A Research Study Investigating Mim8 in People With Haemophilia A

Study Overview
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Brief Summary
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This study is investigating how Mim8 works in people with haemophilia A, who either have inhibitors or do not have inhibitors. Mim8 is a new medication that will be used for prevention of bleeding episodes. Mim8 works by replacing the function of the missing clotting factor VIII (FVIII). Mim8 will be injected with a thin needle in the skin of the stomach, using a pen-injector. The study will last for up to 44 months. It consists of a main phase (part 1 and part 2) and an extension phase. In part 1, participants will be injected only once with either Mim8 or a dummy medicine (placebo) - which one will be decided by chance. In part 2 and the extension phase participants will get an Mim8 injection weekly or monthly.

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Subcutaneous Doses of NNC0365-3769 (Mim8) in Healthy Subjects and in Subjects With Haemophilia A With or Without Factor VIII Inhibitors

Conditions
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Healthy Volunteers, Haemophilia A With or Without Inhibitors

Intervention / Treatment
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* Drug: NNC0365-3769 (Mim8)
* Drug: Placebo (Mim8)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Single ascending dose part 1: Male, aged 18-45 years (both inclusive) at the time of signing informed consent Considered to be generally healthy based on the medical history, physical examination, and the results of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as judged by the investigator Multiple ascending dose part 2: Male, aged 12-64 years (both inclusive) at the time of signing informed consent (Germany and Japan have local requirements) Diagnosis of congenital haemophilia A with FVIII activity below 1% based on medical records Exploratory biomarker cohort: Male, aged equal to or above 12 years at the time of signing informed consent (Germany and Japan have local requirements) Diagnosis of congenital haemophilia A with FVIII activity below 1% based on medical recordsv Exclusion Criteria: Part 1: Factor VIII activity equal to or above 150% at screening Increased risk of thrombosis, e.g. known history of personal or first degree relative(s) with unprovoked deep vein thrombosis Any clinical signs or established diagnosis of venous or arterial thromboembolic disease Part 2: Known congenital or acquired coagulation disorders other than haemophilia A Increased risk of thrombosis as evaluated by the investigator. E.g. known history of personal or first degree relative(s) with unprovoked deep vein thrombosis with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing Any clinical signs or established diagnosis of venous or arterial thromboembolic disease with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing Advanced atherosclerotic disease (e.g. known history of ischemic heart disease, ischemic stroke) as evaluated by the investigator Any autoimmune disease that may increase the risk of thrombosis Receipt of emicizumab or drugs with similar modes of action within 5 half-lives before trial product administration Ongoing or planned immune tolerance induction therapy Exploratory biomarker cohort: Known congenital or acquired coagulation disorders other than haemophilia A Increased risk of thrombosis as evaluated by the investigator. E.g. known history of personal or first degree relative(s) with unprovoked deep vein thrombosis with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing Any clinical signs or established diagnosis of venous or arterial thromboembolic disease with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing Advanced atherosclerotic disease (e.g. known history of ischemic heart disease, ischemic stroke) as evaluated by the investigator Any autoimmune disease that may increase the risk of thrombosis Ongoing or planned immune tolerance induction therapy

