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Engineered therapy shows promise for life-threatening blood clotting disorder
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An investigational, engineered therapy that mimics clotting enzyme ADAMTS-13 demonstrated safety and efficacy in patients with hereditary thrombotic thrombocytopenic purpura, according to multicenter study results published in Blood.
Plasma infusions are the most common treatment for patients with thrombotic thrombocytopenic purpura — which occurs when congenital or acquired ADAMTS-13 deficiency causes increased binding of platelets to ultralarge von Willebrand factor — to replenish the ADAMTS-13 enzyme. However, many patients become intolerant to plasma and can develop severe allergic reactions.
Untreated thrombotic thrombocytopenic purpura can lead to strokes, heart attacks and kidney damage.
“Today, thrombotic thrombocytopenic purpura patients are under-treated because of the complications associated with blood plasma infusions, which has remained the standard treatment for at least half a century,” Bruce Ewenstein, MD, PhD, senior fellow at Shire, lecturer on medicine at Harvard Medical School and scientist at Brigham and Women’s Hospital, said in a press release. “Plasma as a source of enzyme replacement is a sledgehammer approach to treatment, but it’s the best we have right now. Our novel therapy has the potential to be safer, more convenient and achieve better outcomes.”
BAX 930 (Shire) is a fully glycosylated recombinant human ADAMTS-13 protein that restores the missing enzyme in patient’s blood without the risk for complications for human-donor plasma. Patients eventually could administer their infusions at home once every 2 weeks.
Ewenstein and colleagues evaluated the safety, immunogenicity, tolerability and pharmacokinetics of BAX 930 in 15 patients diagnosed with congenital thrombotic thrombocytopenic purpura assigned to one of three dose cohorts: 5 U/kg (n = 3), 20 U/kg (n = 3) or 40 U/kg (n = 9).
Researchers observed dose-related increases in ADAMTS-13 concentrations after a single infusion of BAX 930. ADAMTS-13 activity remained quantifiable for 24 hours in the 5 U/kg cohort, 240 hours in the 20 U/kg cohort, and the full 288-hour study period in the 40 U/kg cohort.
Patients also demonstrated normalization of the structure of von Willebrand factor and an improvement in platelet counts.
BAX 930 appeared well tolerated, and no patient experienced anaphylaxis or other allergic reactions.
Twelve patients (80%) experienced at least one temporally emergent adverse event. Three patients in the highest dose cohort experienced five temporally emergent adverse events, including decrease in von Willebrand factor antigen and activity 30 minutes post-infusion, which returned to normal 1 hour post-infusion; flatulence; and nausea.
No serious adverse events, adverse events leading to discontinuation or breakthrough thrombotic thrombocytopenic purpura events occurred after treatment.
Researchers are planning a phase 3 trial — expected to begin this year — to evaluate long-term safety and efficacy of BAX 930 in patients exposed repeatedly over 12 months to prevent and treat acute attacks.
“This recombinant protein mimics what we would expect the normal protein to do in patients who do not have congenital thrombotic thrombocytopenic purpura,” Marie Scully, MD, consultant at University College London Hospitals NHS Trust, said in a press release. “This treatment is a complete game-changer for people with thrombotic thrombocytopenic purpura, not only for the patients, but also for clinicians to be able to give the right treatment so that patients have reduced episodes.” – by Alexandra Todak
Disclosures: Ewenstein reports employment with Shire. Scully and other researchers report consultant fees for conducting the research. Other researchers report employment with Shire and Quintiles, which assisted in the study conduct.
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