BT200 in Hereditary Bleeding Disorders

Study Overview
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Brief Summary
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BT200 is a PEGylated aptamer that binds to the A1 domain of human von Willebrand factor (VWF). At low doses, BT200 blocks the clearance of VWF antigen (VWF Ag) from the circulation and causes an increase in concentrations of both VWF Ag and Factor VIII (FVIII), but has negligible effect on the activity of either. At higher doses, BT200 blocks clearance of VWF and also inhibits its activity, but still does not inhibit FVIII activity. Therefore, low dose BT200 could potentially be used to correct deficiency of VWF and/or FVIII in patients with hereditary bleeding disorders. This study is designed as a basket design pilot study to determine the relevant dose and pharmacological activity of BT200 in such patients. In this open basket study up to 25 patients with the following congenital blood-clotting disorders are to be included: Patients with hemophilia A, heterozygous carriers of hemophilia A with subnormal FVIII levels; patients with von Willebrand syndrome (VWD) type 1, Vicenza type, and with VWD type 2b. Participants will receive BT200 subcutaneously on day 0, day 4 and day 7 in the first week and then once a week for a total of five weeks - initially in a dose of 3 mg, then in week 3 individually after response in a dose of 3 to 9 mg. Subsequently, blood samples are taken once a week for a further three weeks (wash-out phase). Patients may be enrolled in an additional pharmacokinetics sub-study. For this purpose, approximately three blood samples are taken to estimate the half-life of substituted FVIII under the influence of BT200. The primary objective of this study is to obtain clinical proof of mechanism for BT200 in one or more hereditary bleeding disorders.

Official Title
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A Phase 2a Multiple Dose Basket Study of the Safety, Tolerability, and Pharmacologic Activity of BT200 in Patients With Hereditary Bleeding Disorders

Conditions
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Von Willebrand Diseases, Hemophilia A

Intervention / Treatment
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* Drug: BT200


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:To be eligible for this study, patients must meet all of the following inclusion criteria: Hereditary bleeding disorder: Congenital hemophilia A without inhibitors with a prophylactic treatment regime Heterozygous carriers of hemophilia A with subnormal FVIII levels VWD Type 1, Vicenza type VWD Type 2b Male or female, age ≥18-70 years old at Screening If female, must be post-menopausal or surgically sterilized Able to comprehend and to give informed consent Able to cooperate with the Investigator, to comply with the requirements of the study, and to complete the full sequence of protocol-related procedures - Exclusion Criteria: Patients meeting any of the following criteria will be excluded from the study: Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the patient or compromise the quality of the data derived from his/her participation in this study Medical History of spontaneous (not FVIII or FEIBA-associated) venous or arterial thromboembolic events History of significant drug allergy or anaphylactic reactions Substance abuse, mental illness, or any reason that makes it unlikely in the judgment of the Investigator for the patient to be able to comply fully with study procedures Use of medication during 2 weeks before the start of the study, which in the judgment of the Investigator may adversely affect the patient's welfare or the integrity of the study's results Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 elimination half-lives (whichever is longer) prior to treatment start -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, individual dose titration-to-response, basket trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Subcutaneous (SC) injection: BT200 dose 3 mg on Day 0, Day 4, and again on Day 7 BT200 dose titrated thereafter between 3 and 9 mg on Days 14, 21, and 28. It is anticipated that dose adjustments will be performed in 2 mg steps. The 9 mg dose will only be applied on day 28 in exceptional circumstances, if no relevant changes in pharmacodynamic and safety parameters will be observed on day 21. | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemophilia A | increase in FVIII activity | Baseline through 4 weeks after dosing | 
| VWD Type 1 | increase in FVIII activity | Baseline through 4 weeks after dosing | 
| VWD Type 2b | increase in platelet count and/or FVIII activity | Baseline through 4 weeks after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Measured concentration of BT200 (and derived PK parameters) | Measured concentration of BT200 | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | PFA-100 | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | Multiplate electrode platelet aggregometer (ristocetin induced) | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | VWF antigen | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | VWF:ristocetin co-factor assay | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | VWF activity | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | VWF collagen bindign assay | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | ELISA for unbound VWF-A1 domain | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | VWF propeptide | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | Fibrin D-Dimer | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | Prothrombin fragement (F1.2) | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | Rotational thrombelastometry | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | Clot strength assay | Baseline through 4 weeks after dosing | 
| Pharmacodynamics | Calibrated Thrombogram assay | Baseline through 4 weeks after dosing |