Therapeutic switch from plasma to recombinant ADAMTS13 for patients with congenital TTP from Japanese real-world data Free

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultrarare disorder characterized by persistent thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ damage.^1,2 ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), a cleaving protease against von Willebrand factor (VWF), plays an important role in modulating the multimerization of VWF in the blood circulation according to shear force. In the absence of ADAMTS13 activity due to pathogenic ADAMTS13 variants, stretched ultralarge VWF multimers can bind to circulating platelets, forming platelet VWF-rich thrombi in the microvasculature. Finally, ischemic organ damage, represented by ischemic stroke or myocardial infarction, can result in fatal outcomes.^3,4 

It has been reported that the clinical picture of cTTP does not completely correspond to that of the immune-mediated TTP, caused by the production of anti-ADAMTS13 autoantibodies.^2,5,6 Underlying conditions, including patent ductus arteriosus,⁷ pregnancy,^8,9 trauma, and viral infections,¹⁰ often evoke TTP symptoms in patients with cTTP. Platelet counts efficiently increase in response to fresh-frozen plasma (FFP) infusions, and prophylactic FFP infusions are empirically used to supply intact ADAMTS13 protein.¹¹ Plasma-derived factor VIII concentrates are also candidates to supply ADAMTS13, especially for young children in some countries.^12,13 Although 5 to 10 mL/kg of FFP infusion every 2 weeks is recommended in Japanese guidelines¹⁴ and the International Society on Thrombosis and Haemostasis guidelines also suggest 10 to 15 mL/kg of plasma infusion every 1 to 3 weeks,¹⁵ the lack of sufficient evidence for a target level of ADAMTS13 replenishment remains unclear. Furthermore, patients have experienced burdensome adverse events associated with FFP infusions, including potential risks of viral infections and allergic reactions, sometimes leading to anaphylaxis. Additionally, the need for frequent hospital visits imposes significant restrictions on patients’ daily lives.

To address the needs of patients with cTTP, a recombinant ADAMTS13 (rADAMTS13) product was developed to deliver ADAMTS13 efficiently and reduce the unwanted adverse effects. In 2017, the first-in-human international clinical trial revealed the favorable pharmacokinetic (PK) parameters for rADAMTS13.¹⁶ Subsequently, an open-label phase 3 crossover trial was initiated to compare the manifestations of TTP, and the safety and PK were assessed between rADAMTS13 and standard plasma therapy, resulting in a better PK parameter and safety profiles in 2024.¹⁷ In Japan, rADAMTS13 (Azynma) was finally launched at the end of May 2024, and some patients decided to switch FFP to rADATMS13 accordingly. Here, we present the results of a prospective observational study focusing on patients in whom the treatment was switched from FFP to rADAMTS13.

On the basis of the diagnostic and treatment guidelines for TTP in Japan 2023, TTP was diagnosed when patients with severe thrombocytopenia and microangiopathic hemolytic anemia presented with a severe deficiency in ADAMTS13 activity (<10% of healthy individuals).¹² In case of undetectable ADAMTS13 functional inhibitor and anti-ADAMTS13 autoantibodies, we proceeded with ADAMTS13 gene analysis using Sanger sequencing methods. Identification of a pair of pathogenic ADAMTS13 variants (homozygous or compound heterozygous) established the diagnosis of cTTP.

A sensitive chromogenic activity enzyme-linked immunosorbent assay kit (Kainos, Japan)¹⁸ was used to measure ADAMTS13 activity. A plasma mixing assay was used to measure ADAMTS13 inhibitor titers. Anti-ADAMTS13 IgG autoantibody enzyme-linked immunosorbent assay (Technoclone, Austria) was performed according to the manufacturer’s instructions.

This study was approved by the Ethics Committee of Nara Medical University and all collaborative institutes and was conducted in accordance with the tenets of the Declaration of Helsinki. Written informed consents were obtained from all patients.