Ages Eligible for Study
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Minimum Age: 12 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1 placebo-controlled double-blind within cohorts (phase 1) Part 2 open-label (phase 2)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose (part 1) Mim8<br>Blinded. Single doses in healthy volunteers. Dose escalation. In each of the 6 cohorts, 6 participants will receive Mim8. | Drug: NNC0365-3769 (Mim8)<br>* Mim8 administered subcutaneously (s.c., under the skin). The treatment period will consist of 12 once-weekly doses or 3 once-monthly doses<br>|
| Placebo Comparator: Single dose (part 1) placebo<br>Blinded. Single doses in healthy volunteers. In each of the 6 cohorts, 2 participants will receive placebo. | Drug: Placebo (Mim8)<br>* Mim8 placebo administered subcutaneously (s.c., under the skin)<br>|
| Experimental: Multiple dose (part 2)<br>Open-label. There will be 4 cohorts receiving once-weekly doses (part 2 cohorts 1, 2, 3 and 5) and one cohort receiving once-monthly doses (part 2 cohort 4). Participants will continue into the part 2 extension on the same treatment regimen. | Drug: NNC0365-3769 (Mim8)<br>* Mim8 administered subcutaneously (s.c., under the skin). The treatment period will consist of 12 once-weekly doses or 3 once-monthly doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of treatment emergent adverse events | Count | From time of dosing (Day 1) to Week 16 | 
| Part 2: Number of treatment emergent adverse events | Count | From time of first dosing (Day 1) to Week 12 | 
| Part 2, extension: Number of treatment emergent adverse events | Count | From Week 12 up to Week 176 (16 weeks after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of injection site reactions | Count | From time of dosing (Day 1) to Week 16 | 
| Part 1: Relative change in D-dimer | Percent | From baseline (Day 1) to Week 16 | 
| Part 1: Relative change in prothrombin fragment 1 and 2 | Percent | From baseline (Day 1) to Week 16 | 
| Part 1: Relative change in fibrinogen | Percent | From baseline (Day 1) to Week 16 | 
| Part 1: Relative change in platelets | Percent | From baseline (Day 1) to Week 16 | 
| Part 1: Cmax, SD: the maximum concentration of Mim8 after a single dose | μg/mL | From baseline (Day 1) to Week 16 | 
| Part 1: AUC0-inf, SD: the area under the Mim8 concentration-time curve from time 0 to infinity after a single dose | μg*day/mL | From baseline (Day 1) to Week 16 | 
| Part 1: t1/2, SD: the terminal half-life of Mim8 after a single dose | Days | From baseline (Day 1) to Week 16 | 
| Part 1: tmax, SD: the time to maximum concentration of Mim8 after a single dose | Days | From baseline (Day 1) to Week 16 | 
| Part 1: Change in activated partial thromboplastin time | Seconds | From baseline (Day 1) to Week 16 | 
| Part 2 (weekly and monthly dosing): Number of injection site reactions | Count | From time of first dosing (Day 1) to Week 12 | 
| Part 2 (weekly and monthly dosing): Occurrence of anti-Mim8 antibodies | Count | From baseline (Day 1) to Week 12 | 
| Part 2 (weekly and monthly dosing): Relative change in D-dimer | Percent | From baseline (Day 1) to Week 12 | 
| Part 2 (weekly and monthly dosing): Relative change in prothrombin fragment 1 and 2 | Percent | From baseline (Day 1) to Week 12 | 
| Part 2 (weekly and monthly dosing): Relative change in fibrinogen | Percent | From baseline (Day 1) to Week 12 | 
| Part 2 (weekly and monthly dosing): Relative change in platelets | Percent | From baseline (Day 1) to Week 12 | 
| Part 2 PK session 2 (weekly dosing): Cmax, MD: the maximum concentration of Mim8 after multiple doses | μg/mL | From Day 57 to Day 64 | 
| Part 2 PK session 2 (weekly dosing): AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses | μg*day/mL | From Day 57 to Day 64 | 
| Part 2 PK session 2 (monthly dosing): Cmax, MD: the maximum concentration of Mim8 after multiple doses | μg/mL | From Day 57 to Day 85 | 
| Part 2 PK session 2 (monthly dosing): AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses | μg*day/mL | From Day 57 to Day 85 | 
| Part 2 (weekly dosing): Mean of maximum thrombin generation (peak height) | nM | From Day 57 to Day 64 | 
| Part 2 (monthly dosing): Mean of maximum thrombin generation (peak height) | nM | From Day 57 to Day 85 | 
| Part 2, extension: Number of injection site reactions | Count | From Week 12 up to Week 176 (16 weeks after last dose) | 
| Part 2, extension: Occurrence of anti-Mim8 antibodies | Count | From Week 12 up to Week 176 (16 weeks after last dose) |