<br>Dose escalation steps for participants with inhibitors - intravenous infusion and subcutaneous injection | Drug: BAY1093884<br>* Single escalating dose with a starting dose of 0.3 mg/kg for the first cohort. Drug will be administered via IV infusion over 1 hour and SC injection. Based on safety, PK and PD results the doses for the other cohorts will be determined.<br>|
| Experimental: Without inhibitors_multiple dose<br>Multiple dose cohort for participants without inhibitors - a single subcutaneous injection once a week for 6 weeks | Drug: BAY1093884<br>* Multiple dose cohort with a single 150-mg SC injection once a week for 6 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants (single dose cohors) with adverse events as measure of safety and tolerability | Adverse events including abnormal laboratory findings and local injection site reactions | Up to 56 days | 
| Plasma levels of anti-BAY1093884 antibodies |  | Pre-dose, Day 14, 21,28, 43 and 56 | 
| Plasma concentration of BAY1093884 characterized by AUC(0-tlast) | AUC from time 0 to the last data point > LLOQ (lower limit of quantitation) | Day 0 [pre-dose (within 1 hour), at the end of infusion or injection (=1hr), 2hrs, 4hrs, 8hrs], Days 1, 3, 5, 7, 14, 21, 28, 43, and 56 (for cohorts 3, 4 and I-SC2, S-2, S-3) after the start of infusion | 
| Plasma concentration of BAY1093884 characterized by AUC(0-tlast)/D | AUC(0-last) divided by dose | Day 0 [pre-dose (within 1 hour), at the end of infusion or injection (=1hr), 2hrs, 4hrs, 8hrs], Days 1, 3, 5, 7, 14, 21, 28, 43, and 56 (for cohorts 3, 4 and I-SC2, S-2, S-3) after the start of infusion | 
| Plasma concentration of BAY1093884 characterized by Cmax | Maximum observed drug concentration in measured matrix after single dose administration | Day 0 [pre-dose (within 1 hour), at the end of infusion or injection (=1hr), 2hrs, 4hrs, 8hrs], Days 1, 3, 5, 7, 14, 21, 28, 43, and 56 (for cohorts 3, 4 and I-SC2, S-2, S-3) after the start of infusion | 
| Plasma concentration of BAY1093884 characterized by Cmax/D | Cmax divided by dose | Day 0 [pre-dose (within 1 hour), at the end of infusion or injection (=1hr), 2hrs, 4hrs, 8hrs], Days 1, 3, 5, 7, 14, 21, 28, 43, and 56 (for cohorts 3, 4 and I-SC2, S-2, S-3) after the start of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue factor pathway inhibitor (TFPI) activity |  | Up to 77 days | 
| Number of participants (multiple dose cohort) with adverse events as a measure of safety and tolerability | Adverse events including abnormal laboratory findings and local injection site reactions | Up to 77 days | 
| Plasma levels of anti-BAY1093884 antibodies (multiple dose cohort) |  | Pre-dose, Day 14, 28, 49 and 77 | 
| Plasma concentration of BAY1093884 characterized by AUC(0-7d and AUC(0-tau) (multiple dose cohort) | AUC from time 0 to 7d after first and last dose (AUC(0-tau) | Day 0 (prior to start of SC injection) and 8 hrs after start of SC injection, Days 1, 3, 5 and Days 7, and Day 35 (prior to start of SC injection) and 8 hrs after start of SC injection on Day 35; Days 36, 38, 40, 42 | 
| Plasma concentration of BAY1093884 characterized by AUC(0-7d/D and AUC(0-tau)/D after multiple dose | AUC(0-7d) after first dose and AUC(0-tau) after last dose divided by dose | Day 0 (prior to start of SC injection) and 8 hrs after start of SC injection, Days 1, 3, 5 and Days 7, and Day 35 (prior to start of SC injection) and 8 hrs after start of SC injection on Day 35; Days 36, 38, 40, 42 | 
| Plasma concentration of BAY1093884 characterized by Cmax after first dose and last dose (Cmax,md) | maximum observed drug concentration in measured matrix after first and last dose | Day 0 (prior to start of SC injection) and 8 hrs after start of SC injection, Days 1, 3, 5 and Days 7, and Day 35 (prior to start of SC injection) and 8 hrs after start of SC injection on Day 35; Days 36, 38, 40, 42 | 
| Plasma concentration of BAY1093884 characterized by Cmax/D after first dose and last dose (Cmax,md/D) | Cmax after first and last dose divided by dose | Day 0 (prior to start of SC injection) and 8 hrs after start of SC injection, Days 1, 3, 5 and Days 7, and Day 35 (prior to start of SC injection) and 8 hrs after start of SC injection on Day 35; Days 36, 38, 40, 42 | 
| Accumulation of BAY 1093884 in plasma as defined by ratio for Cmax and AUC (after first and last dose) | Cmax after last dose divided by Cmax after first dose, AUC after last dose divided by AUC after first dose | Day 0 (prior to start of SC injection) and 8 hrs after start of SC injection, Days 1, 3, 5 and Days 7, and Day 35 (prior to start of SC injection) and 8 hrs after start of SC injection on Day 35; Days 36, 38, 40, 42 |