Long half-life
BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).
In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.
The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.
The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.
At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.
But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).
“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.
They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
‘Super-exciting strategy’
“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 hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.
“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.
The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.