This study was designed to compare the PK parameters after FFP infusion and rADAMTS13 injection in the same patients with cTTP in Japan. We recruited patients diagnosed with cTTP through ADAMTS13 gene analysis, who were receiving FFP infusions to prevent TTP episodes. Whole blood was collected at 4 time points for FFP and rADAMTS13: before infusion (trough level), immediately after infusion, 1 week after infusion, and 2 weeks after infusion. In addition to the standard biochemical and blood tests, TTP-related markers (ADAMTS13 activity, ADAMTS13 inhibitor, anti-ADAMTS13 IgG autoantibodies, VWF antigen, and VWF ristocetin cofactor) were examined. Biochemical and blood tests were conducted at each medical facility, and TTP-related markers were measured at the Department of Blood Transfusion Medicine, Nara Medical University. Additionally, each patient was asked to comment on the (1) inconveniences associated with FFP infusion, (2) positive impressions after the introduction of rADAMTS13 therapy, and (3) negative impressions during or after rADAMTS13 therapy through a questionnaire. The occurrence of TTP events was evaluated over a 3-month period both retrospectively and prospectively from the initial infusion of rADAMTS13.

Continuous variables were described as medians with interquartile ranges (25% and 75%), considering the small sample size. The Wilcoxon signed-rank test was used to analyze continuous variables for paired groups. Correlation between 2 parameters was represented using the Spearman correlation coefficient. All statistical analyses were performed using EZR (version 1.68).¹⁹ A 2-sided test was used with a 95% confidence interval.

This study included a total of 14 patients with cTTP, including 5 patients with end-stage renal disease (ESRD) who were excluded from the phase 3 trial. Demographic data are summarized in Table 1 and supplemental Table 1 (available on the Blood website). The median age of the patients when they initiated rADAMTS13 therapy was 41 years (interquartile range, 37.5-50 years). The female-to-male ratio was 1.33 (female 8 vs male 6). Thirteen patients received regular FFP infusions, and 1 patient received FFP only during TTP episodes. All patients who received prophylactic FFP infusion received regular long-term FFP infusions, with a median total duration of 29 years (interquartile range, 20-38 years). More than 4 units of FFP (480 mL) were infused every 2 weeks in 11 patients. Patients frequently experienced adverse events during FFP infusion, with 10 cases involving allergic reactions, including 3 cases of anaphylaxis. Empiric antiallergic agents were routinely used before FFP infusions among these cases. Five of the 14 patients developed ESRD: 4 had undergone hemodialysis, and 1 underwent transplant with a kidney from a parent. Four patients presented with thrombotic events, including 3 cases of ischemic stroke and 1 stenosis of the left carotid artery.

rADAMTS13 was IV injected (40 IU/kg per dose) according to the manufacturer’s instructions. Because 500-IU vial is not available in Japan, some physicians administer a shot of 3000 IU (2× 1500-IU vials), as shown in Table 1. Temporal changes in ADAMTS13 activity in each patient are shown in Figure 1. The median peak level of ADAMTS13 activity 15 minutes after rADAMTS13 administration was significantly higher than that after FFP infusion (68.4% vs 15.9%; P < .001). Notably, the observed peak value of ADAMTS13 activity among our patients was relatively lower than that reported in a recent publication.¹⁶ One possible explanation for this is that ≈70% of the patients in the phase 3 study were White, which may suggest differences in the volume of distribution of rADAMTS13 between White and Asian patients. ADAMTS13 activity 1 week after rADAMTS13 was well maintained compared with FFP infusion (11.6% vs 5.1%; P < .001). The median level of ADAMTS13 activity 2 weeks after rADAMTS13 administration was still 4.3%. Underlying ESRD did not reduce the efficacy of ADAMTS13 supplementation, as shown in supplemental Figure 2. Notably, despite long-term exposure to ADAMTS13 in FFP, patients who received prophylactic FFP infusion developed neither anti-ADAMTS13 IgG autoantibodies nor ADAMTS13 inhibitors at enrollment. supplemental Table 2 summarizes the laboratory data examined in this study. Intriguingly, TTP markers, including lactate dehydrogenase, platelet count, VWF antigen, and VWF ristocetin cofactor, were mostly within the normal range, regardless of ADAMTS13 supplementation. Among 13 patients receiving prophylactic ADAMTS13 supplementation, the 3-month TTP events were evaluated. One TTP event was observed in 1 patient with prophylactic FFP infusion due to viral infection. In contrast, any TTP event did not occur during rADAMTS13 prophylaxis.

In the questionnaire survey shown in supplemental Figure 1, the following are the disadvantages of FFP infusions as answered by the patients: restrictions of their daily activities because of frequent hospital visits and long hospital stays, and concerns about intolerant allergic adverse events. Once FFP infusion was switched to rADAMTS13 injections, most patients were greatly impressed by its shorter time of the ADAMTS13 supplementation achieved by the quick shot of rADAMTS13. They also did not need to be concerned about allergic reactions. However, some patients were concerned about unexpected adverse events, including inhibitor production.

