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Fitusiran lowers antithrombin levels in hemophilia A, B
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Monthly subcutaneous injections of fitusiran lowered antithrombin levels and increased thrombin generation in patients with hemophilia A or B who did not have inhibitory alloantibodies, according to results of an international phase 1, open-label study published in The New England Journal of Medicine.
“Fitusiran is an exciting drug and provides the opportunity to treat severe hemophilia A and B with and without inhibitors in a wholly new way,” K. John Pasi, MB, ChB, PhD, professor of hemostasis and thrombosis and director of the hemophilia center of Royal London Hospital, told HemOnc Today. “We wanted to collect more information from an open-label extension study while we moved from the formal phase 1 to the phase 3, which we have now initiated. This will be a multicenter global study spanning five continents.”
Hemophilia A and B are inherited bleeding disorders that result from insufficient thrombin generation to prevent bleeding caused by deficiencies in coagulation.
Standard replacement regimens require two or three IV infusions per week and can result in the development of inhibitory alloantibodies in up to 30% of patients with severe hemophilia A and in 5% of those with hemophilia B.
“Fitusiran (ALN-AT3, Alnylam Pharmaceuticals) is a small RNA molecule that harnesses natural RNA inhibition processes in cells to modulate gene expression,” Pasi said. “It is attached to a GalNac ligand, which ensures specific take up in the liver. Fitusiran is designed to target antithrombin, the key natural anticoagulant protein, that is produced in the liver. In hemophilia A and B, lack of Factor VIII or IX, respectively, leads to poor and inadequate generation of thrombin, which leads to bleeding. By reducing antithrombin level, we hope to rest the balance of hemostasis to increase thrombin generation and protect against bleeding.”
Pasi and colleagues enrolled four healthy volunteers (median age, 31.5 years), as well as 25 participants with moderate (n = 3) or severe (n = 22) hemophilia A (n = 18) or B (n = 7) who did not have inhibitory alloantibodies.
Healthy volunteers received a single subcutaneous injection of 0.03 mg/kg fitusiran or placebo. Participants with hemophilia A or B received three injections of fitusiran administered either once weekly (0.015 mg/kg, 0.045 mg/kg or 0.075 mg/kg) or once monthly (0.225 mg/kg, 0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg or at a fixed dose of 80 mg).
The pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran served as the primary study objectives.
The study began in January 2014. Follow-ups occurred at 56, 70 and 112 days.
Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration.
A single dose in healthy volunteers led to a mean maximum antithrombin lowering of 19% (± 4.4%) on day 21, with recovery toward baseline values by day 56. Based on these findings, the study advanced to the patient stage.
The mean maximum lowering was 61% (± 8%) at the highest dose of 0.075 mg/kg with once-weekly dosing and ranged from 70% (± 9%) at 0.225 mg/kg to 89 (± 1%) at 1.8 mg/kg with once-monthly dosing. Mean maximum lowering was 87% (± 1%) in patients who received the fixed dose.
Researchers reported that in patients with hemophilia, the association between the antithrombin level and thrombin generation showed that a lower antithrombin level led to increased thrombin generation. A reduction in the antithrombin level by more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy volunteers.
A post hoc analysis showed patients had fewer bleeding episodes per month after monthly treatment with fitusiran than before treatment.
Participants experienced no thromboembolic events during the study.
Seventy-six percent (n = 19) of the patients with hemophilia experienced an adverse event — most commonly mild injection-site reactions. One patient reported severe chest pain and discontinued treatment.
“We need to remember that the best treatment for hemophilia today is prophylaxis given often — in hemophilia A, every alternate day intravenously,” Pasi said. “Here, we have a once-monthly subcutaneous treatment of significantly under 1 mL volume that has shown very encouraging results in terms of low rates of bleeding. The impact seems amazing — alternate day IV injection or once-a-month subcutaneous injection. [Fitusiran] can be used in hemophilia A and B and with or without inhibitors. It offers to shift the paradigm of hemophilia.”
Researchers acknowledged limitations including the study’s open-label design, short duration, and small number of patients with hemophilia. Researchers also described the results as preliminary and in need of confirmation in larger clinical studies of longer duration.
“What really excites me is what this type of treatment could do at a public health level in less developed countries, where current state-of-the-art factor replacement therapies for hemophilia are either impracticable or unaffordable,” Pasi said. “It could transform care for many patients currently unable to access any form or effective hemophilia treatment. The one group who could see a huge benefit from fitusiran are patients with hemophilia B with inhibitors, whose current treatment options are profoundly limited. It is a small group, but with an enormous unmet clinical need.” – by Chuck Gormley
For more information:
K. John Pasi , MB, ChB, PhD , can be reached at the Hemophilia Centre, Royal London Hospital, London E1 1BB, United Kingdom; email: k.j.pasi@qmul.ac.uk.
Disclosure: Alnylam Pharmaceuticals funded this study. Pasi reports grants, personal fees or nonfinancial support from Alnylam and Genzyme during the conduct of the study, as well as grants, personal fees or nonfinancial support from Baxalta/Shire, Biogen, NovoNordisk, Octapharma, Pfizer and Sobi outside the study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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