The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease

Cihan Ay, Ingrid Pabinger, Katarina D Kovacevic, Georg Gelbenegger, Christian Schörgenhofer, Peter Quehenberger, Petra Jilma-Stohlawetz, Raute Sunder-Plassman, James C Gilbert, Shuhao Zhu, Bernd Jilma, Ulla Derhaschnig, Cihan Ay, Ingrid Pabinger, Katarina D Kovacevic, Georg Gelbenegger, Christian Schörgenhofer, Peter Quehenberger, Petra Jilma-Stohlawetz, Raute Sunder-Plassman, James C Gilbert, Shuhao Zhu, Bernd Jilma, Ulla Derhaschnig

Abstract

Type 2B von Willebrand disease (VWD) is characterized by an increased binding affinity of von Willebrand factor (VWF) to platelet glycoprotein Ib. This can lead to clearance of high-molecular-weight (HMW) multimers and thrombocytopenia with a resulting moderate-severe bleeding phenotype. Rondoraptivon pegol (BT200) is a pegylated aptamer binding to the A1 domain of VWF with a novel mechanism of action: it enhances VWF/factor VIII (FVIII) levels by decreasing their clearance. To study the potential benefit of rondoraptivon pegol in patients with type 2B VWD, we conducted a prospective phase 2 trial. Patients with type 2B VWD received 3 mg rondoraptivon pegol subcutaneously on study days 1, 4, and 7, followed by 6 to 9 mg every week until day 28. Five patients (male:female ratio = 3:2) were included. Rondoraptivon pegol rapidly tripled platelet counts from a median of 60 to 179 × 10E9/L (P < .001). Circulating VWF antigen increased from a median of 64% to 143%, which doubled FVIII activity levels from 67% to 134%. In all thrombocytopenic patients, plasma levels of VWF:GPIbM normalized, VWF ristocetin cofactor and VWF collagen-binding activity increased, and HMW multimers appeared. These pronounced improvements reversed during washout of the drug, thus demonstrating causality. The A1 domain binding aptamer directly corrects the underlying defect of type 2B VWD, thus providing a novel potential option for prophylaxis and treatment of patients with this VWD type. These data provide the basis for a phase 2b/3 trial in such patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Dose escalation scheme of rondoraptivon pegol. Study scheme: the last dose was escalated to 9 mg only in patients with thrombocytopenia at baseline. biw, biweekly; ew, every week.
Figure 2.
Figure 2.
Rondoraptivon pegol effects on VWF multimers. Rondoraptivon pegol increases intermediate and HMW multimers of VWF. Three milligrams of rondoraptivon pegol was injected subcutaneously on days 1, 4, and 7, followed by up-titration to 6 to 9 mg at weekly intervals. (A) Time course in patient 3. (B) Comparison between baseline and day 35 (1 week after the last rondoraptivon pegol dose) for the other patients. Patients 1 and 4 were on substitution therapy with recombinant VWF.
Figure 3.
Figure 3.
Pharmacokinetics of rondoraptivon pegol. Pharmacokinetics of rondoraptivon pegol after subcutaneous injections in patients with type 2B VWD. Rondoraptivon pegol was given as 3 mg on days 0, 4, and 7, followed by weekly doses of 6 or 9 mg (only in patients with thrombocytopenia at baseline). The solid line with the stars indicates the median.
Figure 4.
Figure 4.
Effects of rondoraptivon pegol on platelet counts. Rondoraptivon pegol increases platelet counts (×10E9/L) in patients with VWD type 2B. Rondoraptivon pegol was given as 3 mg on days 0, 4, and 7, followed by up-titration to 6 to 9 mg at weekly intervals. The highest dose was only given to patients with thrombocytopenia at baseline (open symbols). The horizontal dashed line indicates the lower normal range. The solid line with the stars indicates the median with standard deviation error bars.
Figure 5.
Figure 5.
Effects of rondoraptivon pegol on VWF antigen, FVIII activity, and aPTT. Rondoraptivon pegol increases circulating von Willebrand factor mass (%) and coagulation factor FVIII activity (%), with a reciprocal normalization of activated partial thromboplastin time (s) (aPTT actin factor specific). Medians are indicated by solid lines and stars. The horizontal dashed lines indicate the lower normal range for VWF and FVIII and the upper normal range for the aPTT. Note logarithmic scale of y axis for VWF and FVIII layers.
Figure 6.
Figure 6.
Effects of rondoraptivon pegol on VWF parameters. Rondoraptivon pegol increases plasma levels of VWF–GpIbM (%), ristocetin cofactor (VWF:RCo) (%), and collagen binding activity (VWF:CB) (%) in patients with type 2B VWD. The dotted line represents the nonthrombocytopenic patient, and the horizontal dashed line is the lower normal limit. Note logarithmic scale of y axis.

