Treatment with the pegylated aptamer rondoraptivon pegol significantly improved levels of von Willebrand factor (VWF)/factor VIII (FVIII), multimer patterns, and thrombocytopenia in patients with type 2B von Willebrand disease (VWD), according to findings from a small phase II study published in Blood Advances.
According to Cihan Ay, MD, of the Medical University of Vienna, and colleagues, rondoraptivon pegol is a long-acting VWF A1 domain binding aptamer that increases VWF and FVIII levels. This feature may prove useful in patients with “type 2B VWD where binding the A1 domain of VWF may not only increase VWF concentrations due to decreased clearance but also block the pathological interaction with ADAMTS13 and platelets.”
Five patients with type 2B VWD were included in the study. For the trial’s primary objective, the researchers evaluated the effect of subcutaneous rondoraptivon pegol injections on FVIII levels and platelet counts, as well as the safety associated with the therapy.
Patients received 3-mg injections on days zero, four, and seven, followed by weekly 3- to 9-mg treatments until day 28 during the dose-titration phase. Because the patients maintained their routine VWF infusion during the study, the researchers noted the assessed VWF parameters represent an interaction between rondoraptivon pegol and the recombinant VWF infusions.
The median age of the patient population was 61 years (range = 24-72). There were three men and two women in the study cohort. All participants entered with low levels of VWF ristocetin cofactor (RCo) and VWF GPIbM activity, leading to VWF activity/antigen ratios below 0.4, which the researchers stated were well below recently recommended cutoffs of less than 0.7. Additionally, all participants lacked intermediate- and high-molecular-weight VWF multimers at baseline.
Treatment with rondoraptivon pegol resulted in rapid and significant increases in platelet counts. Specifically, platelet counts rose from a median of 60 × 109/L (range = 44-166 × 109/L) to a peak of 179 × 109/L (range = 89-264 × 109/L) on day 35 (p<0.001). All patients with thrombocytopenia (n=4) had a rapid and sustained increase in platelet counts, and three exhibited normalization.
There was a median three-fold increase in circulating VWF antigen (VWF:Ag), starting from a median of 64% (range = 32-106%) to 143% (range = 103-351%; p<0.001). The researchers explained that because VWF serves as the carrier of FVIII, there was a consequential doubling of FVIII from a median of 67% (range = 44-91%) to 134% (range = 114-200%; p=0.002). In addition, there was a reciprocal reduction in activated partial thromboplastin time from 43 seconds (range = 39-44) to 31 seconds (range = 30-33; p<0.001) on day 35.
Plasma VWF:GPIbM activity levels increased from a median of 18% (range = 3-40%) at baseline to a peak of 72% (range = 3-95%; p<0.001) at day 35. Additionally, there was a significant increase in VWF:RCo from 17% (range = 9-21%) to 48% (range = 15-69%; p<0.001) and VWF collagen binding (VWF:CB) activity from 50% (range = 15-72%) to 100% (range = 32-133%; p=0.002) during this same period.
Rondoraptivon pegol also improved multimer patterns in all patients with thrombocytopenia. The treatment did not increase intermediate- and high-molecular-weight multimers in a patient without thrombocytopenia, which the researchers wrote was “consistent with a limited increase in the VWF platelet-dependent activity levels, although her FVIII, VWF:Ag, and VWF:CB activity levels increased” approximately two-fold.
According to the researchers, the improvements observed during the study reversed during a wash-out period, indicating causality between these improvements and treatment with rondoraptivon pegol.
The small sample size and the short treatment duration of one month were the primary limitations of the study. Despite these limitations, the researchers noted that the data reported in the trial “build the basis for a subsequent phase IIb/III trial in this patient population.”
Any conflicts of interest declared by the authors can be found in the original article.
Ay C, Pabinger I, Kovacevic KD, et al. The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease [published online, 2022 Jun 30]. Blood Adv. doi: 10.1182/bloodadvances.2022007805.