Enzyme replacement therapy curbs bleeding events in congenital blood clotting disorder
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Key takeaways:
- Mean maximum ADAMTS13 activity after recombinant ADAMTS13 exceeded 100%.
- Markedly fewer patients receiving recombinant ADAMTS13 experience treatment-related adverse events.
Among patients with congenital thrombotic thrombocytopenic purpura, prophylactic therapy with recombinant ADAMTS13 restored normal levels of the enzyme, according to results of a randomized phase 3 study.
The findings — published in The New England Journal of Medicine — revealed that no patient who received prophylaxis with recombinant ADAMTS13 experienced an acute thrombotic thrombocytopenic purpura (TTP) event during the study period, researchers reported. Meanwhile, markedly fewer treatment-related adverse events occurred among study participants who received recombinant ADAMTS13 compared with control patients who received standard therapy with plasma-derived products.
“This trial showed that recombinant ADAMTS13 was an effective prophylactic therapeutic approach for patients with congenital TTP,” Marie Scully, MD, of University College London Hospitals, and researchers wrote. “Recombinant ADAMTS13 treatment was associated with approximately normal maximum ADAMTS13 activity and low levels of disease related events and manifestations. No safety concerns were noted with recombinant ADAMTS13, and no neutralizing antibodies to ADAMTS13 were detected.”
Background, methods
TTP is the result of a severe hereditary deficiency of the ADAMTS13 enzyme; the efficacy and safety of recombinant ADAMTS13 and standard therapy administered via routine prophylaxis or on-demand treatment among patients with TTP is unknown.
Researchers conducted an open-label study in 48 patients with TTP. They randomly assigned study participants in a 1:1 ratio to receive two 6-month cycles of prophylaxis plus either recombinant ADAMTS13 (40 IU/kg IV) or standard therapy, followed by an alternate treatment.
Afterward, all patients then received an additional 6 months of recombinant ADAMTS13.
Trial completion by at least 30 participants served as the trigger for an interim analysis. Acute TTP events served as the study’s primary outcome, with manifestations of TTP, safety and pharmacokinetics also being assessed.
Patients who experienced an acute TTP event could receive on-demand treatment.
Of the 48 patients randomly assigned to a treatment group, 32 completed the trial.
Results, next steps
Researchers observed no acute TTP events during prophylaxis with recombinant ADAMTS13 but did note one patient experienced an acute TTP event during prophylaxis with standard therapy.
Thrombocytopenia appeared to be the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy).
Researchers also noted adverse events in 71% of patients with recombinant ADAMTS13 and in 84% of patients with standard therapy; 9% of patients with recombinant ADAMTS13 had adverse events considered to be related to the trial drug, compared with 48% of patients with standard therapy.
None of the patients receiving recombinant ADAMTS13 had a trial-drug interruption or discontinuation due to adverse events, whereas eight patients with standard therapy did.
Researchers noted a mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment of 101%, compared with 19% after standard therapy.
“Until recently, no medications were specifically approved for routine prophylaxis in patients with congenital TTP,” researchers wrote. “Recombinant ADAMTS13 was approved by the Food and Drug Administration in November 2023 for prophylactic or on-demand ADAMTS13 replacement therapy in adults and children with congenital TTP.
“It is difficult to compare rates of TTP events reported here with those in previous observational studies, because the event criteria varied,” they added. “In this trial, criteria were designed to be objective and laboratory-based but were probably conservative as compared with clinical practice and existing literature.”
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