BT200 in Hereditary Bleeding Disorders

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

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Von Willebrand Diseases
• Intervention / Treatment: Drug: BT200

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:To be eligible for this study, patients must meet all of the following inclusion criteria:

1. 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
2. Male or female, age ≥18-70 years old at Screening
3. If female, must be post-menopausal or surgically sterilized
4. Able to comprehend and to give informed consent
5. 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:

1. 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
2. Medical History of spontaneous (not FVIII or FEIBA-associated) venous or arterial thromboembolic events
3. History of significant drug allergy or anaphylactic reactions
4. 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
5. 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
6. 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 -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; 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; BT200 is a PEGylated synthetic RNA oligonucleotide

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall safety and tolerability of BT200	Serious, drug-related adverse events (AEs)	Baseline through 4 weeks after dosing
Overall safety and tolerability of BT200	Patterns of serious or non-serious, drug-related AEs and/or clinically relevant laboratory abnormalities, vital signs, or physical findings suggestive of one or more specific target organs for toxicity of BT200	Baseline through 4 weeks after dosing
Overall safety and tolerability of BT200	Clinically evident bleeding assessed using the International International Society on Thrombosis and Haemostasis (ISTH) Bleeding Score	Baseline through 4 weeks after dosing

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Ulla Derhaschnig, MD, MU Vienna, Dept. of Clinical Pharmacology

Publications and helpful links

General Publications

• Ay C, Kovacevic KD, Kraemmer D, Schoergenhofer C, Gelbenegger G, Firbas CU, Quehenberger P, Jilma-Stohlawetz P, Gilbert JC, Zhu S, Beliveau M, Koenig F, Iorio A, Jilma B, Derhaschnig U, Pabinger I. von Willebrand Factor-binding aptamer rondoraptivon pegol as treatment for severe and non-severe hemophilia A. Blood. 2022 Sep 15:blood.2022016571. doi: 10.1182/blood.2022016571. Online ahead of print.
• Ay C, Pabinger I, Kovacevic KD, Gelbenegger G, Schorgenhofer C, Quehenberger P, Jilma-Stohlawetz P, Sunder-Plassman R, Gilbert JC, Zhu S, Jilma B, Derhaschnig U. The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease. Blood Adv. 2022 Sep 27;6(18):5467-5476. doi: 10.1182/bloodadvances.2022007805.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2020
• Primary Completion (Actual): September 10, 2021
• Study Completion (Actual): September 10, 2021

Study Registration Dates

• First Submitted: December 3, 2020
• First Submitted That Met QC Criteria: December 16, 2020
• First Posted (Actual): December 21, 2020

Study Record Updates

• Last Update Posted (Actual): November 11, 2021
• Last Update Submitted That Met QC Criteria: November 10, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Platelet Disorders; Hemostatic Disorders; Hemophilia A; Blood Coagulation Disorders; Von Willebrand Diseases
• Other Study ID Numbers: BT200-02

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