rondaptivon pegol (BT200) / Guardian Therap - LARVOL DELTA

BT200-VWD2B: Efficacy and Safety of BT200 (Rondaptivon Pegol) in Patients With Type 2B Von Willebrand Disease (clinicaltrials.gov) - P2 | N=6 | Recruiting | Sponsor: Medical University of Vienna

New P2 trial • Hemophilia

Tranexamic Acid and Desmopressin for Heavy Menstrual Bleeding and Their Impact on Iron Level Tests: The West-Central Mexican Experience (ASH 2024) - "There are other options for HMB (Blood Adv 2023; 7 : 7501-7505) : plasma derived products, recombinant vW factor, bridging therapies as emicizumab, investigational (rondoraptivon pegol, VGA039, HMB-001 and platelet inspired hemostatic nanoparticles), but these have high financial costs or are not available in clinical trial in developing countries. We recommend the use of these drugs to provide either of the treatments, as they are easy to administrate low cost access and have a good security profile. This is an original report from Mexico, no other results were find in PubMed."

Anemia • Hematological Disorders • Hemophilia • Rare Diseases

Rondaptivon Pegol (BT200) to Correct Thrombocytopenia in a Peri-Interventional Setting in Type 2B Von Willebrand Disease (VWD) (ASH 2024) - "The second patient had a femoral neck fracture that required hip surgery under prophylactic substitution wirh Haemate P, which increased VWF activity to 101%. Blood. 2024 Jul 12 : blood.2024024055"

Cardiovascular • Hematological Disorders • Hemophilia • Musculoskeletal Diseases • Orthopedics • Thrombocytopenia • LRP1

Aptamer BT200 is protective against myocardial ischemia-reperfusion injury in mice. (PubMed, J Thromb Haemost) - "Pharmacologic targeting of VWF with BT200 alleviates acute MI/R injury in a murine model, and may be a novel therapy strategy for acute myocardial infarction."

Journal • Preclinical • Cardiovascular • Coronary Artery Disease • Heart Failure • Hematological Disorders • Hemophilia • Inflammation • Myocardial Infarction • Myocardial Ischemia • Rare Diseases • Reperfusion Injury

Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1. (PubMed, Blood) - "Collectively, our findings demonstrate that BT200 prolongs VWF half-life by attenuating macrophage-mediated clearance and specifically the interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1. These data support the concept that targeted inhibition of VWF clearance pathways represent a novel therapeutic approach for VWD and hemophilia A."

Journal • Hematological Disorders • Hemophilia • Rare Diseases • LRP1

Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans. (PubMed, AAPS J) - "The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Effects of the von Willebrand Factor binding Aptamer Rondaptivon Pegol (BT200) on Embryo-Fetal Development in Rabbits (ISTH 2024) - "BT200 was well-tolerated at dose levels ≤15 mg/kg/day with regard to both maternal and embryo-fetal developmental toxicity. No BT200-related effects were observed on maternal clinical observations, gestation body weights, body weight gains, food consumption, or macroscopic observations in pregnant rabbits receiving ≤15 mg/kg/day. Fetal body weights were on average 8-11% lower in animals exposed to BT200 (at 100-1000-fold the human dose) compared with concurrent controls."

Preclinical • Hematological Disorders • Hemophilia • Rare Diseases

Aptamer BT200 prolongs VWF half-life by blocking interaction with macrophage scavenger receptor LRP1 (ISTH 2023) - "Background: The pegylated aptamer BT200 binds to the A1 domain of VWF and significantly prolongs VWF half-life in vivo. BT200 dose-dependently inhibited binding of recombinant VWF (Vonvendi) & plasma-derived VWF (Fandhi) to BMDMs (maximal binding inhibition: 88.55 ± 4.73 % at 10 μM BT200). In addition, BT200 significantly inhibited binding of full-length rVWF to purified LRP1-Cluster-IV (p = 0.0005). Plate binding assays confirmed that the truncated VWF-A1A2A3 fragment and the isolated VWF-A1 domain both bound to LRP1 Cluster-II and Cluster-IV."

LRP1

von Willebrand Factor-binding aptamer rondoraptivon pegol as treatment for severe and non-severe hemophilia A. (PubMed, Blood) - P2a | "Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondoraptivon pegol is a first-in-class pro-hemostatic molecule that extended ~3-fold the half-life of substituted FVIII and increased ~2-fold endogenous FVIII levels in hemophilia patients. (NCT04677803)."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease. (PubMed, Blood Adv) - P2a | "These data provide the basis for a phase IIb/III trial in such patients. This trial is registered at www.clinicaltrials.gov as NCT04677803."

Journal • Hematological Disorders • Hemophilia • Thrombocytopenia

Towards novel treatment options in von Willebrand disease. (PubMed, Haemophilia) - "The tools to control bleeding in VWD are dominated by VWF concentrates, desmopressin and antifibrinolytic therapy. It is important therefore to continue to search for innovative treatment options which could better serve the VWD patients. In this short review, two of such options are discussed in more detail: emicizumab to correct for the deficiency of factor VIII (FVIII), and the pegylated aptamer BT200 to increase endogenous levels of the VWF/FVIII complex."