In a phase 3 clinical trial,¹⁷ patients with comorbidities, such as ESRD, requiring hemodialysis, were excluded from recruitment, leading to the concern if excluded patients would benefit from the emerging rADAMTS13 product. Our real-world data demonstrated that rADAMTS13 is the most efficient and safe option for supplying intact ADAMTS13 to patients with cTTP based on the PK study and questionnaire answers. The level of ADAMTS13 activity 1 week after rADAMTS13 injection was much higher than that of conventional FFP infusions in all patients. On the basis of the patients’ feedback, switching from FFP to rADAMTS13 was well tolerated, without any allergic reactions or physical burden of injections. However, there are 2 limitations in rADAMTS13 treatment. First, the production of ADAMTS13 functional inhibitors is a major concern for patients treated with rADAMTS13, even though phase 1/2 and 3 trials of rADAMTS13 did not observe any neutralizing autoantibodies against ADAMTS13.^16,17 On the basis of the established evidence of inhibitors against coagulation factor products in the field of hemophilia, a high titer of ADAMTS13 inhibitors is thought to be critical in cTTP because it neutralizes the delivered rADAMTS13. Autoantibody development should be closely monitored in patients undergoing rADAMTS13 treatment. However, the fact that even longer exposure times to FFP infusion did not cause anti-ADAMTS13 autoantibodies in our patients suggests that the chance of developing clinically relevant ADAMTS13 inhibitors, even with purified rADAMTS13, is low. Second, we have to unravel the optimal therapeutic regimen for cTTP using rADAMTS13 to not only maintain platelet counts within normal range but also prevent end-organ damage and sequelae due to ischemic strokes. Some patients enrolled in this study developed ESRD and/or thrombotic events even with prophylactic FFP infusions to maintain their platelet counts within normal range. To our knowledge, this is the first publication that discusses patients with cTTP who switched FFP to novel rADAMTS13 from Japanese real-world data.

The authors thank Masaaki Doi (Higashiosaka City Medical Center), Seiji Kinoshita (Higashiosaka City Medical Center), Kazuhiro Kono (Oita Koseiren Tsurumi Hospital), Satoshi Higasa (Hyogo Medical University Hospital), Yasuharu Nishida (Osaka National Hospital), Masanobu Morioka (Aiiku Hospital), Itsuki Inamine (Saitama Children's Medical Center), and Naonori Harada (Izumiotsu Medical Center) for managing the patients. Koichi Kokame previously performed ADAMTS13 gene analysis to diagnose congenital thrombotic thrombocytopenic purpura.

This study was supported by research grants from the Ministry of Health, Labour and Welfare of Japan (20FC1024 to M.M.).

Contribution: K. Sakai designed the study protocol, interpreted the data, and wrote the manuscript; Y.Y., M.A., Y.O., K.T., N.H., T. Tokugawa, R.K., F.I., M.T., T. Taoka, N.F., M.K., K.K., and H.S. treated the patients and collected patients’ clinical data and blood samples; H.A., A.H., and K. Saito analyzed patients’ samples; M.M. provided advice about the study design; and all authors critically reviewed the manuscript.

Conflict-of-interest disclosure: K. Sakai has received speaker fees from Sanofi and has participated on advisory boards for Takeda. Y.O. has received speaker fees from Chugai Pharmaceutical. T. Tokugawa has received speaker fees from Takeda. M.T. has received speaker fees from Chugai Pharmaceutical and Sanofi; has received investigator-initiated research grant funding from Chugai Pharmaceutical and Japan Blood Products Organization; and has participated on advisory boards for Chugai Pharmaceutical, Pfizer, Novo Nordick, and Sanofi. M.K.’s spouse is an employee of AbbVie. M.M. provided consultancy services for Takeda, Alexion Pharma, and Sanofi; received speaker fees from Takeda, Alexion Pharma, Asahi Kasei Pharma, and Sanofi; and received research funding from Alexion Pharma, Chugai Pharmaceutical, Asahi Kasei Pharma, and Sanofi. The remaining authors declare no competing financial interests.

Correspondence: Masanori Matsumoto, Department of Hematology and Blood Transfusion Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, 6348521, Nara, Japan; email: mmatsumo@naramed-u.ac.jp.