rADAMTS13 in cTTP: a new standard of care? Free

In this issue of Blood, Sakai et al¹ report their real-world data (RWD) on the use of recombinant ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 [rADAMTS13]) in patients with congenital thrombotic thrombocytopenic purpura (cTTP). The authors show that rADAMTS13 therapy is efficacious and safe, even in patients with cTTP and end-stage renal disease (ESRD).

Congenital or hereditary TTP is a rare autosomal recessive disorder.² This genetic abnormality leads to mutations in the ADAMTS13 gene that result in the severe deficiency or absence of ADAMTS13, which is the von Willebrand factor (VWF)-cleaving protease. Reduced ADAMTS13 activity is associated with the accumulation of ultralarge VWF multimers and an increased risk of hyaline thrombi formation in the microvasculature resulting in thrombocytopenia, microangiopathic hemolysis, and end-organ dysfunction.

Fresh frozen plasma (FFP) infusions are generally adequate to treat acute episodes (on-demand use) in cTTP, and for those with recurrent symptoms, prophylactic FFP therapy can be used.² However, prophylactic FFP therapy is associated with regular hospital visits, and allergic reactions to plasma products are common, both having negative impact on quality of life (QOL). In addition, prophylactic FFP infusion protocols are generally not sufficient to prevent the occurrence of acute episodes and cumulative organ damage in patients with cTTP as clearly shown by the International Hereditary TTP Registry³ and in another Japanese study.⁴ So, among this patient population, alternative treatment options are desperately needed.

To overcome this unmet need, rADAMTS13 was developed, and the first in-human dose escalation study of rADAMTS13 in patients with cTTP was published in 2017.⁵ rADAMTS13 was generally well tolerated over a dose range of 5 to 40 IU/kg, with no severe adverse events (AEs), and there was no evidence of an immune response to rADAMTS13 following a single infusion.⁵ In the phase 3, open-label, crossover trial, rADAMTS13 was administered intravenously with a dose of 40 IU/kg, and it was shown that rADAMTS13 was effective with approximately normal maximum ADAMTS13 activity and with a manageable toxicity profile.⁶ During the follow-up, TTP events were also low, and no neutralizing antibodies to ADAMTS13 were detected. Following these 2 studies, rADAMTS13 has been approved for use in patients with cTTP in the United States, Europe, and Japan.

Although there are clinical data on hand, RWD that would bridge the gap between clinical trials and daily practice are still limited regarding the use of rADAMTS13 in cTTP. Hence, the study of Sakai et al contributes to filling this gap in the literature. This prospective study included 14 Japanese patients who were diagnosed with cTTP through ADAMTS13 gene analysis. Almost all patients were receiving prior prophylactic FFP infusions, and there were 5 patients with ESRD (4 patients were undergoing hemodialysis) in the patient cohort. Prior to rADAMTS13 use, patients experienced AEs during FFP therapy including allergic reactions and anaphylaxis. rADAMTS13 was administered intravenously with the same dose as was used in the phase 3 study (40 IU/kg per dose).

The median peak level of ADAMTS13 activity 15 minutes after rADAMTS13 administration and ADAMTS13 activity 1 week after rADAMTS13 were both significantly higher when compared with FFP infusions. In addition, no TTP event occurred during rADAMTS13 prophylaxis. Supporting these findings, in the RWD from Poland, 9 pediatric patients with cTTP received rADAMTS13 at a prophylactic dose of 40 IU/kg every 2 weeks.⁷ No patient experienced any AEs or complications during rADAMTS13 therapy, and patients reported an improved QOL due to fewer hospital visits and a reduced number of recurrent episodes of cTTP. Likewise, in the study of Sakai and colleagues, the patients completed a questionnaire and complained about the disadvantages of FFP infusions including allergic reactions; on the other hand, they had positive feedback on rADAMTS13 treatment.

As stated by the authors, patients with ESRD were excluded from the phase 3 study,⁶ and this study clearly showed that rADAMTS13 can be safely and efficaciously used in patients with cTTP and ESRD. Similarly, pregnant patients are also excluded from clinical trials, and to date, 3 pregnant patients with cTTP (2 acute episodes^8,9 and 1 prophylactic use¹⁰) were treated successfully with rADAMTS13 without any significant safety signals.

Although there was no documented antibody generation against ADAMTS13 in the dose escalation⁵ and phase 3⁶ studies and in these Japanese RWD, hypothetically, neutralizing autoantibodies against ADAMTS13 can be observed in patients with cTTP receiving rADAMTS13, and some patients in this study were also concerned about inhibitor production. As this is a common concern for both physicians and patients, we need more time to sufficiently address this question in this patient population.

In conclusion, cTTP is an ultrarare disease, and until recently, FFP infusions have been the most widely used treatment modality to both treat acute episodes and prevent recurrent symptoms when used prophylactically. However, FFP infusions are not without AEs including allergic reactions and other factors that might negatively impact QOL of patients. rADAMTS13 was shown to be effective and generally well tolerated in patients with cTTP in the clinical trial setting, and similar outcomes in terms of both efficacy and tolerability were observed in the real-world study by Sakai et al.⁶ In addition, the study included patients with cTTP and demonstrated that rADAMTS13 therapy was efficient and safe in those with ESRD. Patients were happy generally with rADAMTS13 treatment and its possible impact on QOL. Nonetheless, some patients had concerns on the generation of neutralizing antibodies to ADAMTS13 while using rADAMTS13, and the development of neutralizing antibodies to ADAMTS13 should be closely monitored in cTTP patients receiving rADAMTS13 treatment.

rADAMTS13 therapy is obviously a major improvement in the management of patients with cTTP, and it could be called as “a new standard of care” and it would most probably replace FFP transfusions in the future. However, I do believe that a longer follow-up is still needed to draw firmer conclusions on the use rADAMTS13 in patients with cTTP.

Conflict-of-interest disclosure: A.E.E. declares no competing financial interests.