Recombinant ADAMTS13 Prophylaxis Effective Approach for Congenital TTP


An interim analysis of a phase 3 trial displays the effectiveness of prophylaxis with recombinant ADAMTS13, achieving approximately 100% of normal ADAMTS13 levels.

| Image Credit: Infected Blood Inquiry

Marie Scully, MD

Credit: Infected Blood Inquiry

An interim analysis of a phase 3 randomized trial demonstrated the effectiveness of recombinant ADAMTS13 as a prophylactic therapeutic approach among patients with congenital thrombotic thrombocytopenic purpura (TTP).1

Compared with standard therapy, prophylaxis with recombinant ADAMTS13 achieved approximately 100% of normal maximum ADAMTS13 activity and was associated with a low number of TTP-related events and manifestations.

“The better safety and higher average ADAMTS13 activity levels observed with recombinant ADAMTS13 than with standard therapy in this clinical trial may, in clinical practice, help expand patient access to long-term prophylaxis,” wrote the investigative team, led by Marie Scully, MD, department of hematology, University College London Hospitals.

Congenital TTP is an ultra-rate thrombotic microangiopathy, resulting from severe hereditary deficiency of ADAMTS13 and accumulating in ultra large von Willebrand factor multimers with high platelet-binding activity.1 Clinical presentation of congenital TTP can range from life-threatening, acute TTP events to milder manifestations, including thrombocytopenia, hemolytic anemia, abdominal pain, headache, and neurologic symptoms.

Standard therapy involves ADAMTS13 replacement through prophylactic or on-demand infusions of plasma-derived products—however, these products rely on donor plasma and involve limited ADAMTS13 replacement. Recombinant ADAMTS13 was approved by the US Food and Drug Administration (FDA) in November 2023 for prophylactic or on-demand ADAMTS13 replacement therapy in patients with congenital TTP.3

This phase 3, open-label, two-period crossover trial evaluated the efficacy and safety of recombinant ADAMTS13 and standard therapy as routine prophylaxis or on-demand treatment in congenital TTP.1 The interim analysis comprised data for individuals of all ages from October 2017 to August 2022, triggered by the trial completion of ≥30 patients.

Patients were randomly assigned 1:1 to begin prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight) or standard therapy in the crossover pharmacokinetic assessment period. Then, patients moved into the first 6 months on that same assignment. In the second 6-month period, patients received the alternate treatment and all patients received recombinant ADAMTS13 for a third period of 6 months.

The primary outcome measures within the analysis were acute TTP events among patients in the modified full-analysis population. An acute TTP event comprised a decrease in the platelet count by ≥50% from baseline or to less than 100,000 per µL and an elevation of the lactate dehydrogenase (LDH) to more than 2 times the baseline value or upper limit of the normal range (ULN). Manifestations of TTP, safety, and pharmacokinetics were also evaluated in the analysis.

Among 51 patients screened, 48 underwent randomization and received prophylaxis with recombinant ADAMTS13 or standard therapy. At the time of the interim analysis, 32 patients had completed the trial in the prophylactic cohort.

The analysis revealed no patient experienced an acute TTP event during prophylaxis with recombinant ADAMTS13 during periods 1 to 3. Meanwhile, a single patient had an acute TTP event while receiving prophylaxis with standard therapy, for a mean annualized event rate of 0.05 (95% CI, 0.00 - 0.14).

Overall, thrombocytopenia was the most frequently identified TTP manifestation. The fully adjusted model-based annualized event rate of thrombocytopenia was 0.74 (95% CI, 0.37 - 1.50) for recombinant ADAMTS13 and 1.73 (95% CI, 0.92 - 3.23) for standard therapy.

Safety data revealed the percentage of patients who reported adverse events was 71% (95% CI, 56 - 84) with recombinant ADAMTS13 and 84% (95% CI, 70 - 93) with standard therapy. Four of these patients (9%) had adverse events considered to be related to the trial drug, while 21 (48%) had adverse events believed to be related to standard therapy.

No patients treated with recombinant ADAMTS13 experienced trial-drug interruption or discontinuation due to adverse events, while 8 patients on standard therapy were interrupted or discontinued treatment. Despite the possible risk of immunogenicity, no neutralizing antibodies were detected in 12 months of prophylaxis with recombinant ADAMTS13

Scully and colleagues indicated the pharmacokinetic data showed the maximum ADAMTS13 activity was 101% of normal levels with recombinant ADAMTS13 treatment, compared with 19% after standard therapy.

“The better safety and higher average ADAMTS13 activity levels observed with recombinant ADAMTS13 than with standard therapy in this clinical trial may, in clinical practice, help expand patient access to long-term prophylaxis,” they wrote.

  1. Scully M, Antun A, Cataland SR, et al. Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2024;390(17):1584-1596. doi:10.1056/NEJMoa2314793
  2. Kremer Hovinga JA, George JN. Hereditary Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019;381(17):1653-1662. doi:10.1056/NEJMra1813013
  3. Abigail Brooks M. FDA approves Adzynma for congenital thrombotic thrombocytopenic purpura. HCP Live. November 9, 2023. Accessed May 1, 2024.
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