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New Therapy Option for Congenital Thrombotic Thrombocytopenic Purpura
Congenital thrombotic thrombocytopenic purpura (TTP) is caused by inherited deficiency of ADAMTS13, which leads to accumulation of ultra-large von Willebrand multimers. Replenishing ADAMTS-13 with plasma products either as a prophylaxis or on-demand regimen remains the standard of care (SOC).
Researchers report a prespecified interim analysis of an industry-sponsored, multicenter, open-label, phase 3 trial of recombinant ADAMTS13 (rADAMTS13) prophylaxis in children and adults with genetically confirmed congenital TTP. In this randomized, controlled, crossover trial, patients received two 6-month treatments with either rADAMTS-13 infusion (40 IU/kg per week) or standard therapy, followed by 6 months of the alternate treatment, followed by 6 months of rADAMTS13. The primary outcome was acute TTP, either overt or laboratory evidence (thrombocytopenia or elevated lactate dehydrogenase).
Of 48 patients, 32 (median age: 33 years) completed the trial. No patient experienced an acute TTP event during rADAMTS-13 treatment periods. One patient had an acute TTP event while receiving standard therapy. Three severe adverse events unrelated to rADAMTS-13 occurred during rADAMTS-13 treatment. No patient developed ADAMTS-13 antibodies. Pharmacokinetic studies confirmed that 1 IU/mL of rADAMTS-13 was equivalent to plasma ADAMTS activity of 100% and the mean time with ADAMTS-13 level >10% was 5.2 days.
Comment
This trial demonstrated safety and efficacy of rADAMTS-13 for the treatment of congenital TTP. While novel study designs incorporating modeling approaches for rare diseases like congenital TTP help facilitate access to lifesaving therapies such as rADAMTS-13, significant responsibility lies with both clinicians and patients to diligently report therapy-replated adverse events to ensure patient safety. Immunogenicity findings should be interpreted with caution as all patients in the study were pretreated with SOC, which could have contributed to a tolerogenic effect of ADAMTS-13 protein and prevented inhibitor development. Clarification is needed regarding whether all patients must maintain ADAMTS-13 levels >10% while on prophylaxis and if the prophylaxis regimen could be tailored according to baseline ADAMTS-13 levels. Despite these considerations, access to rADAMTS-13 therapy will transform management of congenital TTP.
Citation(s)
Author:
Scully M et al.
Title:
Recombinant ADAMTS13 in congenital thrombotic thrombocytopenic purpura.
Source:
N Engl J Med
2024
May
2; [e-pub].
(Abstract/FREE Full Text)
Empfohlen von
Anjali A. Sharathkumar, MBBS, MD, MS