Journal • Hematological Disorders • Hemophilia

Medical Plenary - Arosenius Lecture: Towards novel treatment options in von Willebrand disease with Peter Lenting (WFH 2022) - "These will include the use of the bispecific antibody emicizumab in the treatment of VWD-type 3 and the aptamer BT200 to increase levels of the VWF/FVIII complex. In addition, I will present novel approaches based on the use of synthetic molecules and single-domain antibodies, both of which being at the preclinical discovery stage."

Hemophilia

Rondoraptivon pegol (BT200) for the treatment of type 2B von Willebrand disease (WFH 2022) - No abstract available

Late-breaking abstract • Hemophilia

Plenary: Arosenius Lecture: Towards novel treatment options in von Willebrand disease (WFH 2022) - "These will include the use of the bispecific antibody emicizumab in the treatment of VWD-type 3 and the aptamer BT200 to increase levels of the VWF/FVIII complex. In addition, I will present novel approaches based on the use of synthetic molecules and single-domain antibodies, both of which being at the preclinical discovery stage."

Hemophilia

VON WILLEBRAND DISEASE (VWD) IN WOMEN (EAHAD 2022) - "Shortened half-life of VWF refers to the need of substitution therapy, including type 1 VWD, as desmopressin will be ineffective due to the deficient storage pools of VWF. Tranexamic acid belongs to the treatment arsenal to prevent from fibrinolysis, and repeated dosing is beneficial. After delivery it is very important to take care that iron deficiency and reduced red cell counts have not developed or will not occur exposing the patient to unnecessarily impaired hemostasis. Recombinant VWF has arrived and the unmet needs of subcutaneous administration mode with extended half-life preparations (e.g. pegylated aptamer BT200) appear to be within reach in near future to reduce the disease burden."

Clinical • Anemia • Endometriosis • Gastrointestinal Disorder • Gynecology • Hematological Disorders • Hemophilia • Long-acting Reversible Contraceptives • Obstetrics • Postpartum Hemorrhage

The von Willebrand Factor A-1 domain binding aptamer BT200 elevates plasma levels of VWF and Factor VIII: a first-in-human trial. (PubMed, Haematologica) - "Participants received one of the following: Single ascending dose of BT200 (0.18-48mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagenadenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (p."

Journal • P1 data

BT200 in Hereditary Bleeding Disorders (clinicaltrials.gov) - P2a; N=26; Completed; Sponsor: Medical University of Vienna; Recruiting ➔ Completed

Clinical • Pan tumor • Trial completion • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] The VWF-A1 Domain Binding Aptamer BT200 Prolongs the Half-lives of Different Factor VIII (FVIII) Products in Patients with Severe Hemophilia A and Increases FVIII Levels in Non-severe Hemophilia A (ISTH 2021) - "Conclusions : BT200 is a first-in-class molecule with a novel mechanism of action representing a new therapeutic strategy to break the ceiling effect VWF imposes on FVIII half-life. This prolongs the half-life of both endogenous and substituted FVIII irrespective of the products used and should enable once weekly substitution in severe haemophilia A. In addition, BT200 is the first drug that could allow regular prophylaxis in non-severe haemophilia A patients by increasing their endogenous FVIII levels."

Clinical • Late-breaking abstract • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] BT200 Increases von Willebrand Factor (VWF), FVIII and Platelet Counts in Patients with von Willebrand Disease (VWD) Type IIb (ISTH 2021) - "This is the first example of which we are aware of a drug causing a sustained normalisation of platelet counts in VWD type IIb. These data build a solid basis for a phase IIb/III trial in patients with type IIb VWD."

Clinical • Hematological Disorders • Hemophilia • Thrombocytopenia

[VIRTUAL] HALF-LIFE PROLONGATION OF VON WILLEBRAND FACTOR: A NEW THERAPEUTIC STRATEGY FOR HAEMOPHILIA A AND VON WILLEBRAND DISEASE (EHA 2021) - "However, intravenous infusion of the A1 domain blocking aptamer ARC1779 was also effective in patients with hyperactive VWF (VWD type IIb), and increased their plasma levels of VWF, FVIII and platelet counts pointing towards a potential hemostatic function, which may also be exploited...Methods Normal healthy volunteers received single ascending doses of the anti VWF aptamer BT200 ranging over 2.5 orders of magnitude from 0.18 mg to 48mg by subcutaneous injection or sc or iv...Conclusion This trial identified a novel mechanism of action for BT200: it decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or haemophilia A, which already confirms the expected effect sizes."

Hematological Disorders • Hemophilia • Rare Diseases • Thrombosis

The aptamer BT200 blocks von Willebrand factor and platelet function in blood of stroke patients. (PubMed, Sci Rep) - "Patients who received clopidogrel or dual antiplatelet therapy did not differ in VWF dependent platelet function tests from aspirin treated patients. Baseline VWF activity correlated (r = 0.86, p < 0.001) with concentrations needed to reduce VWF activity to < 20% of normal, indicating that BT200 acts in a target concentration-dependent manner. Together with a long half-life supporting once weekly administration, the safety and tolerability observed in an ongoing phase I trial, and the existence of a reversal agent, BT200 is an interesting drug candidate."

Clinical • Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Giant Cell Arteritis • Immunology • Thrombosis