New treatment in the pipeline for rare clotting disorder

A recombinant ADAMTS-13 is showing promise for the treatment of patients with congenital thrombotic thrombocytopenic purpura (cTTP).

A phase 1 multi-centre study of the new therapy in patients with severe congenital ADAMTS-13 deficiency found it behaved similarly to the endogenous enzyme and restored ADAMTS-13 activity.

The researchers observed normalisation of the structure of von Willebrand factor and an improvement in platelet counts with a single infusion of rADAMTS-13 at doses of 5, 20 and 40 U/kg body weight.

The therapy was well tolerated in all 15 patients, with no allergic reactions, serious adverse events, or signs of immunogenicity.

The limbic asked co-author Dr Bruce Ewenstein, from biotech company Shire in the US, about the research.

What did you learn about the pharmacodynamics of the recombinant ADAMTS-13?

Although there are limited data on the pharmacokinetics of ADAMTS-13 administered in the form of plasma, the principal standard of care therapy, the terminal half-life of rADAMTS-13 in the phase 1 study – approximately 60 hours – is consistent with the 2-4 days reported in the literature.

The phase 1 data also showed approximate dose proportionality with Cmax and AUC across the 5 U/kg, 20 U/kg, and 40 U/kg dose cohorts. The consistency between the pharmacokinetics of rADAMTS-13 and the published literature on patients treated with plasma, suggests that we can base dosing decisions in future studies on current clinical practice with standard of care products.

Was immunogenicity one of the major concerns in this phase 1 study? 

As with any phase 1 study of a novel therapeutic agent, we sought to assess the possibility of immunogenicity and closely monitored all patients for an immunological response.

In this single-dose study, no anti-ADAMTS-13 antibodies were observed in any patients. Immunogenicity will continue to be monitored closely in the larger phase 3 study with repeat exposures in each patient.

What is the clinical potential of a recombinant ADAMTS-13 compared to existing therapy?

Recombinant ADAMTS-13 has the potential to provide cTTP patients with an enzyme replacement therapy that only targets the underlying cause of the disease, the missing ADAMTS-13.

The smaller volume and potential ease of administration offers the potential to achieve ADAMTS-13 levels that are more precisely adjusted to a patient’s clinical requirements and without many of the adverse reactions associated with current standard of care products.

Based on the results, we also intend to investigate home infusion with rADAMTS-13 in the hope of further improving patients’ quality of life.


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