References

    1. James PD, Connell NT, Ameer B, et al. . ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5(1):280-300.
    1. Sadler JE, Budde U, Eikenboom JC, et al. ; Working Party on von Willebrand Disease Classification . Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4(10):2103-2114.
    1. Leebeek FW, Eikenboom JC. Von Willebrand’s disease. N Engl J Med. 2016;375(21):2067-2080.
    1. Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991;87(4):1220-1226.
    1. Booth WJ, Andrews RK, Castaldi PA, Berndt MC. The interaction of von Willebrand factor and the platelet glycoprotein Ib-IX complex. Platelets. 1990;1(4):169-176.
    1. Casari C, Du V, Wu YP, et al. . Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia. Blood. 2013;122(16):2893-2902.
    1. Nurden P, Debili N, Vainchenker W, et al. . Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood. 2006;108(8):2587-2595.
    1. Wohner N, Legendre P, Casari C, Christophe OD, Lenting PJ, Denis CV. Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance. J Thromb Haemost. 2015;13(5):815-820.
    1. Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood. 1996;87(10):4223-4234.
    1. Shim K, Anderson PJ, Tuley EA, Wiswall E, Sadler JE. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood. 2008;111(2):651-657.
    1. Jilma-Stohlawetz P, Quehenberger P, Schima H, et al. . Acquired von Willebrand factor deficiency caused by LVAD is ADAMTS-13 and platelet dependent. Thromb Res. 2016;137:196-201.
    1. Ruggeri ZM, Lombardi R, Gatti L, Bader R, Valsecchi C, Zimmerman TS. Type IIB von Willebrand’s disease: differential clearance of endogenous versus transfused large multimer von willebrand factor. Blood. 1982;60(6):1453-1456.
    1. Federici AB, Mannucci PM, Castaman G, et al. . Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood. 2009;113(3):526-534.
    1. Kyrle PA, Niessner H, Dent J, et al. . IIB von Willebrand’s disease: pathogenetic and therapeutic studies. Br J Haematol. 1988;69(1):55-59.
    1. Casonato A, Daidone V, Galletta E, Bertomoro A. Type 2B von Willebrand disease with or without large multimers: a distinction of the two sides of the disorder is long overdue. PLoS One. 2017;12(6):e0179566.
    1. Holmberg L, Nilsson IM, Borge L, Gunnarsson M, Sjörin E. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in Type IIB von Willebrand’s disease. N Engl J Med. 1983;309(14):816-821.
    1. Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert JC, Knöbl P. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost. 2011;105(3):545-552.
    1. Rick ME, Williams SB, Sacher RA, McKeown LP. Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrand’s disease. Blood. 1987;69(3):786-789.
    1. Makhamreh MM, Russo ML, Karl T, et al. . Type 2B von Willebrand disease in pregnancy: a systematic literature review. Semin Thromb Hemost. 2021;47(2):201-216.
    1. Hultin MB, Sussman II. Postoperative thrombocytopenia in type IIB von Willebrand disease. Am J Hematol. 1990;33(1):64-68.
    1. Jilma-Stohlawetz P, Knöbl P, Gilbert JC, Jilma B. The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease. Thromb Haemost. 2012;108(2):284-290.
    1. Jilma-Stohlawetz P, Gilbert JC, Gorczyca ME, Knöbl P, Jilma B. A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombocytopenic purpura. Thromb Haemost. 2011;106(3):539-547.
    1. Zhu S, Gilbert JC, Hatala P, et al. . The development and characterization of a long acting anti-thrombotic von Willebrand factor (VWF) aptamer. J Thromb Haemost. 2020;18(5):1113-1123.
    1. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood. 2016;128(16):2007-2016.
    1. Kovacevic KD, Grafeneder J, Schörgenhofer C, et al. . The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of VWF and factor VIII: a first-in-human trial. Haematologica. 2021.
    1. Fazavana J, Brophy TM, Chion A, et al. . Investigating the clearance of VWF A-domains using site-directed PEGylation and novel N-linked glycosylation. J Thromb Haemost. 2020;18(6):1278-1290.
    1. Chion AAS, Fazavana J, Drakeford C, et al. . VWFA1 interacts with scavenger receptor LRP1 via lysine 1408. Res Pract Thromb Haemost. 2019;3(suppl 1):OC67.65.
    1. Jilma B, Paulinska P, Jilma-Stohlawetz P, Gilbert JC, Hutabarat R, Knöbl P. A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb Haemost. 2010;104(3):563-570.
    1. Kalot MA, Husainat N, El Alayli A, et al. . von Willebrand factor levels in the diagnosis of von Willebrand disease: a systematic review and meta-analysis. Blood Adv. 2022;6(1):62-71.
    1. Davies JA, Bowen DJ. The association between the L1565 variant of von Willebrand factor and susceptibility to proteolysis by ADAMTS13. Haematologica. 2007;92(2):240-243.
    1. Rendal E, Penas N, Larrabeiti B, et al. . Type 2B von Willebrand’s disease due to Val1316Met mutation. Heterogeneity in the same sibship. Ann Hematol. 2001;80(6):354-360.
    1. Mazurier C, Parquet-Gernez A, Goudemand J, Taillefer MF, Goudemand M. Investigation of a large kindred with type IIB von Willebrand’s disease, dominant inheritance and age-dependent thrombocytopenia. Br J Haematol. 1988;69(4):499-505.
    1. Mannucci PM. New therapies for von Willebrand disease. Blood Adv. 2019;3(21):3481-3487.
    1. Randi AM, Smith KE, Castaman G. von Willebrand factor regulation of blood vessel formation. Blood. 2018;132(2):132-140.
    1. Kovacevic KD, Gilbert JC, Jilma B. Pharmacokinetics, pharmacodynamics and safety of aptamers. Adv Drug Deliv Rev. 2018;134:36-50.
    1. Saba HI, Saba SR, Dent J, Ruggeri ZM, Zimmerman TS. Type IIB Tampa: a variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation. Blood. 1985;66(2):282-286.
    1. Kruse-Jarres R, Johnsen JM. How I treat type 2B von Willebrand disease [correction published in Blood. 2018;131(20):2272]. Blood. 2018; 131(12):1292-1300.
    1. Connell NT, Flood VH, Brignardello-Petersen R, et al. . ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5(1):301-325.
    1. Ay C, Derhaschnig U, Jilma B, et al. . 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 [abstract]. Res Pract Thromb Haemost. 2021;5 (suppl 2).
    1. Metjian AD, Wang C, Sood SL, et al. ; HTCN Study Investigators . Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease. Haemophilia. 2009;15(4):918-925.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する