Pharmacodynamic Profile of a Recombinant ADAMTS13 (BAX930) in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome (USS))
Authors: Scully Marie , Knoebl Paul , Kentouche Karim , Rice Lawrence , Windyga Jerzy , Schneppenheim Reinhard , Kremer Hovinga Johanna A , Kajiwara Michiko , Maggiore Caterina , Doralt Jennifer , Martell Leah , Ewenstein Bruce M. 
Published: November 2019

Abstract
Introduction
The plasma metalloprotease, ADAMTS13, regulates the size of VWF multimers by cleaving VWF at Tyr1605-Met1606 in the A2 domain. A recombinant ADAMTS13 (rADAMTS13, BAX930), manufactured using a plasma-free method, may provide an important alternative replacement therapy for patients with ADAMTS13 deficiencies, such as hereditary thrombotic thrombocytopenic purpura (hTTP). In contrast to plasma infusions, which are currently the standard treatment of hTTP, rADAMTS13 can be infused at lower volumes and contains no additives of human or animal origin. The safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of rADAMTS13 have been evaluated in a first-in-human phase 1 prospective, open-label, multicenter, dose escalation trial in patients with hTTP (plasma ADAMTS13 activity < 6%) aged 12 to 65 years of age.
Methods
Subjects were assigned to one of three dose cohorts, receiving a single dose of rADAMTS13 at 5, 20 or 40 U/kg BW. PK parameters were assessed for ADAMTS13 activity (using FRETS-VWF73 and the commercially available Technozym assay) and ADAMTS13 antigen (ADAMTS13:Ag) at standardized time points (pre-infusion; 15, 30, 60 minutes and at regular intervals up to 12 days post-infusion). PD effects including the time course of VWF:RCo and VWF:Ag levels and VWF structural analysis were also performed.
Results
Fifteen patients with hTTP were treated with single injections of rADAMTS13 at doses of 5 U/kg (3 subjects), 20 U/kg (3 subjects), and 40 U/kg (9 subjects, 2 of whom were adolescents [<18 years]). Eight subjects were female, 7 male; the median age was 30 years (range: 16-41). Twelve out of 15 subjects had previously received prophylactic plasma infusions, while the remaining 3 subjects had been treated on-demand.
rADAMTS13 was well tolerated; there were no related serious or non-serious AEs. No binding or inhibitory anti-ADAMTS13 antibodies related to rADAMTS13 infusion were detected. Four possibly related AEs (nausea, flatulence, decreased VWF:RCo and VWF:Ag) were observed and all resolved without treatment.
PK parameters were estimated based on data from the 7 adult subjects in the 40 U/kg dose cohort. The incremental recovery (IR; mean ± SD) was 0.023 ± 0.004 (U/mL x kg/U); T1/2 (mean ± SD) was 60.5 ± 13.5 hours; and AUC(0-inf) (mean ± SD) was 54.5±14.9 hours x U/mL (ADAMTS13 activity via FRETS). ADAMTS13 activity measurements by FRETS and chromogenic assays were comparable. Cmax values obtained from the 3 dosing cohorts demonstrated a dose response consistent with dose proportionality, with means of 0.08, 0.42 and 0.96 U/mL for the 5, 20, and 40 U/kg dose groups, respectively. The estimated clearances for the two adolescent subjects were 64.9 and 54.5 mL/h, respectively, which were within the range observed with adult subjects (n=7; range: 44.4 - 115 mL/h).[1]
There was a dose-dependent increase in ADAMTS13-mediated VWF cleavage products observed over time, in line with the dose-dependent increases of ADAMTS13:Ag and activity markers. Specifically, ultra-large VWF multimers, a typical biomarker in hTTP subjects, were detected in the samples collected prior to dosing and decreased in the first 24 hours post-dose at the higher doses of 20 U/kg or 40 U/kg rADAMTS13. In parallel, the intermediate size VWF multimer fraction increased. ADAMTS13-mediated VWF cleavage products were detectable in all subjects up to 3 hours, 24 hours, and 48 hours after injection of 5 U/kg, 20 U/kg, and 40 U/kg, respectively. In all dosing groups, changes in VWF were accompanied by an increase in the platelet count and a decrease of LDH during the first 96 hours after rADAMTS13 injection. Taken together, these findings provide evidence of in vivo ADAMTS13 activity following rADAMTS13 administration.
Conclusion
In this first-in-man, phase 1 study, rADAMTS13 was safe and well tolerated, demonstrated a PK profile comparable to that estimated from plasma infusion studies, and showed evidence of PD activity in vivo, including effects on VWF multimers, platelet count, and serum LDH.
[1] There were differences in sampling schedules between adults (extensive sampling) and adolescents (sparse sampling).

Disclosures
Scully: Baxalta, now part of Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knoebl:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rice:Selexys: Other: Participation in multi-center research trial; Ablynx: Other: Participation in multi-center research trial; Apellis/Synergy: Other: Data Safety Monitoring Committee member; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Participation in registry studies; Novartis Pharma: Speakers Bureau; Incyte: Other: Participation in multi-center research trial. Windyga:Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Schneppenheim:Baxalta, now part of Shire: Membership on an entity's Board of Directors or advisory committees. Kremer Hovinga:NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Maggiore:Quintiles: Employment. Doralt:Baxalta, now part of Shire: Employment. Martell:Baxalta, now part of Shire: Employment. Ewenstein:Shire: Employment, Equity Ownership.