The Nanobody ALX-0681 is Efficacious and Safe in a Baboon Model of Acquired TTP

Transcription

1 The Nanobody ALX-0681 is Efficacious and Safe in a Baboon Model of Acquired TTP Filip Callewaert, Jan Roodt, Hans Ulrichts, Thomas Stohr, Walter Janse van Rensburg, Seb Lamprecht, Stefaan Rossenu, Sofie Priem, Wouter Willems, Josefin-Beate Holz 17 th Congress of EHA, Amsterdam, June 14-17, 2012 Nanobodies - Inspired by nature

2 Outline Nanobody platform anti-vwf Nanobody ALX-0081/ALX-0681 Overview of the clinical status of ALX-0681 In vivo efficacy and safety study of ALX-0681 in a baboon model of acquired TTP study design preventive and therapeutic efficacy safety Summary and conclusions 2

3 Nanobody platform: ALX-0081/ALX-0681 The anti-vwf Nanobody ALX-0081/ALX bivalent, humanized construct, 28kDa - high potency through formatting new generation biologic, potentially first-inclass specifically binds the A1 domain of the vwf molecule, no binding with GpIb adopts the half-life of its target vwf - target mediated disposition contributes to favorable safety profile 2 forms of administration (ALX-0081 iv and ALX-0681 sc) 3

4 Status of the ALX-0081/ALX-0681 programme in acquired TTP Mode of action in acquired TTP ALX-0081/ALX-0681 in acquired TTP: Phase II study ongoing 40+ sites will participate worldwide Possible qualification and acceptance of Phase II study as pivotal study for MAA in Europe potential launch in 2015 Initiate an end-of-phase II meeting to discuss possible BLA submission in USA 4

5 ALX-0681 in a pre-clinical baboon model of TTP Pre-clinical in vivo model of TTP: neutralizing anti-adamts13 mab induces acute early episodes of TTP (Feys et al., Blood 2010) severe thrombocytopenia schistocytic hemolytic anemia presence of occlusions in multiple organs Goal of the efficacy and safety study preventive and therapeutic efficacy of ALX-0681 safety monitoring in the condition of thrombocytopenia and inhibition of vwf activity study endpoints: - daily laboratory parameters of TTP - biomarkers (PD, renal failure, brain injury) - vessel occlusion - bleeding risk assessment (brain CT, post mortem evaluation of organs) 5

6 Study design Control animals (n = 4) Preventive animals (n = 4) Therapeutic animals (n = 4) 6

7 Biomarkers for the pharmacological activity of the anti- ADAMTS13 mab and ALX-0681 Rapid and sustained suppression of ADAMTS13 activity by the mab sustained suppression > 6 days after last administration Complete but reversible neutralization of vwf activity by ALX-0681 full recovery achieved 4 days after last administration 7

8 ALX-0681 prevents and treats thrombocytopenia and intravascular hemolysis ALX-0681 completely prevents and rapidly reverses thrombocytopenia ALX-0681 prevents the pronounced drop in haptoglobin and is able to stop and reverse the intravascular hemolysis 8

9 Preventive and therapeutic effects of ALX-0681 on schistocytosis and LDH ALX-0681 completely prevents and blocks further progression of red blood cell fragmentation (with partial recovery) ALX-0681 prevents and restores the rise in LDH related to hemolysis and tissue damage 9

10 ALX-0681 treatment did not result in an increased bleeding risk in the therapeutic animals Post-mortem analysis of the major parenchyms did not reveal any sign of bleeding in any of the organs one control animal showed cardiac injury (tissue necropsy) and had elevated Troponin-T levels no evidence of renal failure or brain injury, as assessed through post-mortem analysis and biomarker analysis (creatinin and NSE) In vivo brain CT scans did not detect any trace of bleeding in any of the animals examined CT scans were performed on day 4, 7 and 11 10

11 ALX-0681 prevents progression of vessel occlusion 10 vessels were randomly scored for occlusion in each organ ALX-0681 prevents the further progression of vessel occlusion, but does not dissolve the formed aggregates Platelet-rich occlusions Control (n=1) Therapeutic (mean; n=4) vwf-rich occlusions Control (n=1) Therapeutic (mean; n=4) Kidney 0% 2.5% 0% 2.5% Spleen 0% 0% 0% 2.5% Heart 10% 7.5% 20% 10% Lung 0% 0% 0% 0% Brain 40% 37.5% 20% 40% 11

12 Summary and conclusions Full neutralization of vwf by ALX-0681 in the baboon model prevented and fully reversed the pronounced thrombocytopenia and schistocytic hemolytic anemia, without evidence of an increased bleeding risk ALX-0681 prevents the progressing formation of aggregates in the microvasculature, but does not dissolve occlusions Marked effects on LDH and haptoglobin highlight the potential to reduce ischemic complications and improve long-term neurological disorders Clinical program overview of ALX phase I studies completed (single and multiple doses; iv and sc administration) TTP Phase II study ongoing Orphan designation for TTP in EU and US These data provide support for the continued study of UL-vWF inhibition as promising new concept for the treatment of acquired TTP

13 Acknowledgements ALX-0081/ALX-0681 ALX-0681 team Sandy Jacobs Sofie Priem Stefaan Rossenu Kris Cosyns Laura Sargentini Thomas Stohr Hans Ulrichts Judith Baumeister Brian Devlin (PM) and team UFS - Bloemfontein Jan Roodt Sep Lamprecht Walter Janse van Rensburg Clinical team Wouter Willems Josefin-Beate Holz PDTM Bioanalytics Toxicology PK Pharma team 13