TiumBio’s hemophilia bypassing agent shows extended half-life
TU7710's median half-life was from 10.4-16.6 hours; longer than NovoSeven's
TU7710, an experimental treatment for managing bleeds in people with hemophilia who have inhibitors, demonstrated an average half-life that ranged from 10.4 to 16.6 hours across different doses in a Phase 1a study with healthy volunteers.
This extended half-life, that is, the time it takes for a medication’s levels to drop by half after administration, was five to seven times longer than that of NovoSeven (eptacog alfa [activated]), a conventional hemophilia treatment for inhibitor-positive patients, according to TU7710’s maker TiumBio. With a longer half-life, the therapy should remain active longer, requiring fewer injections to stop bleeds.
“The extended half-life of TU7710 has been demonstrated in preclinical and first-in-human studies,” Hun-Taek Kim, PhD, CEO of TiumBio, said in a company press release.
The data were recently presented in the poster “Phase 1a Study to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of Single Ascending Doses of Intravenous TU7710, in Warfarin Pretreated Healthy Male Subjects,” at the 32nd Congress of the International Society on Thrombosis and Haemostasis (ISTH) in Bangkok.
In hemophilia, there is a deficiency in certain blood clotting proteins, factor VIII in hemophilia A and factor IX in hemophilia B. The standard treatment, replacement therapies, provide a working version of the missing clotting factor. In some patients, however, replacement therapies can trigger an immune response and the production of neutralizing antibodies, reducing a clotting factor’s effectiveness.
Bypassing agents are treatments that “bypass” the need for clotting factor replacement and promote clotting via mechanisms independent of missing factors or inhibitors.
Using TiumBio’s transferrin fusion technology, TU7710 contains a lab-made version of a clotting protein called activated factor VII (FVIIa) that’s fused to the human transferrin protein.
Controlling bleeds with an extended half-life
TU7710 acts in two steps. First, transferrin interacts with its receptor, contributing to TU7710’s long half-life. Then, the linker between FVIIa and transferrin is cleaved at the bleeding site, letting FVIIa function as a free molecule to control bleeds where needed.
NovoSeven also contains a lab-made version of FVIIa, but without extended half-life modifications. When bleeding occurs, treatment with NovoSeven is recommended every two hours until a complete response is achieved, due to its half-life of 2.3 hours.
“NovoSeven has been widely used for hemophilia patients,” Kim said. “However, due to its short half-life, there are significant unmet medical needs for patients and healthcare professionals.”
In preclinical studies, TU7710 worked as intended by controlling bleeds with a prolonged half-life.
The Phase 1a (NCT06025552) study included five dose groups (100, 200, 400, 800, and 1,600 micrograms/kg), each with eight healthy men. Six were randomly assigned to TU7710 at each dose level, while two received a placebo. The first four lower dose groups have been completed, but the highest dose group is still being tested.
All the participants were treated with the anticoagulant warfarin to prevent blood clotting before treatment. Prothrombin time/international normalized ratio (PT INR) values, a test for how long it takes blood to clot, were maintained between 2.0 and 3.0, the effective therapeutic range for warfarin. PT INR values of 1.1 or below are considered normal.
After TU7710 was administered into a vein, or intravenously, all six patients across all the dose groups showed a significant increase in blood FVIIa. The median half-life of TU7710 ranged from 10.4 to 16.6 hours, which was five to seven times longer than that of NovoSeven.
PT INR values were normalized immediately after TU7710 was administered across all the participants. No signs of an immune response against the therapy were observed. No serious adverse and blood clotting events occurred, and most side effects were mild.
“This study provides support for the potential application of TU7710 in the treatment of hemophilia patients with inhibitors,” the researchers said in the poster.
In March, TiumBio asked regulatory authorities in Spain and Italy for permission to test TU7710 in a Phase 1b trial. The study is expected to enroll 18 people with hemophilia A or B with inhibitors, evaluate TU7710’s safety and pharmacological properties, and establish an optimal dose for future Phase 2 studies.
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